bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2022‒02‒27
43 papers selected by
Kıvanç Görgülü
Technical University of Munich
  1. Susceptibility to autophagy inhibition is enhanced by dual IGF1R and MAPK/ERK inhibition in pancreatic cancer.
  2. NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer.
  3. Early Neutrophilia Marked by Aerobic Glycolysis Sustains Host Metabolism and Delays Cancer Cachexia.
  4. Iron supplementation is sufficient to rescue skeletal muscle mass and function in cancer cachexia.
  5. Emerging signaling mediators in the anorexia-cachexia syndrome of cancer.
  6. How Cells Deal with the Fluctuating Environment: Autophagy Regulation under Stress in Yeast and Mammalian Systems.
  7. Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment.
  8. TSPAN6 is a suppressor of Ras-driven cancer.
  9. Getting closer to the clinic.
  10. Deletion of Slc6a14 reduces cancer growth and metastatic spread and improves survival in KPC mouse model of spontaneous pancreatic cancer.
  11. Effective drug combinations in breast, colon and pancreatic cancer cells.
  12. Association Between Systemic Inflammation and Malnutrition With Survival in Patients With Cancer Sarcopenia-A Prospective Multicenter Study.
  13. CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4.
  14. The Fate of Resectable Pancreatic Adenocarcinoma After Neoadjuvant Chemotherapy.
  15. CRISPR in cancer biology and therapy.
  16. ERK signaling dissolves ERF repression condensates in living embryos.
  17. The chaperone Tsr2 regulates Rps26 release and reincorporation from mature ribosomes to enable a reversible, ribosome-mediated response to stress.
  18. Therapeutic antibody activation of the glucocorticoid-induced TNF receptor by a clustering mechanism.
  19. The role of neoadjuvant therapy for resectable pancreatic cancer remains uncertain.
  20. The methyltransferase enzymes, KMT2D, SETD1B, and ASH1L, are key mediators of both metabolic and epigenetic changes during cellular senescence.
  21. Prognostic Implications of an Autophagy-related Gene Signature in Pancreatic Ductal Adenocarcinoma.
  22. Cancer causes dysfunctional insulin signaling and glucose transport in a muscle-type-specific manner.
  23. Addressing unmet needs for people with cancer cachexia: recommendations from a multistakeholder workshop.
  24. Tumor Suppressor Role of Wild-Type P53-Dependent Secretome and Its Proteomic Identification in PDAC.
  25. Fracture in living tissues.
  26. Dermal αSMA+ myofibroblasts orchestrate skin wound repair via β1 integrin and independent of type I collagen production.
  27. Network analysis of TCGA and GTEx gene expression datasets for identification of trait-associated biomarkers in human cancer.
  28. Metabolomics and its Applications in Cancer Cachexia.
  29. Poly(ADP-ribose) drives condensation of FUS via a transient interaction.
  30. Single-cell atlases: shared and tissue-specific cell types across human organs.
  31. An immune-sympathetic neuron communication axis guides adipose tissue browning in cancer-associated cachexia.
  32. Circulating tumour DNA: a challenging innovation to develop "precision onco-surgery" in pancreatic adenocarcinoma.
  33. Identification of electroporation sites in the complex lipid organization of the plasma membrane.
  34. Quantifying the Patterns of Metabolic Plasticity and Heterogeneity along the Epithelial-Hybrid-Mesenchymal Spectrum in Cancer.
  35. IL-9/STAT3/fatty acid oxidation-mediated lipid peroxidation contributes to Tc9 cell longevity and enhanced antitumor activity.
  36. The spectrum of sex differences in cancer.
  37. Low-dose metformin targets the lysosomal AMPK pathway through PEN2.
  38. Revealing the transcriptional heterogeneity of organ-specific metastasis in human gastric cancer using single-cell RNA Sequencing.
  39. Platelet Membrane: An Outstanding Factor in Cancer Metastasis.
  40. Camptothecin effectively treats obesity in mice through GDF15 induction.
  41. Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions.
  42. Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology.
  43. Low level lysosomal membrane permeabilization for limited release and sub-lethal functions of cathepsin proteases in the cytosol and nucleus.
  1. Autophagy. 2022 Feb 24. 1-3
    Susceptibility to autophagy inhibition is enhanced by dual IGF1R and MAPK/ERK inhibition in pancreatic cancer.
    Clint A Stalnecker, Michael F Coleman, Kirsten L Bryant.
      Macroautophagy/autophagy is upregulated in pancreatic ductal adenocarcinoma (PDAC) and PDAC growth is reliant on autophagy. However, autophagy inhibitors as monotherapy have shown limited clinical efficacy. To identify targets that sensitize PDAC cells to autophagy inhibition, we performed a CRISPR-Cas9 genetic loss-of-function screen in cells treated with the lysosomal inhibitor chloroquine (CQ) and identified IGF1R as a sensitizer. IGF1R inhibition increases autophagic flux and sensitivity to CQ-mediated growth suppression both in vitro and in vivo. Importantly, sensitization is further enhanced with the concurrent inhibition of MAPK1/ERK2 (mitogen-activated protein kinase 1)-MAPK3/ERK1. IGF1R and MAPK/ERK inhibition converge on suppression of glycolysis. In summary, IGF1R and MAPK/ERK signaling promotes resistance to CQ/HCQ in PDAC, and their dual inhibition increases sensitivity to autophagy inhibitors.
    Keywords:  Autophagy; IGF1R; MAPK/ERK; pancreatic cancer; targeted therapies
    DOI:  https://doi.org/10.1080/15548627.2022.2042782
  2. Proc Natl Acad Sci U S A. 2022 Mar 01. pii: e2105691119. [Epub ahead of print]119(9):
    NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer.
    Josefina Doffo, Stefanos A Bamopoulos, Hazal Köse, Felix Orben, Chuanbing Zang, Miriam Pons, Alexander T den Dekker, Rutger W W Brouwer, Apoorva Baluapuri, Stefan Habringer, Maximillian Reichert, Anuradha Illendula, Oliver H Krämer, Markus Schick, Elmar Wolf, Wilfred F J van IJcken, Irene Esposito, Ulrich Keller, Günter Schneider, Matthias Wirth.
      Evasion from drug-induced apoptosis is a crucial mechanism of cancer treatment resistance. The proapoptotic protein NOXA marks an aggressive pancreatic ductal adenocarcinoma (PDAC) subtype. To identify drugs that unleash the death-inducing potential of NOXA, we performed an unbiased drug screening experiment. In NOXA-deficient isogenic cellular models, we identified an inhibitor of the transcription factor heterodimer CBFβ/RUNX1. By genetic gain and loss of function experiments, we validated that the mode of action depends on RUNX1 and NOXA. Of note is that RUNX1 expression is significantly higher in PDACs compared to normal pancreas. We show that pharmacological RUNX1 inhibition significantly blocks tumor growth in vivo and in primary patient-derived PDAC organoids. Through genome-wide analysis, we detected that RUNX1-loss reshapes the epigenetic landscape, which gains H3K27ac enrichment at the NOXA promoter. Our study demonstrates a previously unknown mechanism of NOXA-dependent cell death, which can be triggered pharmaceutically. Therefore, our data show a way to target a therapy-resistant PDAC, an unmet clinical need.
    Keywords:  NOXA; PDAC; RUNX1; apoptosis; pancreatic cancer
    DOI:  https://doi.org/10.1073/pnas.2105691119
  3. Cancers (Basel). 2022 Feb 15. pii: 963. [Epub ahead of print]14(4):
    Early Neutrophilia Marked by Aerobic Glycolysis Sustains Host Metabolism and Delays Cancer Cachexia.
    Michele Petruzzelli, Miriam Ferrer, Martijn J Schuijs, Sam O Kleeman, Nicholas Mourikis, Zoe Hall, David Perera, Shwethaa Raghunathan, Michele Vacca, Edoardo Gaude, Michael J Lukey, Duncan I Jodrell, Christian Frezza, Erwin F Wagner, Ashok R Venkitaraman, Timotheus Y F Halim, Tobias Janowitz.
      An elevated neutrophil-lymphocyte ratio negatively predicts the outcome of patients with cancer and is associated with cachexia, the terminal wasting syndrome. Here, using murine model systems of colorectal and pancreatic cancer we show that neutrophilia in the circulation and multiple organs, accompanied by extramedullary hematopoiesis, is an early event during cancer progression. Transcriptomic and metabolic assessment reveals that neutrophils in tumor-bearing animals utilize aerobic glycolysis, similar to cancer cells. Although pharmacological inhibition of aerobic glycolysis slows down tumor growth in C26 tumor-bearing mice, it precipitates cachexia, thereby shortening the overall survival. This negative effect may be explained by our observation that acute depletion of neutrophils in pre-cachectic mice impairs systemic glucose homeostasis secondary to altered hepatic lipid processing. Thus, changes in neutrophil number, distribution, and metabolism play an adaptive role in host metabolic homeostasis during cancer progression. Our findings provide insight into early events during cancer progression to cachexia, with implications for therapy.
    Keywords:  aerobic glycolysis; cachexia; cancer; host; metabolism; neutrophils
    DOI:  https://doi.org/10.3390/cancers14040963
  4. EMBO Rep. 2022 Feb 24. e53746
    Iron supplementation is sufficient to rescue skeletal muscle mass and function in cancer cachexia.
    Elisabeth Wyart, Myriam Y Hsu, Roberta Sartori, Erica Mina, Valentina Rausch, Elisa S Pierobon, Mariarosa Mezzanotte, Camilla Pezzini, Laure B Bindels, Andrea Lauria, Fabio Penna, Emilio Hirsch, Miriam Martini, Massimiliano Mazzone, Antonella Roetto, Simonetta Geninatti Crich, Hans Prenen, Marco Sandri, Alessio Menga, Paolo E Porporato.
      Cachexia is a wasting syndrome characterized by devastating skeletal muscle atrophy that dramatically increases mortality in various diseases, most notably in cancer patients with a penetrance of up to 80%. Knowledge regarding the mechanism of cancer-induced cachexia remains very scarce, making cachexia an unmet medical need. In this study, we discovered strong alterations of iron metabolism in the skeletal muscle of both cancer patients and tumor-bearing mice, characterized by decreased iron availability in mitochondria. We found that modulation of iron levels directly influences myotube size in vitro and muscle mass in otherwise healthy mice. Furthermore, iron supplementation was sufficient to preserve both muscle function and mass, prolong survival in tumor-bearing mice, and even rescues strength in human subjects within an unexpectedly short time frame. Importantly, iron supplementation refuels mitochondrial oxidative metabolism and energy production. Overall, our findings provide new mechanistic insights in cancer-induced skeletal muscle wasting, and support targeting iron metabolism as a potential therapeutic option for muscle wasting diseases.
    Keywords:  cachexia; iron; metabolism; mitochondria; muscle
    DOI:  https://doi.org/10.15252/embr.202153746
  5. Trends Cancer. 2022 Feb 18. pii: S2405-8033(22)00010-3. [Epub ahead of print]
    Emerging signaling mediators in the anorexia-cachexia syndrome of cancer.
    Erin E Talbert, Denis C Guttridge.
      The cachexia syndrome in cancer is characterized by weight loss resulting from the combination of anorexia and atrophy of adipose and skeletal muscle. For decades, inflammatory circulatory factors have been identified to regulate wasting, but inhibitors of these factors have not yielded the same clinical benefit as in animal models. Therefore, additional mediators of cachexia likely regulate this syndrome, and such factors might be more suitable for targeted intervention. We highlight several anorexia-cachexia signaling mediators, including activin A, myostatin, GDF15, and lipocalin-2. We discuss current evidence that these factors associate with cachexia in cancer patients, and summarize translational efforts including essential early-phase clinical trials. We conclude with thoughts on targeted and personalized approaches for future anti-cachexia treatments.
    Keywords:  anorexia; cachexia; cytokines; inflammation; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.trecan.2022.01.004
  6. Antioxidants (Basel). 2022 Feb 02. pii: 304. [Epub ahead of print]11(2):
    How Cells Deal with the Fluctuating Environment: Autophagy Regulation under Stress in Yeast and Mammalian Systems.
    Yuchen Lei, Yuxiang Huang, Xin Wen, Zhangyuan Yin, Zhihai Zhang, Daniel J Klionsky.
      Eukaryotic cells frequently experience fluctuations of the external and internal environments, such as changes in nutrient, energy and oxygen sources, and protein folding status, which, after reaching a particular threshold, become a type of stress. Cells develop several ways to deal with these various types of stress to maintain homeostasis and survival. Among the cellular survival mechanisms, autophagy is one of the most critical ways to mediate metabolic adaptation and clearance of damaged organelles. Autophagy is maintained at a basal level under normal growing conditions and gets stimulated by stress through different but connected mechanisms. In this review, we summarize the advances in understanding the autophagy regulation mechanisms under multiple types of stress including nutrient, energy, oxidative, and ER stress in both yeast and mammalian systems.
    Keywords:  ER stress; autophagy; energy stress; nutrient stress; oxidative stress; regulation
    DOI:  https://doi.org/10.3390/antiox11020304
  7. Gastroenterology. 2022 Feb 21. pii: S0016-5085(22)00154-8. [Epub ahead of print]
    Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment.
    Carolina J Garcia Garcia, Yanqing Huang, Natividad R Fuentes, Madeleine C Turner, Maria E Monberg, Daniel Lin, Nicholas D Nguyen, Tara N Fujimoto, Jun Zhao, Jaewon J Lee, Vincent Bernard, Meifang Yu, Abagail M Delahoussaye, Iancarlos Jimenez Sacarello, Emily G Caggiano, Jae L Phan, Amit Deorukhkar, Jessica M Molkentine, Dieter Saur, Anirban Maitra, Cullen M Taniguchi.
      BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma, which contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, but their role within the PDAC tumor microenvironment remains unknown.METHODS: We used a dual recombinase mouse model to delete Hif1α or Hif2α in α-smooth muscle actin (αSMA)-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF HIF2 expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, a HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade.
    RESULTS: CAF-specific deletion of Hif2α, but not Hif1α, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = .0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models.
    CONCLUSIONS: Together, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease.
    Keywords:  cancer-associated fibroblasts; hypoxia; pancreatic ductal adenocarcinoma; tumor-associated macrophages
    DOI:  https://doi.org/10.1053/j.gastro.2022.02.024
  8. Oncogene. 2022 Feb 19.
    TSPAN6 is a suppressor of Ras-driven cancer.
    Patrick O Humbert, Tamara Zoranovic Pryjda, Blanka Pranjic, Andrew Farrell, Kohei Fujikura, Ricardo de Matos Simoes, Rezaul Karim, Ivona Kozieradzki, Shane J F Cronin, G Gregory Neely, Thomas F Meyer, Astrid Hagelkruys, Helena E Richardson, Josef M Penninger.
      Oncogenic mutations in the small GTPase RAS contribute to ~30% of human cancers. In a Drosophila genetic screen, we identified novel and evolutionary conserved cancer genes that affect Ras-driven tumorigenesis and metastasis in Drosophila including confirmation of the tetraspanin Tsp29Fb. However, it was not known whether the mammalian Tsp29Fb orthologue, TSPAN6, has any role in RAS-driven human epithelial tumors. Here we show that TSPAN6 suppressed tumor growth and metastatic dissemination of human RAS activating mutant pancreatic cancer xenografts. Whole-body knockout as well as tumor cell autonomous inactivation using floxed alleles of Tspan6 in mice enhanced KrasG12D-driven lung tumor initiation and malignant progression. Mechanistically, TSPAN6 binds to the EGFR and blocks EGFR-induced RAS activation. Moreover, we show that inactivation of TSPAN6 induces an epithelial-to-mesenchymal transition and inhibits cell migration in vitro and in vivo. Finally, low TSPAN6 expression correlates with poor prognosis of patients with lung and pancreatic cancers with mesenchymal morphology. Our results uncover TSPAN6 as a novel tumor suppressor receptor that controls epithelial cell identify and restrains RAS-driven epithelial cancer.
    DOI:  https://doi.org/10.1038/s41388-022-02223-y
  9. Elife. 2022 02 25. pii: e77180. [Epub ahead of print]11
    Getting closer to the clinic.
    Toshiko Tanaka, Luigi Ferrucci.
      Associations between plasma protein levels and DNA methylation patterns can be used to predict the onset of age-related chronic disease.
    Keywords:  aging; biomarker; epidemiology; epigenetic; genetics; genomics; global health; human; morbidity; prediction; proteomics
    DOI:  https://doi.org/10.7554/eLife.77180
  10. Biochem J. 2022 Feb 25. pii: BCJ20210855. [Epub ahead of print]
    Deletion of Slc6a14 reduces cancer growth and metastatic spread and improves survival in KPC mouse model of spontaneous pancreatic cancer.
    Bradley Schniers, Mitchell Wachtel, Meenu Sharma, Ksenija Korac, Devaraja Rajasekaran, Shengping Yang, Tyler Sniegowski, Vadivel Ganapathy, Yangzom Doma Bhutia.
      Pancreatic ductal adenocarcinoma (PDAC) is lethal. There is a dire need for better therapeutic targets. Cancer cells have increased demand for sugars, amino acids, and lipids and therefore upregulate various nutrient transporters to meet this demand. In PDAC, SLC6A14 (an amino acid transporter) is upregulated, affecting overall patient survival. Previously we have shown using in vitro cell culture models and in vivo xenograft mouse models that pharmacological inhibition of SLC6A14 with a-methyl-L-tryptophan (a-MLT) attenuates PDAC growth. Mechanistically, blockade of SLC6A14-mediated amino acid transport with a-MLT leads to amino acid deprivation, eventually inhibiting mTORC1 signaling pathway, in tumor cells. Here we report on the effect of Slc6a14 deletion on various parameters of PDAC in KPC mice, a model for spontaneous PDAC. Pancreatic tumors in KPC mice show evidence of Slc6a14 upregulation. Deletion of Slc6a14 in this mouse attenuates PDAC growth, decreases metastatic spread of the tumor, reduces ascites fluid accumulation, and improves overall survival. At molecular level, we show lower proliferation index and reduced desmoplastic reaction following Slc6a14 deletion. Furthermore, we find that deletion of Slc6a14 does not lead to compensatory upregulation in any of the other amino transporters. In fact, some of the amino acid transporters are actually downregulated in response to Slc6a14 deletion, most likely related to altered mTORC1 signaling. Taken together, these results underscore the positive role SLC6A14 plays in PDAC growth and metastasis. Therefore, SLC6A14 is a viable drug target for treatment of PDAC and also for any other cancer that overexpresses this transporter.
    Keywords:  KPC; Pancreatic Cancer; SLC6A14; ascites fluid; metastasis; survival
    DOI:  https://doi.org/10.1042/BCJ20210855
  11. Nature. 2022 Feb 23.
    Effective drug combinations in breast, colon and pancreatic cancer cells.
    Patricia Jaaks, Elizabeth A Coker, Daniel J Vis, Olivia Edwards, Emma F Carpenter, Simonetta M Leto, Lisa Dwane, Francesco Sassi, Howard Lightfoot, Syd Barthorpe, Dieudonne van der Meer, Wanjuan Yang, Alexandra Beck, Tatiana Mironenko, Caitlin Hall, James Hall, Iman Mali, Laura Richardson, Charlotte Tolley, James Morris, Frances Thomas, Ermira Lleshi, Nanne Aben, Cyril H Benes, Andrea Bertotti, Livio Trusolino, Lodewyk Wessels, Mathew J Garnett.
      Combinations of anti-cancer drugs can overcome resistance and provide new treatments1,2. The number of possible drug combinations vastly exceeds what could be tested clinically. Efforts to systematically identify active combinations and the tissues and molecular contexts in which they are most effective could accelerate the development of combination treatments. Here we evaluate the potency and efficacy of 2,025 clinically relevant two-drug combinations, generating a dataset encompassing 125 molecularly characterized breast, colorectal and pancreatic cancer cell lines. We show that synergy between drugs is rare and highly context-dependent, and that combinations of targeted agents are most likely to be synergistic. We incorporate multi-omic molecular features to identify combination biomarkers and specify synergistic drug combinations and their active contexts, including in basal-like breast cancer, and microsatellite-stable or KRAS-mutant colon cancer. Our results show that irinotecan and CHEK1 inhibition have synergistic effects in microsatellite-stable or KRAS-TP53 double-mutant colon cancer cells, leading to apoptosis and suppression of tumour xenograft growth. This study identifies clinically relevant effective drug combinations in distinct molecular subpopulations and is a resource to guide rational efforts to develop combinatorial drug treatments.
    DOI:  https://doi.org/10.1038/s41586-022-04437-2
  12. Front Nutr. 2021 ;8 811288
    Association Between Systemic Inflammation and Malnutrition With Survival in Patients With Cancer Sarcopenia-A Prospective Multicenter Study.
    Guo-Tian Ruan, Yi-Zhong Ge, Hai-Lun Xie, Chun-Lei Hu, Qi Zhang, Xi Zhang, Meng Tang, Meng-Meng Song, Xiao-Wei Zhang, Tong Liu, Xiang-Rui Li, Kang-Ping Zhang, Ming Yang, Qin-Qin Li, Yong-Bing Chen, Kai-Ying Yu, Marco Braga, Ming-Hua Cong, Kun-Hua Wang, Rocco Barazzoni, Han-Ping Shi.
      Objective: Systemic inflammation and malnutrition are correlated with cancer sarcopenia and have deleterious effects on oncological outcomes. However, the combined effect of inflammation and malnutrition in patients with cancer sarcopenia remains unclear.Methods: We prospectively collected information on 1,204 patients diagnosed with cancer sarcopenia. the mean (SD) age was 64.5 (11.4%) years, and 705 (58.60%) of the patients were male. The patients were categorized into the high advanced lung cancer inflammation index (ALI) group (≥18.39) and the low ALI group (<18.39) according to the optimal survival cut-off curve. We selected the optimal inflammation marker using the C-index, decision curve analysis (DCA), and a prognostic receiver operating characteristic curve. Univariate and multivariate survival analyses were performed to determine the prognostic value of the optimal inflammation indicator. We also analyzed the association between inflammation and malnutrition in patients with cancer.
    Results: The C-index, DCA, and prognostic area under the curve of ALI in patients with cancer sarcopenia were higher or better than those of neutrophil-lymphocyte ratio (NLR), prognostic nutritional index (PNI), systemic immune-inflammation index (SII), and platelet-lymphocyte ratio (PLR). The prognosis for patients in the low ALI group was worse than that of patients in the high ALI group [HR (95%CI) = 1.584 (1.280-1.959), P < 0.001]. When the ALI was divided into quartiles, we observed that decreased ALI scores strongly correlated with decreased overall survival (OS). Patients with both a low ALI and severe malnutrition (vs. patients with high ALI and well-nourished) had a 2.262-fold death risk (P < 0.001). Subgroup analysis showed a significant interactive association between the ALI and death risk in terms of TNM stage (P for interaction = 0.030).
    Conclusions: The inflammation indicator of the ALI was better than those of the NLR, PNI, SII, and PLR in patients with cancer sarcopenia. Inflammation combined with severe malnutrition has a nearly 3-fold death risk in patients with cancer sarcopenia, suggesting that reducing systemic inflammation, strengthening nutritional intervention, and improving skeletal muscle mass are necessary.
    Keywords:  ALI; cancer sarcopenia; malnutrition; overall survival; systemic inflammation
    DOI:  https://doi.org/10.3389/fnut.2021.811288
  13. Cancer Cell. 2022 Feb 15. pii: S1535-6108(22)00036-8. [Epub ahead of print]
    CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4.
    Peng Liao, Weimin Wang, Weichao Wang, Ilona Kryczek, Xiong Li, Yingjie Bian, Amanda Sell, Shuang Wei, Sara Grove, Jeffrey K Johnson, Paul D Kennedy, Miguel Gijón, Yatrik M Shah, Weiping Zou.
      Tumor cell intrinsic ferroptosis-initiating mechanisms are unknown. Here, we discover that T cell-derived interferon (IFN)γ in combination with arachidonic acid (AA) induces immunogenic tumor ferroptosis, serving as a mode of action for CD8+ T cell (CTL)-mediated tumor killing. Mechanistically, IFNγ stimulates ACSL4 and alters tumor cell lipid pattern, thereby increasing incorporations of AA into C16 and C18 acyl chain-containing phospholipids. Palmitoleic acid and oleic acid, two common C16 and C18 fatty acids in blood, promote ACSL4-dependent tumor ferroptosis induced by IFNγ plus AA. Moreover, tumor ACSL4 deficiency accelerates tumor progression. Low-dose AA enhances tumor ferroptosis and elevates spontaneous and immune checkpoint blockade (ICB)-induced anti-tumor immunity. Clinically, tumor ACSL4 correlates with T cell signatures and improved survival in ICB-treated cancer patients. Thus, IFNγ signaling paired with selective fatty acids is a natural tumor ferroptosis-promoting mechanism and a mode of action of CTLs. Targeting the ACSL4 pathway is a potential anti-cancer approach.
    Keywords:  ACSL4; PD-L1; T cell; arachidonic acid; cancer; ferroptosis; immunotherapy; interferon; oleic acid; palmitoleic acid
    DOI:  https://doi.org/10.1016/j.ccell.2022.02.003
  14. Pancreas. 2022 Jan 01. 51(1): 100-105
    The Fate of Resectable Pancreatic Adenocarcinoma After Neoadjuvant Chemotherapy.
    Ahmer Irfan, J Bart Rose, Thomas N Wang, Selwyn M Vickers, Vikas Dudeja, Olumide Gbolahan, Sushanth Reddy.
      OBJECTIVES: Pancreatic cancer continues to be a major cause of cancer-related mortality. There has been a greater implementation of up-front chemotherapy for pancreatic adenocarcinoma patients. Although there are many theoretical benefits to neoadjuvant chemotherapy, its clinical impact is uncertain. We sought to understand the outcomes of patients with resectable and borderline-resectable pancreatic adenocarcinoma who underwent neoadjuvant chemotherapy.METHODS: Patients were collected in a secure database from September 2018 to May 2020. Patients were excluded if they presented with locally advanced or metastatic disease, inability to complete chemotherapy, or if they were not a surgical candidate.
    RESULTS: Sixty-six patients with resectable disease underwent chemotherapy. Folinic acid/5-fluorouracil/irinotecan/oxaliplatin was used in 41 patients (62.1%) and gemcitabine-based regimens in 28 patients (42.4%, greater than 100% as some patients underwent both regimens). After restaging, 47 patients (71.2%) were thought to have resectable disease. Of these patients, 36 have been successfully resected to date. Metastatic disease was found in 12 patients (18.2%) and 6 patients (9.1%) had locally advanced disease.
    CONCLUSIONS: Most patients with resectable pancreatic cancer are resected after neoadjuvant chemotherapy, but a subset will develop local or distant progression. Further studies will be needed to determine which patients will progress locally and may benefit from an up-front surgical approach.
    DOI:  https://doi.org/10.1097/MPA.0000000000001972
  15. Nat Rev Cancer. 2022 Feb 22.
    CRISPR in cancer biology and therapy.
    Alyna Katti, Bianca J Diaz, Christina M Caragine, Neville E Sanjana, Lukas E Dow.
      Over the past decade, CRISPR has become as much a verb as it is an acronym, transforming biomedical research and providing entirely new approaches for dissecting all facets of cell biology. In cancer research, CRISPR and related tools have offered a window into previously intractable problems in our understanding of cancer genetics, the noncoding genome and tumour heterogeneity, and provided new insights into therapeutic vulnerabilities. Here, we review the progress made in the development of CRISPR systems as a tool to study cancer, and the emerging adaptation of these technologies to improve diagnosis and treatment.
    DOI:  https://doi.org/10.1038/s41568-022-00441-w
  16. Proc Natl Acad Sci U S A. 2022 Mar 01. pii: e2119187119. [Epub ahead of print]119(9):
    ERK signaling dissolves ERF repression condensates in living embryos.
    Claire J Weaver, Aleena L Patel, Stanislav Y Shvartsman, Michael S Levine, Nicholas Treen.
      Phase separation underlies the organization of the nucleus, including the biogenesis of nucleoli and the packaging of heterochromatin. Here we explore the regulation of transcription factor condensates involved in gene repression by ERK signaling in gastrulating embryos of a simple proto-vertebrate (Ciona). ERK signaling induces nuclear export of the transcriptional repressor Ets-2 repressive factor (ERF), which has been linked to various human developmental disorders. Using high-resolution imaging, we show that ERF is localized within discrete nuclear condensates that dissolve upon ERK activation. Interestingly, we observe dynamic pulses of assembly and dissociation during interphase, providing visualization of a nuclear phase separation process regulated by cell signaling. We discuss the implications of these observations for producing sharp on/off switches in gene activity and suppressing noise in cell-cell signaling events.
    Keywords:  developmental biology; phase separation; transcriptional repression
    DOI:  https://doi.org/10.1073/pnas.2119187119
  17. Sci Adv. 2022 Feb 25. 8(8): eabl4386
    The chaperone Tsr2 regulates Rps26 release and reincorporation from mature ribosomes to enable a reversible, ribosome-mediated response to stress.
    Yoon-Mo Yang, Katrin Karbstein.
      Although ribosome assembly is quality controlled to maintain protein homeostasis, different ribosome populations have been described. How these form, especially under stress conditions that affect energy levels and stop the energy-intensive production of ribosomes, remains unknown. Here, we demonstrate how a physiologically relevant ribosome population arises during high Na+, sorbitol, or pH stress via dissociation of Rps26 from fully assembled ribosomes to enable a translational response to these stresses. The chaperone Tsr2 releases Rps26 in the presence of high Na+ or pH in vitro and is required for Rps26 release in vivo. Moreover, Tsr2 stores free Rps26 and promotes reincorporation of the protein, thereby repairing the subunit after the Na+ stress subsides. Our data implicate a residue in Rps26 involved in Diamond Blackfan Anemia in mediating the effects of Na+. These data demonstrate how different ribosome populations can arise rapidly, without major energy input and without bypass of quality control mechanisms.
    DOI:  https://doi.org/10.1126/sciadv.abl4386
  18. Sci Adv. 2022 Feb 25. 8(8): eabm4552
    Therapeutic antibody activation of the glucocorticoid-induced TNF receptor by a clustering mechanism.
    Changhao He, Rachana R Maniyar, Yahel Avraham, Roberta Zappasodi, Radda Rusinova, Walter Newman, Heidi Heath, Jedd D Wolchok, Rony Dahan, Taha Merghoub, Joel R Meyerson.
      GITR is a TNF receptor, and its activation promotes immune responses and drives antitumor activity. The receptor is activated by the GITR ligand (GITRL), which is believed to cluster receptors into a high-order array. Immunotherapeutic agonist antibodies also activate the receptor, but their mechanisms are not well characterized. We solved the structure of full-length mouse GITR bound to Fabs from the antibody DTA-1. The receptor is a dimer, and each subunit binds one Fab in an orientation suggesting that the antibody clusters receptors. Binding experiments with purified proteins show that DTA-1 IgG and GITRL both drive extensive clustering of GITR. Functional data reveal that DTA-1 and the anti-human GITR antibody TRX518 activate GITR in their IgG forms but not as Fabs. Thus, the divalent character of the IgG agonists confers an ability to mimic GITRL and cluster and activate GITR. These findings will inform the clinical development of this class of antibodies for immuno-oncology.
    DOI:  https://doi.org/10.1126/sciadv.abm4552
  19. Nat Rev Clin Oncol. 2022 Feb 22.
    The role of neoadjuvant therapy for resectable pancreatic cancer remains uncertain.
    Christoph Springfeld, John P Neoptolemos.
      
    DOI:  https://doi.org/10.1038/s41571-022-00612-6
  20. Mol Biol Cell. 2022 Feb 23. mbcE20080523
    The methyltransferase enzymes, KMT2D, SETD1B, and ASH1L, are key mediators of both metabolic and epigenetic changes during cellular senescence.
    Timothy Nacarelli, Ashley Azar, Manali Potnis, Gregg Johannes, Joshua Mell, F Brad Johnson, Holly Brown-Borg, Eishi Nogouchi, Christian Sell.
      Cellular senescence is a terminal cell fate characterized by growth arrest, and a metabolically active state characterized by high glycolytic activity. Human fibroblasts were placed in a unique metabolic state using a combination of methionine restriction and rapamycin. This combination induced a metabolic reprogramming that prevented the glycolytic shift associated with senescence. Surprisingly, cells treated in this manner did not undergo senescence, but continued to divide at a slow rate even at high passage, in contrast to either rapamycin treatment or methionine restriction, both of which extended lifespan but eventually resulted in growth arrest. Transcriptome-wide analysis revealed a coordinated regulation of metabolic enzymes related to one-carbon metabolism, including three methyltransferase enzymes (KMT2D, SETD1B, and ASH1L), key enzymes for both carnitine synthesis and histone modification. These enzymes appear to be involved in both the metabolic phenotype of senescent cells and the chromatin changes required for establishing the senescence arrest. Targeting one of these enzymes, ASH1L, produced both a glycolytic shift and senescence, providing proof of concept. These findings reveal a mechanistic link between a major metabolic hallmark of senescence and nuclear events required for senescence.
    DOI:  https://doi.org/10.1091/mbc.E20-08-0523
  21. Am J Clin Oncol. 2022 Mar 01. 45(3): 95-104
    Prognostic Implications of an Autophagy-related Gene Signature in Pancreatic Ductal Adenocarcinoma.
    Wei-Shuai Liu, Yi-Xing Feng, Sheng-Nan Li, Yue-Juan Shao, Kun Wang.
      BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is difficult to diagnose and resistant to therapy and has a poor prognosis. Autophagy plays a vital role in PDAC development and progression. This study aimed to establish an autophagy-related gene (ARG) signature to predict the prognosis of patients with PDAC.MATERIALS AND METHODS: The expression profiles of PDAC and healthy pancreatic tissues were obtained from The Cancer Genome of Atlas (TCGA) and GTEx (Genotype-Tissue Expression) databases, respectively. Univariate and multivariate Cox regression analyses were performed on differentially expressed ARGs to identify the optimal prognosis-related genes.
    RESULTS: A total of 73 ARGs demonstrated significant differences in expression levels between PDAC and healthy pancreatic tissues. Several pathways that play crucial roles in biological processes were identified via enrichment analyses. Furthermore, an ARG signature was established based on overall survival-related ARGs (CASP4, BAK1, PIK3R4, CASP8, BIRC5, RPTOR, and CAPN1) using least absolute shrinkage and selection operator (LASSO) regression. Cox regression analysis confirmed that the 7-gene signature was an independent prognostic factor for patients with PDAC (P<0.001). In addition, the GSE21501 and GSE28735 datasets were used to validate the predictive value of the prognostic model for PDAC. We also constructed a clinical nomogram with a concordance index of 0.712 to predict the overall survival of patients by integrating clinical characteristics and the ARG signature. Calibration curves substantiated fine concordance between nomogram prediction and actual observation.
    CONCLUSION: We constructed a new ARG-related prognostic model, which can be a prognostic biomarker and offers insights into identifying potential therapeutic targets for PDAC.
    DOI:  https://doi.org/10.1097/COC.0000000000000890
  22. FASEB J. 2022 03;36(3): e22211
    Cancer causes dysfunctional insulin signaling and glucose transport in a muscle-type-specific manner.
    Steffen H Raun, Jonas Roland Knudsen, Xiuqing Han, Thomas E Jensen, Lykke Sylow.
      Metabolic dysfunction and insulin resistance are emerging as hallmarks of cancer and cachexia, and impair cancer prognosis. Yet, the molecular mechanisms underlying impaired metabolic regulation are not fully understood. To elucidate the mechanisms behind cancer-induced insulin resistance in muscle, we isolated extensor digitorum longus (EDL) and soleus muscles from Lewis Lung Carcinoma tumor-bearing mice. Three weeks after tumor inoculation, muscles were isolated and stimulated with or without a submaximal dose of insulin (1.5 nM). Glucose transport was measured using 2-[3 H]Deoxy-Glucose and intramyocellular signaling was investigated using immunoblotting. In soleus muscles from tumor-bearing mice, insulin-stimulated glucose transport was abrogated concomitantly with abolished insulin-induced TBC1D4 and GSK3 phosphorylation. In EDL, glucose transport and TBC1D4 phosphorylation were not impaired in muscles from tumor-bearing mice, while AMPK signaling was elevated. Anabolic insulin signaling via phosphorylation of the mTORC1 targets, p70S6K thr389, and ribosomal-S6 ser235, were decreased by cancer in soleus muscle while increased or unaffected in EDL. In contrast, the mTOR substrate, pULK1 ser757, was reduced in both soleus and EDL by cancer. Hence, cancer causes considerable changes in skeletal muscle insulin signaling that is dependent on muscle-type, which could contribute to metabolic dysregulation in cancer. Thus, the skeletal muscle could be a target for managing metabolic dysfunction in cancer.
    Keywords:  AMPK; Akt; Lewis lung carcinoma; TBC1D4; cachexia; cancer; glucose metabolism; insulin resistance; mTORC1; muscle
    DOI:  https://doi.org/10.1096/fj.202101759R
  23. J Cachexia Sarcopenia Muscle. 2022 Feb 26.
    Addressing unmet needs for people with cancer cachexia: recommendations from a multistakeholder workshop.
    Jose M Garcia, Richard F Dunne, Kristen Santiago, Lisa Martin, Morris J Birnbaum, Jeffrey Crawford, Andrew E Hendifar, Martin Kochanczyk, Cassadie Moravek, Doris Piccinin, Vincent Picozzi, Eric J Roeland, Wendy K D Selig, Teresa A Zimmers.
      
    Keywords:  Cachexia; Cancer; Cholangiocarcinoma; Colorectal cancer; Congress; Lung cancer; Nutrition; Pancreatic cancer; Supportive care
    DOI:  https://doi.org/10.1002/jcsm.12910
  24. Biomolecules. 2022 Feb 13. pii: 305. [Epub ahead of print]12(2):
    Tumor Suppressor Role of Wild-Type P53-Dependent Secretome and Its Proteomic Identification in PDAC.
    Giovanna Butera, Marcello Manfredi, Alessandra Fiore, Jessica Brandi, Raffaella Pacchiana, Veronica De Giorgis, Elettra Barberis, Virginia Vanella, Marilisa Galasso, Maria Teresa Scupoli, Emilio Marengo, Daniela Cecconi, Massimo Donadelli.
      The study of the cancer secretome is gaining even more importance in cancers such as pancreatic ductal adenocarcinoma (PDAC), whose lack of recognizable symptoms and early detection assays make this type of cancer highly lethal. The wild-type p53 protein, frequently mutated in PDAC, prevents tumorigenesis by regulating a plethora of signaling pathways. The importance of the p53 tumor suppressive activity is not only primarily involved within cells to limit tumor cell proliferation but also in the extracellular space. Thus, loss of p53 has a profound impact on the secretome composition of cancer cells and marks the transition to invasiveness. Here, we demonstrate the tumor suppressive role of wild-type p53 on cancer cell secretome, showing the anti-proliferative, apoptotic and chemosensitivity effects of wild-type p53 driven conditioned medium. By using high-resolution SWATH-MS technology, we characterized the secretomes of p53-deficient and p53-expressing PDAC cells. We found a great number of secreted proteins that have known roles in cancer-related processes, 30 of which showed enhanced and 17 reduced secretion in response to p53 silencing. These results are important to advance our understanding on the link between wt-p53 and cancer microenvironment. In conclusion, this approach may detect a secreted signature specifically driven by wild-type p53 in PDAC.
    Keywords:  onco-suppressor gene; pancreatic ductal adenocarcinoma; secretome; wild-type p53
    DOI:  https://doi.org/10.3390/biom12020305
  25. Trends Cell Biol. 2022 Feb 18. pii: S0962-8924(22)00006-X. [Epub ahead of print]
    Fracture in living tissues.
    Alessandra Bonfanti, Julia Duque, Alexandre Kabla, Guillaume Charras.
      During development and in adult physiology, living tissues are continuously subjected to mechanical stresses originating either from cellular processes intrinsic to the tissue or from external forces. As a consequence, rupture is a constant risk and can arise as a result of excessive stresses or because of tissue weakening through genetic abnormalities or pathologies. Tissue fracture is a multiscale process involving the unzipping of intercellular adhesions at the molecular scale in response to stresses arising at the tissue or cellular scale that are transmitted to adhesion complexes via the cytoskeleton. In this review we detail experimental characterization and theoretical approaches for understanding the fracture of living tissues at the tissue, cellular, and molecular scales.
    Keywords:  cadherin; cytoskeleton; desmosome; fracture
    DOI:  https://doi.org/10.1016/j.tcb.2022.01.005
  26. EMBO J. 2022 Feb 25. e109470
    Dermal αSMA+ myofibroblasts orchestrate skin wound repair via β1 integrin and independent of type I collagen production.
    Kathleen M McAndrews, Toru Miyake, Ehsan A Ehsanipour, Patience J Kelly, Lisa M Becker, Daniel J McGrail, Hikaru Sugimoto, Valerie S LeBleu, Yejing Ge, Raghu Kalluri.
      Skin wound repair is essential for organismal survival and failure of which leads to non-healing wounds, a leading health issue worldwide. However, mechanistic understanding of chronic wounds remains a major challenge due to lack of appropriate genetic mouse models. αSMA+ myofibroblasts, a unique class of dermal fibroblasts, are associated with cutaneous wound healing but their precise function remains unknown. We demonstrate that genetic depletion of αSMA+ myofibroblasts leads to pleiotropic wound healing defects, including lack of reepithelialization and granulation, dampened angiogenesis, and heightened hypoxia, hallmarks of chronic non-healing wounds. Other wound-associated FAP+ and FSP1+ fibroblasts do not exhibit such dominant functions. While type I collagen (COL1) expressing cells play a role in the repair process, COL1 produced by αSMA+ myofibroblasts is surprisingly dispensable for wound repair. In contrast, we show that β1 integrin from αSMA+ myofibroblasts, but not TGFβRII, is essential for wound healing, facilitating contractility, reepithelization, and vascularization. Collectively, our study provides evidence for the functions of myofibroblasts in β1 integrin-mediated wound repair with potential implications for treating chronic non-healing wounds.
    Keywords:  extracellular matrix; myofibroblasts; wound healing
    DOI:  https://doi.org/10.15252/embj.2021109470
  27. STAR Protoc. 2022 Mar 18. 3(1): 101168
    Network analysis of TCGA and GTEx gene expression datasets for identification of trait-associated biomarkers in human cancer.
    Huey-Miin Chen, Justin A MacDonald.
      Advances in high-throughput sequencing technologies now yield unprecedented volumes of OMICs data with opportunities to conduct systematic data analyses and derive novel biological insights. Here, we provide protocols to perform differential-expressed gene analysis of TCGA and GTEx RNA-Seq data from human cancers, complete integrative GO and network analyses with focus on clinical and survival data, and identify differential correlation of trait-associated biomarkers. For complete details on the use and execution of this protocol, please refer to Chen and MacDonald (2021).
    Keywords:  Bioinformatics; Cancer; Gene Expression; Genomics; RNAseq; Systems biology
    DOI:  https://doi.org/10.1016/j.xpro.2022.101168
  28. Front Mol Biosci. 2022 ;9 789889
    Metabolomics and its Applications in Cancer Cachexia.
    Pengfei Cui, Xiaoyi Li, Caihua Huang, Qinxi Li, Donghai Lin.
      Cancer cachexia (CC) is a complicated metabolic derangement and muscle wasting syndrome, affecting 50-80% cancer patients. So far, molecular mechanisms underlying CC remain elusive. Metabolomics techniques have been used to study metabolic shifts including changes of metabolite concentrations and disturbed metabolic pathways in the progression of CC, and expand further fundamental understanding of muscle loss. In this article, we aim to review the research progress and applications of metabolomics on CC in the past decade, and provide a theoretical basis for the study of prediction, early diagnosis, and therapy of CC.
    Keywords:  biomarker; cancer cachexia; metabolic alterations; metabolomics; progress
    DOI:  https://doi.org/10.3389/fmolb.2022.789889
  29. Mol Cell. 2022 Feb 12. pii: S1097-2765(22)00061-2. [Epub ahead of print]
    Poly(ADP-ribose) drives condensation of FUS via a transient interaction.
    Kevin Rhine, Morgan Dasovich, Joseph Yoniles, Mohsen Badiee, Sophie Skanchy, Laura R Ganser, Yingda Ge, Charlotte M Fare, James Shorter, Anthony K L Leung, Sua Myong.
      Poly(ADP-ribose) (PAR) is an RNA-like polymer that regulates an increasing number of biological processes. Dysregulation of PAR is implicated in neurodegenerative diseases characterized by abnormal protein aggregation, including amyotrophic lateral sclerosis (ALS). PAR forms condensates with FUS, an RNA-binding protein linked with ALS, through an unknown mechanism. Here, we demonstrate that a strikingly low concentration of PAR (1 nM) is sufficient to trigger condensation of FUS near its physiological concentration (1 μM), which is three orders of magnitude lower than the concentration at which RNA induces condensation (1 μM). Unlike RNA, which associates with FUS stably, PAR interacts with FUS transiently, triggering FUS to oligomerize into condensates. Moreover, inhibition of a major PAR-synthesizing enzyme, PARP5a, diminishes FUS condensation in cells. Despite their structural similarity, PAR and RNA co-condense with FUS, driven by disparate modes of interaction with FUS. Thus, we uncover a mechanism by which PAR potently seeds FUS condensation.
    Keywords:  FUS; LLPS; PARP5a; PARylation; RNA; condensation; length dependence; poly(ADP-ribose); stress response; transient interaction
    DOI:  https://doi.org/10.1016/j.molcel.2022.01.018
  30. Nat Rev Genet. 2022 Feb 25.
    Single-cell atlases: shared and tissue-specific cell types across human organs.
    Rasa Elmentaite, Cecilia Domínguez Conde, Lu Yang, Sarah A Teichmann.
      The development of single-cell and spatial transcriptomics methods was instrumental in the conception of the Human Cell Atlas initiative, which aims to generate an integrated map of all cells across the human body. These technology advances are bringing increasing depth and resolution to maps of human organs and tissues, as well as our understanding of individual human cell types. Commonalities as well as tissue-specific features of primary and supportive cell types across human organs are beginning to emerge from these human tissue maps. In this Review, we highlight key biological insights obtained from cross-tissue studies into epithelial, fibroblast, vascular and immune cells based on single-cell gene expression data in humans and contrast it with mechanisms reported in mice.
    DOI:  https://doi.org/10.1038/s41576-022-00449-w
  31. Proc Natl Acad Sci U S A. 2022 Mar 01. pii: e2112840119. [Epub ahead of print]119(9):
    An immune-sympathetic neuron communication axis guides adipose tissue browning in cancer-associated cachexia.
    Hao Xie, Christoph Heier, Xia Meng, Latifa Bakiri, Isabella Pototschnig, Zhiyuan Tang, Silvia Schauer, Vanessa J Baumgartner, Gernot F Grabner, Gernot Schabbauer, Heimo Wolinski, Graham R Robertson, Gerald Hoefler, Wenwen Zeng, Erwin F Wagner, Martina Schweiger, Rudolf Zechner.
      Cancer-associated cachexia (CAC) is a hypermetabolic syndrome characterized by unintended weight loss due to the atrophy of adipose tissue and skeletal muscle. A phenotypic switch from white to beige adipocytes, a phenomenon called browning, accelerates CAC by increasing the dissipation of energy as heat. Addressing the mechanisms of white adipose tissue (WAT) browning in CAC, we now show that cachexigenic tumors activate type 2 immunity in cachectic WAT, generating a neuroprotective environment that increases peripheral sympathetic activity. Increased sympathetic activation, in turn, results in increased neuronal catecholamine synthesis and secretion, β-adrenergic activation of adipocytes, and induction of WAT browning. Two genetic mouse models validated this progression of events. 1) Interleukin-4 receptor deficiency impeded the alternative activation of macrophages, reduced sympathetic activity, and restrained WAT browning, and 2) reduced catecholamine synthesis in peripheral dopamine β-hydroxylase (DBH)-deficient mice prevented cancer-induced WAT browning and adipose atrophy. Targeting the intraadipose macrophage-sympathetic neuron cross-talk represents a promising therapeutic approach to ameliorate cachexia in cancer patients.
    Keywords:  adipose tissue; browning; cancer cachexia; immunometabolism; macrophage
    DOI:  https://doi.org/10.1073/pnas.2112840119
  32. Br J Cancer. 2022 Feb 23.
    Circulating tumour DNA: a challenging innovation to develop "precision onco-surgery" in pancreatic adenocarcinoma.
    Daniel Pietrasz, Elisabetta Sereni, Francesco Lancelotti, Antonio Pea, Claudio Luchini, Giulio Innamorati, Roberto Salvia, Claudio Bassi.
      Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the third leading cause of cancer-related mortality within the next decade. Management of PDAC remains challenging with limited effective treatment options and a dismal long-term prognosis. Liquid biopsy and circulating biomarkers seem to be promising to improve the multidisciplinary approach in PDAC treatment. Circulating tumour DNA (ctDNA) is the most studied blood liquid biopsy analyte and can provide insight into the molecular profile and individual characteristics of the tumour in real-time and in advance of standard imaging modalities. This could pave the way for identifying new therapeutic targets and markers of tumour response to supplement diagnostic and provide enhanced stratified treatment. Although its specificity seems excellent, the current sensitivity of ctDNA remains a limitation for clinical use, especially in patients with a low tumour burden. Increasing evidence suggests that ctDNA is a pertinent candidate biomarker to assess minimal residual disease after surgery but also a strong independent prognostic biomarker. This review explores the current knowledge and recent developments in ctDNA as a screening, diagnostic, prognostic and predictive biomarker in the management of resectable PDAC but also technical and analytical challenges that must be overcome to move toward "precision onco-surgery."
    DOI:  https://doi.org/10.1038/s41416-022-01745-2
  33. Elife. 2022 Feb 23. pii: e74773. [Epub ahead of print]11
    Identification of electroporation sites in the complex lipid organization of the plasma membrane.
    Lea Rems, Xinru Tang, Fangwei Zhao, Sergio Pérez-Conesa, Ilaria Testa, Lucie Delemotte.
      The plasma membrane of a biological cell is a complex assembly of lipids and membrane proteins, which tightly regulate transmembrane transport. When a cell is exposed to strong electric field, the membrane integrity becomes transiently disrupted by formation of transmembrane pores. This phenomenon termed electroporation is already utilized in many rapidly developing applications in medicine including gene therapy, cancer treatment, and treatment of cardiac arrythmias. However, the molecular mechanisms of electroporation are not yet sufficiently well understood; in particular, it is unclear where exactly pores form in the complex organization of the plasma membrane. In this study we combine coarse-grained molecular dynamics simulations, machine learning methods, and Bayesian survival analysis to identify how formation of pores depends on the local lipid organization. We show that pores do not form homogeneously across the membrane, but colocalize with domains that have specific features, the most important being high density of polyunsaturated lipids. We further show that knowing the lipid organization is sufficient to reliably predict poration sites with machine learning. Additionally, by analysing poration kinetics with Bayesian survival analysis we show that poration does not depend solely on local lipid arrangement, but also on membrane mechanical properties and the polarity of the electric field. Finally, we discuss how the combination of atomistic and coarse-grained molecular dynamics simulations, machine learning methods, and Bayesian survival analysis can guide the design of future experiments and help us to develop an accurate description of plasma membrane electroporation on the whole-cell level. Achieving this will allow us to shift the optimization of electroporation applications from blind trial-and-error approaches to mechanistic-driven design.
    Keywords:  molecular biophysics; none; structural biology
    DOI:  https://doi.org/10.7554/eLife.74773
  34. Biomolecules. 2022 Feb 12. pii: 297. [Epub ahead of print]12(2):
    Quantifying the Patterns of Metabolic Plasticity and Heterogeneity along the Epithelial-Hybrid-Mesenchymal Spectrum in Cancer.
    Srinath Muralidharan, Sarthak Sahoo, Aryamaan Saha, Sanjay Chandran, Sauma Suvra Majumdar, Susmita Mandal, Herbert Levine, Mohit Kumar Jolly.
      Cancer metastasis is the leading cause of cancer-related mortality and the process of the epithelial-to-mesenchymal transition (EMT) is crucial for cancer metastasis. Both partial and complete EMT have been reported to influence the metabolic plasticity of cancer cells in terms of switching among the oxidative phosphorylation, fatty acid oxidation and glycolysis pathways. However, a comprehensive analysis of these major metabolic pathways and their associations with EMT across different cancers is lacking. Here, we analyse more than 180 cancer cell datasets and show the diverse associations of these metabolic pathways with the EMT status of cancer cells. Our bulk data analysis shows that EMT generally positively correlates with glycolysis but negatively with oxidative phosphorylation and fatty acid metabolism. These correlations are also consistent at the level of their molecular master regulators, namely AMPK and HIF1α. Yet, these associations are shown to not be universal. The analysis of single-cell data for EMT induction shows dynamic changes along the different axes of metabolic pathways, consistent with general trends seen in bulk samples. Further, assessing the association of EMT and metabolic activity with patient survival shows that a higher extent of EMT and glycolysis predicts a worse prognosis in many cancers. Together, our results reveal the underlying patterns of metabolic plasticity and heterogeneity as cancer cells traverse through the epithelial-hybrid-mesenchymal spectrum of states.
    Keywords:  AMPK; HIF1α; cancer metabolism; epithelial–mesenchymal transition; fatty acid metabolism; glycolysis; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/biom12020297
  35. J Clin Invest. 2022 Feb 22. pii: e153247. [Epub ahead of print]
    IL-9/STAT3/fatty acid oxidation-mediated lipid peroxidation contributes to Tc9 cell longevity and enhanced antitumor activity.
    Liuling Xiao, Xingzhe Ma, Lingqun Ye, Pan Su, Wei Xiong, Enguang Bi, Qiang Wang, Miao Xian, Maojie Yang, Jianfei Qian, Qing Yi.
      CD8+ T cell longevity regulated by metabolic activity plays important roles in cancer immunotherapy. Although in vitro polarized, transferred IL-9-secreting CD8+ Tc9 cells exert greater persistence and antitumor efficacy than Tc1/CTL cells, the underlying mechanism remains unclear. Here, we show that tumor-infiltrating Tc9 cells display significantly lower lipid peroxidation than Tc1 cells in several mouse models, which is strongly correlated with their persistence. Using RNA-sequence and functional validation, we found that Tc9 cells exhibited unique lipid metabolic programs. Tc9 cell-derived IL-9 activated STAT3, upregulated fatty acid oxidation and mitochondrial activity, and rendered Tc9 cells with reduced lipid peroxidation and resistant to tumor or ROS induced ferroptosis in TME. IL-9 signal deficiency, inhibiting STAT3 or fatty acid oxidation increased lipid peroxidation and ferroptosis of Tc9 cells, resulting in impaired longevity and antitumor ability. Similarly, human Tc9 cells also possessed lower lipid peroxidation than Tc1 cells and tumor-infiltrating CD8+ T cells expressed lower IL-9 and higher lipid peroxidation- and ferroptosis-related genes than circulating CD8+ T cells in melanoma patients. This study indicates that lipid peroxidation regulates Tc9-cell longevity and antitumor effects via IL-9-STAT3-fatty acid oxidation pathway and regulating T-cell lipid peroxidation can be used to enhance T-cell based immunotherapy in human cancer.
    Keywords:  Cancer immunotherapy; Fatty acid oxidation; Immunology; Metabolism; T cells
    DOI:  https://doi.org/10.1172/JCI153247
  36. Trends Cancer. 2022 Feb 18. pii: S2405-8033(22)00020-6. [Epub ahead of print]
    The spectrum of sex differences in cancer.
    Joshua B Rubin.
      Sex differences in cellular and systems biology have been evolutionarily selected to optimize reproductive success in all species with little (sperm) and big (ova) gamete producers. They are evident from the time of fertilization and accrue throughout development through genetic, epigenetic, and circulating sex hormone-dependent mechanisms. Among other effects, they significantly impact on chromatin organization, metabolism, cell cycle regulation, immunity, longevity, and cancer risk and survival. Sex differences in cancer should be expected and accounted for in basic, translational, and clinical oncology research.
    Keywords:  DNA repair; X chromosome; cancer; immunity; sex differences; tumor suppressor
    DOI:  https://doi.org/10.1016/j.trecan.2022.01.013
  37. Nature. 2022 Feb 23.
    Low-dose metformin targets the lysosomal AMPK pathway through PEN2.
    Teng Ma, Xiao Tian, Baoding Zhang, Mengqi Li, Yu Wang, Chunyan Yang, Jianfeng Wu, Xiaoyan Wei, Qi Qu, Yaxin Yu, Shating Long, Jin-Wei Feng, Chun Li, Cixiong Zhang, Changchuan Xie, Yaying Wu, Zheni Xu, Junjie Chen, Yong Yu, Xi Huang, Ying He, Luming Yao, Lei Zhang, Mingxia Zhu, Wen Wang, Zhi-Chao Wang, Mingliang Zhang, Yuqian Bao, Weiping Jia, Shu-Yong Lin, Zhiyun Ye, Hai-Long Piao, Xianming Deng, Chen-Song Zhang, Sheng-Cai Lin.
      Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects1-4. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action4,5; however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation6. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase7, as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase8, which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of PEN2 or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of Pen2 impairs its glucose-lowering effects. Furthermore, knockdown of pen-2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects.
    DOI:  https://doi.org/10.1038/s41586-022-04431-8
  38. Clin Transl Med. 2022 Feb;12(2): e730
    Revealing the transcriptional heterogeneity of organ-specific metastasis in human gastric cancer using single-cell RNA Sequencing.
    Haiping Jiang, Dingyi Yu, Penghui Yang, Rongfang Guo, Mei Kong, Yuan Gao, Xiongfei Yu, Xiaoyan Lu, Xiaohui Fan.
      BACKGROUND: Deciphering intra- and inter-tumoural heterogeneity is essential for understanding the biology of gastric cancer (GC) and its metastasis and identifying effective therapeutic targets. However, the characteristics of different organ-tropism metastases of GC are largely unknown.METHODS: Ten fresh human tissue samples from six patients, including primary tumour and adjacent non-tumoural samples and six metastases from different organs or tissues (liver, peritoneum, ovary, lymph node) were evaluated using single-cell RNA sequencing. Validation experiments were performed using histological assays and bulk transcriptomic datasets.
    RESULTS: Malignant epithelial subclusters associated with invasion features, intraperitoneal metastasis propensity, epithelial-mesenchymal transition-induced tumour stem cell phenotypes, or dormancy-like characteristics were discovered. High expression of the first three subcluster-associated genes displayed worse overall survival than those with low expression in a GC cohort containing 407 samples. Immune and stromal cells exhibited cellular heterogeneity and created a pro-tumoural and immunosuppressive microenvironment. Furthermore, a 20-gene signature of lymph node-derived exhausted CD8+ T cells was acquired to forecast lymph node metastasis and validated in GC cohorts. Additionally, although anti-NKG2A (KLRC1) antibody have not been used to treat GC patients even in clinical trials, we uncovered not only malignant tumour cells but one endothelial subcluster, mucosal-associated invariant T cells, T cell-like B cells, plasmacytoid dendritic cells, macrophages, monocytes, and neutrophils may contribute to HLA-E-KLRC1/KLRC2 interaction with cytotoxic/exhausted CD8+ T cells and/or natural killer (NK) cells, suggesting novel clinical therapeutic opportunities in GC. Additionally, our findings suggested that PD-1 expression in CD8+ T cells might predict clinical responses to PD-1 blockade therapy in GC.
    CONCLUSIONS: This study provided insights into heterogeneous microenvironment of GC primary tumours and organ-specific metastases and provide support for precise diagnosis and treatment.
    Keywords:  HLA-E-KLRC1/KLRC2; gastric cancer; metastasis; single-cell RNA sequencing; tumoural heterogeneity
    DOI:  https://doi.org/10.1002/ctm2.730
  39. Membranes (Basel). 2022 Feb 03. pii: 182. [Epub ahead of print]12(2):
    Platelet Membrane: An Outstanding Factor in Cancer Metastasis.
    Nazly Z Durán-Saenz, Alejandra Serrano-Puente, Perla I Gallegos-Flores, Brenda D Mendoza-Almanza, Edgar L Esparza-Ibarra, Susana Godina-González, Irma E González-Curiel, Jorge L Ayala-Luján, Marisa Hernández-Barrales, Cecilia F Cueto-Villalobos, Sharahy Y Frausto-Fierros, Luis A Burciaga-Hernandez, Gretel Mendoza-Almanza.
      In addition to being biological barriers where the internalization or release of biomolecules is decided, cell membranes are contact structures between the interior and exterior of the cell. Here, the processes of cell signaling mediated by receptors, ions, hormones, cytokines, enzymes, growth factors, extracellular matrix (ECM), and vesicles begin. They triggering several responses from the cell membrane that include rearranging its components according to the immediate needs of the cell, for example, in the membrane of platelets, the formation of filopodia and lamellipodia as a tissue repair response. In cancer, the cancer cells must adapt to the new tumor microenvironment (TME) and acquire capacities in the cell membrane to transform their shape, such as in the case of epithelial-mesenchymal transition (EMT) in the metastatic process. The cancer cells must also attract allies in this challenging process, such as platelets, fibroblasts associated with cancer (CAF), stromal cells, adipocytes, and the extracellular matrix itself, which limits tumor growth. The platelets are enucleated cells with fairly interesting growth factors, proangiogenic factors, cytokines, mRNA, and proteins, which support the development of a tumor microenvironment and support the metastatic process. This review will discuss the different actions that platelet membranes and cancer cell membranes carry out during their relationship in the tumor microenvironment and metastasis.
    Keywords:  cancer cell membrane; microenvironment; platelet membrane; receptors
    DOI:  https://doi.org/10.3390/membranes12020182
  40. PLoS Biol. 2022 Feb;20(2): e3001517
    Camptothecin effectively treats obesity in mice through GDF15 induction.
    Jun Feng Lu, Meng Qing Zhu, Bao Cai Xie, Xiao Chen Shi, Huan Liu, Rui Xin Zhang, Bo Xia, Jiang Wei Wu.
      Elevated circulating levels of growth differentiation factor 15 (GDF15) have been shown to reduce food intake and lower body weight through activation of hindbrain receptor glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) in rodents and nonhuman primates, thus endogenous induction of this peptide holds promise for obesity treatment. Here, through in silico drug-screening methods, we found that small molecule Camptothecin (CPT), a previously identified drug with potential antitumor activity, is a GDF15 inducer. Oral CPT administration increases circulating GDF15 levels in diet-induced obese (DIO) mice and genetic ob/ob mice, with elevated Gdf15 expression predominantly in the liver through activation of integrated stress response. In line with GDF15's anorectic effect, CPT suppresses food intake, thereby reducing body weight, blood glucose, and hepatic fat content in obese mice. Conversely, CPT loses these beneficial effects when Gdf15 is inhibited by a neutralizing antibody or AAV8-mediated liver-specific knockdown. Similarly, CPT failed to reduce food intake and body weight in GDF15's specific receptor GFRAL-deficient mice despite high levels of GDF15. Together, these results indicate that CPT is a promising anti-obesity agent through activation of GDF15-GFRAL pathway.
    DOI:  https://doi.org/10.1371/journal.pbio.3001517
  41. Autophagy. 2022 Feb 23. 1-16
    Defective autophagy contributes to endometrial epithelial-mesenchymal transition in intrauterine adhesions.
    Zhenhua Zhou, Huiyan Wang, Xiwen Zhang, Minmin Song, Simin Yao, Peipei Jiang, Dan Liu, Zhiyin Wang, Haining Lv, Ruotian Li, Ying Hong, Jianwu Dai, Yali Hu, Guangfeng Zhao.
      Intrauterine adhesions (IUA), characterized by endometrial fibrosis, is a common cause of uterine infertility. We previously demonstrated that partial epithelial-mesenchymal transition (EMT) and the loss of epithelial homeostasis play a vital role in the development of endometrial fibrosis. As a pro-survival strategy in maintaining cell and tissue homeostasis, macroautophagy/autophagy, conversely, may participate in this process. However, the role of autophagy in endometrial fibrosis remains unknown. Here, we demonstrated that autophagy is defective in endometria of IUA patients, which aggravates EMT and endometrial fibrosis, and defective autophagy is related to DIO2 (iodothyronine deiodinase 2) downregulation. In endometrial epithelial cells (EECs), pharmacological inhibition of autophagy by chloroquine (CQ) promoted EEC-EMT, whereas enhanced autophagy by rapamycin extenuated this process. Mechanistically, silencing DIO2 in EECs blocked autophagic flux and promoted EMT via the MAPK/ERK-MTOR pathway. Inversely, overexpression of DIO2 or triiodothyronine (T3) treatment could restore autophagy and partly reverse EEC-EMT. Furthermore, in an IUA-like mouse model, the autophagy in endometrium was defective accompanied by EEC-EMT, and CQ could inhibit autophagy and aggravate endometrial fibrosis, whereas rapamycin or T3 treatment could improve the autophagic levels and blunt endometrial fibrosis. Together, we demonstrated that defective autophagy played an important role in EEC-EMT in IUA via the DIO2-MAPK/ERK-MTOR pathway, which provided a potential target for therapeutic implications.Abbreviations: ACTA2/α-SMA: actin alpha 2, smooth muscle; AMPK: adenosine 5'-monophosphate-activated protein kinase; AKT/protein kinase B: AKT serine/threonine kinase; ATG: autophagy related; CDH1/E-cadherin: cadherin 1; CDH2/N-cadherin: cadherin 2; CQ: chloroquine; CTSD: cathepsin D; DIO2: iodothyronine deiodinase 2; DEGs: differentially expressed genes; EECs: endometrial epithelial cells; EMT: epithelial-mesenchymal transition; FN1: fibronectin 1; IUA: intrauterine adhesions; LAMP1: lysosomal associated membrane protein 1; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MTOR: mechanistic target of rapamycin kinase; Rapa: rapamycin; SQSTM1/p62: sequestosome 1; T3: triiodothyronine; T4: tetraiodothyronine; TFEB: transcription factor EB; PBS: phosphate-buffered saline; TEM: transmission electron microscopy; TGFB/TGFβ: transforming growth factor beta.
    Keywords:  Autophagy; epithelial-mesenchymal transition; intrauterine adhesions; iodothyronine deiodinase 2; thyroid hormone
    DOI:  https://doi.org/10.1080/15548627.2022.2038994
  42. Nat Rev Mol Cell Biol. 2022 Feb 21.
    Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology.
    Helmut Sies, Vsevolod V Belousov, Navdeep S Chandel, Michael J Davies, Dean P Jones, Giovanni E Mann, Michael P Murphy, Masayuki Yamamoto, Christine Winterbourn.
      'Reactive oxygen species' (ROS) is a generic term that defines a wide variety of oxidant molecules with vastly different properties and biological functions that range from signalling to causing cell damage. Consequently, the description of oxidants needs to be chemically precise to translate research on their biological effects into therapeutic benefit in redox medicine. This Expert Recommendation article pinpoints key issues associated with identifying the physiological roles of oxidants, focusing on H2O2 and O2.-. The generic term ROS should not be used to describe specific molecular agents. We also advocate for greater precision in measurement of H2O2, O2.- and other oxidants, along with more specific identification of their signalling targets. Future work should also consider inter-organellar communication and the interactions of redox-sensitive signalling targets within organs and whole organisms, including the contribution of environmental exposures. To achieve these goals, development of tools that enable site-specific and real-time detection and quantification of individual oxidants in cells and model organisms are needed. We also stress that physiological O2 levels should be maintained in cell culture to better mimic in vivo redox reactions associated with specific cell types. Use of precise definitions and analytical tools will help harmonize research among the many scientific disciplines working on the common goal of understanding redox biology.
    DOI:  https://doi.org/10.1038/s41580-022-00456-z
  43. FEBS Open Bio. 2022 Feb 24.
    Low level lysosomal membrane permeabilization for limited release and sub-lethal functions of cathepsin proteases in the cytosol and nucleus.
    Thomas Reinheckel, Martina Tholen.
      For a long time, lysosomes were purely seen as organelles in charge of garbage disposal within the cell. They destroy any cargo delivered into their lumen with a plethora of highly potent hydrolytic enzymes, including various proteases. In case of damage to their limiting membranes, the lysosomes release their soluble content with detrimental outcomes for the cell. In recent years however, this view of the lysosome changed towards acknowledging it as a platform for integration of manifold intra- and extracellular signals. Even impaired lysosomal membrane integrity is no longer considered to be a one-way street to cell death. Increasing evidence suggests that lysosomal enzymes, mainly cathepsin proteases, can be released in a spatially and temporarily restricted manner that is compatible with cellular survival. This way, cathepsins can act in the cytosol and the nucleus, where they affect important cellular processes such as cell division. Here, we review this evidence and discuss the routes and molecular mechanisms by which the cathepsins may reach their unusual destination.
    Keywords:  Cathepsin; Cell Cycle; Cell Death; Lysosome; Protease
    DOI:  https://doi.org/10.1002/2211-5463.13385
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