bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2024‒03‒10
thirty-six papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Connectivity mapping-based identification of pharmacological inhibitor targeting HDAC6 in aggressive pancreatic ductal adenocarcinoma.
  2. Cytidine deaminases APOBEC3C and APOBEC3D promote DNA replication stress resistance in pancreatic cancer cells.
  3. Lipid droplets and cellular lipid flux.
  4. Intracellular lipase and regulation of the lipid droplet.
  5. Transcriptomic signature of cancer cachexia by integration of machine learning, literature mining and meta-analysis.
  6. Body composition measurements and clinical outcomes in patients with resectable pancreatic adenocarcinoma - analysis from SWOG S1505.
  7. Severely polarized extracellular acidity around tumour cells.
  8. Metabolomics analysis reveals novel serum metabolite alterations in cancer cachexia.
  9. International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis.
  10. Compartmentalized role of xCT in supporting pancreatic tumor growth, inflammation and mood disturbance in mice.
  11. Growth Signaling Networks Orchestrate Cancer Metabolic Networks.
  12. Metabolic remodeling in cancer and senescence and its therapeutic implications.
  13. Mustn1 is a smooth muscle cell-secreted microprotein that modulates skeletal muscle extracellular matrix composition.
  14. Identification of Pancreatic Metastasis Cells and Cell Spheroids by the Organelle-Targeting Sensor Array.
  15. An in vivo screening platform identifies senolytic compounds that target p16INK4a+ fibroblasts in lung fibrosis.
  16. Measurement of Autophagic Activity in Cancer Cells with Flow Cytometric Analysis Using Cyto-ID Staining.
  17. Using Tumor Marker Gene Variants to Improve the Diagnostic Accuracy of DUPAN-2 and Carbohydrate Antigen 19-9 for Pancreatic Cancer.
  18. Riboformer: a deep learning framework for predicting context-dependent translation dynamics.
  19. Body mass index, weight change, and cancer prognosis: a meta-analysis and systematic review of 73 cohort studies.
  20. Live Cell Imaging and Real-Time Monitoring of Nucleolus Morphology and Mitophagy with a Red Fluorescent and Photostable rRNA-Specific Probe in Human Cancer Cells.
  21. Lack of SPNS1 results in accumulation of lysolipids and lysosomal storage disease in mouse models.
  22. CDK-independent role of D-type cyclins in regulating DNA mismatch repair.
  23. KRAS Mutation Detection with (2S,4R)-4-[18F]FGln for Noninvasive PDAC Diagnosis.
  24. Proteome-scale movements and compartment connectivity during the eukaryotic cell cycle.
  25. Targeting MHC-I inhibitory pathways for cancer immunotherapy.
  26. The search for CDK4/6 inhibitor biomarkers has been hampered by inappropriate proliferation assays.
  27. Advances in cancer mechanobiology: Metastasis, mechanics, and materials.
  28. Proteomic analysis of ferroptosis pathways reveals a role of CEPT1 in suppressing ferroptosis.
  29. Adjuvant Gemcitabine Versus Neoadjuvant/Adjuvant FOLFIRINOX in Resectable Pancreatic Cancer: The Randomized Multicenter Phase II NEPAFOX Trial.
  30. Improved identification of cancer mutational processes.
  31. Pink1 balances reticulophagy and mitophagy by regulating distinct E3 ubiquitin ligases.
  32. A deep learning model of tumor cell architecture elucidates response and resistance to CDK4/6 inhibitors.
  33. Phospholipid Membranes as Chemically and Functionally Tunable Materials.
  34. Mitochondrial ATP generation is more proteome efficient than glycolysis.
  35. TRPV4-dependent Ca2+ influx determines cholesterol dynamics at the plasma membrane.
  36. Transcriptome analysis of polyploid giant cancer cells and their progeny reveals a functional role for p21 in polyploidization and depolyploidization.
  1. NPJ Precis Oncol. 2024 Mar 07. 8(1): 66
    Connectivity mapping-based identification of pharmacological inhibitor targeting HDAC6 in aggressive pancreatic ductal adenocarcinoma.
    Pranita Atri, Ashu Shah, Gopalakrishnan Natarajan, Satyanarayana Rachagani, Sanchita Rauth, Koelina Ganguly, Joseph Carmicheal, Dario Ghersi, Jesse L Cox, Lynette M Smith, Maneesh Jain, Sushil Kumar, Moorthy P Ponnusamy, Parthasarathy Seshacharyulu, Surinder K Batra.
      Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to limited therapeutic options and expensive/burdensome drug discovery processes. Utilizing genomic-data-driven Connectivity Mapping (CMAP) to identify a drug closer to real-world PC targeting may improve pancreatic cancer (PC) patient outcomes. Initially, we mapped CMAP data to gene expression from 106 PC patients, identifying nine negatively connected drugs. These drugs were further narrowed down using a similar analysis for PC cell lines, human tumoroids, and patient-derived xenografts datasets, where ISOX emerged as the most potent agent to target PC. We used human and mouse syngeneic PC cells, human and mouse tumoroids, and in vivo mice to assess the ability of ISOX alone and in combination with 5FU to inhibit tumor growth. Global transcriptomic and pathway analysis of the ISOX-LINCS signature identified HDAC 6/cMyc as the target axis for ISOX. Specifically, we discovered that genetic and pharmacological targeting of HDAC 6 affected non-histone protein cMyc acetylation, leading to cMyc instability, thereby disrupting PC growth and metastasis by affecting cancer stemness. Finally, KrasG12D harboring tumoroids and mice responded effectively against ISOX and 5FU treatment by enhancing survival and controlling metastasis incidence. Overall, our data validate ISOX as a new drug to treat advanced PC patients without toxicity to normal cells. Our study supports the clinical utility of ISOX along with 5FU in future PC clinical trials.
    DOI:  https://doi.org/10.1038/s41698-024-00562-5
  2. Nat Cancer. 2024 Mar 06.
    Cytidine deaminases APOBEC3C and APOBEC3D promote DNA replication stress resistance in pancreatic cancer cells.
    Tajinder Ubhi, Olga Zaslaver, Andrew T Quaile, Dennis Plenker, Pinjiang Cao, Nhu-An Pham, Angéla Békési, Gun-Ho Jang, Grainne M O'Kane, Faiyaz Notta, Jason Moffat, Julie M Wilson, Steven Gallinger, Beáta G Vértessy, David A Tuveson, Hannes L Röst, Grant W Brown.
      Gemcitabine is a potent inhibitor of DNA replication and is a mainstay therapeutic for diverse cancers, particularly pancreatic ductal adenocarcinoma (PDAC). However, most tumors remain refractory to gemcitabine therapies. Here, to define the cancer cell response to gemcitabine, we performed genome-scale CRISPR-Cas9 chemical-genetic screens in PDAC cells and found selective loss of cell fitness upon disruption of the cytidine deaminases APOBEC3C and APOBEC3D. Following gemcitabine treatment, APOBEC3C and APOBEC3D promote DNA replication stress resistance and cell survival by deaminating cytidines in the nuclear genome to ensure DNA replication fork restart and repair in PDAC cells. We provide evidence that the chemical-genetic interaction between APOBEC3C or APOBEC3D and gemcitabine is absent in nontransformed cells but is recapitulated across different PDAC cell lines, in PDAC organoids and in PDAC xenografts. Thus, we uncover roles for APOBEC3C and APOBEC3D in DNA replication stress resistance and offer plausible targets for improving gemcitabine-based therapies for PDAC.
    DOI:  https://doi.org/10.1038/s43018-024-00742-z
  3. Nat Cell Biol. 2024 Mar 07.
    Lipid droplets and cellular lipid flux.
    Alyssa J Mathiowetz, James A Olzmann.
      Lipid droplets are dynamic organelles that store neutral lipids, serve the metabolic needs of cells, and sequester lipids to prevent lipotoxicity and membrane damage. Here we review the current understanding of the mechanisms of lipid droplet biogenesis and turnover, the transfer of lipids and metabolites at membrane contact sites, and the role of lipid droplets in regulating fatty acid flux in lipotoxicity and cell death.
    DOI:  https://doi.org/10.1038/s41556-024-01364-4
  4. Curr Opin Lipidol. 2024 Apr 01. 35(2): 85-92
    Intracellular lipase and regulation of the lipid droplet.
    Ainara G Cabodevilla, Ni Son, Ira J Goldberg.
      PURPOSE OF REVIEW: Lipid droplets are increasingly recognized as distinct intracellular organelles that have functions exclusive to the storage of energetic lipids. Lipid droplets modulate macrophage inflammatory phenotype, control the availability of energy for muscle function, store excess lipid, sequester toxic lipids, modulate mitochondrial activity, and allow transfer of fatty acids between tissues.RECENT FINDINGS: There have been several major advances in our understanding of the formation, dissolution, and function of this organelle during the past two years. These include new information on movement and partition of amphipathic proteins between the cytosol and lipid droplet surface, molecular determinants of lipid droplet formation, and pathways leading to lipid droplet hydrophobic lipid formation. Rapid advances in mitochondrial biology have also begun to define differences in their function and partnering with lipid droplets to modulate lipid storage versus oxidation.
    SUMMARY: This relationship of lipid droplets biology and cellular function provides new understanding of an important cellular organelle that influences muscle function, adipose lipid storage, and diseases of lipotoxicity.
    DOI:  https://doi.org/10.1097/MOL.0000000000000918
  5. Comput Biol Med. 2024 Feb 28. pii: S0010-4825(24)00317-2. [Epub ahead of print]172 108233
    Transcriptomic signature of cancer cachexia by integration of machine learning, literature mining and meta-analysis.
    Kening Zhao, Esmaeil Ebrahimie, Manijeh Mohammadi-Dehcheshmeh, Mathew G Lewsey, Lei Zheng, Nick J Hoogenraad.
      BACKGROUND: Cancer cachexia is a severe metabolic syndrome marked by skeletal muscle atrophy. A successful clinical intervention for cancer cachexia is currently lacking. The study of cachexia mechanisms is largely based on preclinical animal models and the availability of high-throughput transcriptomic datasets of cachectic mouse muscles is increasing through the extensive use of next generation sequencing technologies.METHODS: Cachectic mouse muscle transcriptomic datasets of ten different studies were combined and mined by seven attribute weighting models, which analysed both categorical variables and numerical variables. The transcriptomic signature of cancer cachexia was identified by attribute weighting algorithms and was used to evaluate the performance of eleven pattern discovery models. The signature was employed to find the best combination of drugs (drug repurposing) for developing cancer cachexia treatment strategies, as well as to evaluate currently used cachexia drugs by literature mining.
    RESULTS: Attribute weighting algorithms ranked 26 genes as the transcriptomic signature of muscle from mice with cancer cachexia. Deep Learning and Random Forest models performed better in differentiating cancer cachexia cases based on muscle transcriptomic data. Literature mining revealed that a combination of melatonin and infliximab has negative interactions with 2 key genes (Rorc and Fbxo32) upregulated in the transcriptomic signature of cancer cachexia in muscle.
    CONCLUSIONS: The integration of machine learning, meta-analysis and literature mining was found to be an efficient approach to identifying a robust transcriptomic signature for cancer cachexia, with implications for improving clinical diagnosis and management of this condition.
    Keywords:  Cancer cachexia; Drug discovery; Literature mining; Machine learning; Transcriptomics
    DOI:  https://doi.org/10.1016/j.compbiomed.2024.108233
  6. J Gastrointest Surg. 2024 Mar;pii: S1091-255X(23)07794-6. [Epub ahead of print]28(3): 232-235
    Body composition measurements and clinical outcomes in patients with resectable pancreatic adenocarcinoma - analysis from SWOG S1505.
    Davendra P S Sohal, Robert D Boutin, Leon Lenchik, Jiyoon Kim, M Shaalan Beg, Andrea Wang-Gillam, James Lloyd Wade, Katherine A Guthrie, E Gabriela Chiorean, Syed A Ahmad, Andrew M Lowy, Philip Agop Philip, Victor Tsu-Shih Chang.
      BACKGROUND: Sarcopenic obesity and muscle attenuation have been associated with survival in patients with borderline resectable and advanced pancreatic ductal adenocarcinoma (PDA); however, these relationships are unknown for patients with resectable PDA. This study examined the associations between skeletal muscle and adipose tissue as measured on baseline computed tomography (CT) and the overall survival (OS) of participants with resectable PDA in a secondary analysis of the Southwest Oncology Group S1505 clinical trial (identifier: NCT02562716).METHODS: The S1505 phase II clinical trial enrolled patients with resectable PDA who were randomized to receive modified FOLFIRINOX or gemcitabine and nab-paclitaxel as perioperative chemotherapy, followed by surgical resection. Baseline axial CT images at the L3 level were analyzed with externally validated software, and measurements were recorded for skeletal muscle area and skeletal muscle density, visceral adipose tissue area (VATA) and density, and subcutaneous adipose tissue area and density. The relationships between CT metrics and OS were analyzed using Cox regression models, with adjustment for baseline participant characteristics.
    RESULTS: Of 98 eligible participants with available baseline abdominal CT, 8 were excluded because of imaging quality (eg, orthopedic hardware), resulting in 90 evaluable cases: 51 men (57.0%; mean age, 63.2 years [SD, 8.5]; mean body mass index [BMI], 29.3 kg/m2 [SD, 6.4]), 80 White (89.0%), 6 Black (7.0%), and 4 unknown race (4.0%). Sarcopenia was present in 32 participants (35.9%), and sarcopenic obesity was present in 10 participants (11.2%). Univariable analyses for the 6 variables of interest indicated that the standardized mean difference (hazard ratio [HR], 0.75; 95% CI, 0.57-0.98; P = .04) was statistically significantly associated with OS. In models adjusted for sex, race, age, BMI, performance score, contrast use, sarcopenia, and sarcopenic obesity, VATA was statistically significantly associated with OS (HR, 1.58; 95% CI, 1.00-2.51; P = .05). No difference was observed in OS between participants according to sarcopenic obesity or sarcopenia categories. The median OS estimates were 25.1 months for participants without sarcopenic obesity, 18.6 months for participants with sarcopenic obesity, 23.6 months for participants without sarcopenia, and 27.9 months for participants with sarcopenia.
    CONCLUSION: This was the first study to systematically evaluate body composition parameters in a prospective multicenter trial of patients with resectable PDA who received perioperative chemotherapy. Visceral adipose tissue was associated with survival; however, there was no association between OS and sarcopenia or sarcopenic obesity. Further studies should evaluate these findings in more detail.
    Keywords:  Body composition; Measurements; Pancreatic adenocarcinoma
    DOI:  https://doi.org/10.1016/j.gassur.2023.12.022
  7. Nat Biomed Eng. 2024 Mar 04.
    Severely polarized extracellular acidity around tumour cells.
    Qiang Feng, Zachary Bennett, Anthony Grichuk, Raymundo Pantoja, Tongyi Huang, Brandon Faubert, Gang Huang, Mingyi Chen, Ralph J DeBerardinis, Baran D Sumer, Jinming Gao.
      Extracellular pH impacts many molecular, cellular and physiological processes, and hence is tightly regulated. Yet, in tumours, dysregulated cancer cell metabolism and poor vascular perfusion cause the tumour microenvironment to become acidic. Here by leveraging fluorescent pH nanoprobes with a transistor-like activation profile at a pH of 5.3, we show that, in cancer cells, hydronium ions are excreted into a small extracellular region. Such severely polarized acidity (pH <5.3) is primarily caused by the directional co-export of protons and lactate, as we show for a diverse panel of cancer cell types via the genetic knockout or inhibition of monocarboxylate transporters, and also via nanoprobe activation in multiple tumour models in mice. We also observed that such spot acidification in ex vivo stained snap-frozen human squamous cell carcinoma tissue correlated with the expression of monocarboxylate transporters and with the exclusion of cytotoxic T cells. Severely spatially polarized tumour acidity could be leveraged for cancer diagnosis and therapy.
    DOI:  https://doi.org/10.1038/s41551-024-01178-7
  8. Front Oncol. 2024 ;14 1286896
    Metabolomics analysis reveals novel serum metabolite alterations in cancer cachexia.
    Tushar H More, Karsten Hiller, Martin Seifert, Thomas Illig, Rudi Schmidt, Raphael Gronauer, Thomas von Hahn, Hauke Weilert, Axel Stang.
      Background: Cachexia is a body wasting syndrome that significantly affects well-being and prognosis of cancer patients, without effective treatment. Serum metabolites take part in pathophysiological processes of cancer cachexia, but apart from altered levels of select serum metabolites, little is known on the global changes of the overall serum metabolome, which represents a functional readout of the whole-body metabolic state. Here, we aimed to comprehensively characterize serum metabolite alterations and analyze associated pathways in cachectic cancer patients to gain new insights that could help instruct strategies for novel interventions of greater clinical benefit.Methods: Serum was sampled from 120 metastatic cancer patients (stage UICC IV). Patients were grouped as cachectic or non-cachectic according to the criteria for cancer cachexia agreed upon international consensus (main criterium: weight loss adjusted to body mass index). Samples were pooled by cachexia phenotype and assayed using non-targeted gas chromatography-mass spectrometry (GC-MS). Normalized metabolite levels were compared using t-test (p < 0.05, adjusted for false discovery rate) and partial least squares discriminant analysis (PLS-DA). Machine-learning models were applied to identify metabolite signatures for separating cachexia states. Significant metabolites underwent MetaboAnalyst 5.0 pathway analysis.
    Results: Comparative analyses included 78 cachectic and 42 non-cachectic patients. Cachectic patients exhibited 19 annotable, significantly elevated (including glucose and fructose) or decreased (mostly amino acids) metabolites associating with aminoacyl-tRNA, glutathione and amino acid metabolism pathways. PLS-DA showed distinct clusters (accuracy: 85.6%), and machine-learning models identified metabolic signatures for separating cachectic states (accuracy: 83.2%; area under ROC: 88.0%). We newly identified altered blood levels of erythronic acid and glucuronic acid in human cancer cachexia, potentially linked to pentose-phosphate and detoxification pathways.
    Conclusion: We found both known and yet unknown serum metabolite and metabolic pathway alterations in cachectic cancer patients that collectively support a whole-body metabolic state with impaired detoxification capability, altered glucose and fructose metabolism, and substrate supply for increased and/or distinct metabolic needs of cachexia-associated tumors. These findings together imply vulnerabilities, dependencies and targets for novel interventions that have potential to make a significant impact on future research in an important field of cancer patient care.
    Keywords:  GC-MS metabolomics; body metabolism; cancer cachexia; erythronic acid; glucuronic acid; metabolic pathways; serum metabolites
    DOI:  https://doi.org/10.3389/fonc.2024.1286896
  9. Autophagy. 2024 Mar 05.
    International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis.
    Xin Chen, Andrey S Tsvetkov, Han-Ming Shen, Ciro Isidoro, Nicholas T Ktistakis, Andreas Linkermann, Werner J H Koopman, Hans-Uwe Simon, Lorenzo Galluzzi, Shouqing Luo, Daqian Xu, Wei Gu, Olivier Peulen, Qian Cai, David C Rubinsztein, Jen-Tsan Chi, Donna D Zhang, Changfeng Li, Shinya Toyokuni, Jinbao Liu, Jong-Lyel Roh, Enyong Dai, Gabor Juhasz, Wei Liu, Jianhua Zhang, Minghua Yang, Jiao Liu, Ling-Qiang Zhu, Weiping Zou, Mauro Piacentini, Wen-Xing Ding, Zhenyu Yue, Yangchun Xie, Morten Petersen, David A Gewirtz, Michael A Mandell, Charleen T Chu, Debasish Sinha, Eftekhar Eftekharpour, Boris Zhivotovsky, Sébastien Besteiro, Dmitry I Gabrilovich, Do-Hyung Kim, Valerian E Kagan, Hülya Bayir, Guang-Chao Chen, Scott Ayton, Jan D Lünemann, Masaaki Komatsu, Stefan Krautwald, Ben Loos, Eric H Baehrecke, Jiayi Wang, Jon D Lane, Junichi Sadoshima, Wan Seok Yang, Minghui Gao, Christian Münz, Michael Thumm, Martin Kampmann, Di Yu, Marta M Lipinski, Jace W Jones, Xuejun Jiang, Herbert J Zeh, Rui Kang, Daniel J Klionsky, Guido Kroemer, Daolin Tang.
      Macroautophagy/autophagy is a complex degradation process with a dual role in cell death that is influenced by the cell types that are involved and the stressors they are exposed to. Ferroptosis is an iron-dependent oxidative form of cell death characterized by unrestricted lipid peroxidation in the context of heterogeneous and plastic mechanisms. Recent studies have shed light on the involvement of specific types of autophagy (e.g. ferritinophagy, lipophagy, and clockophagy) in initiating or executing ferroptotic cell death through the selective degradation of anti-injury proteins or organelles. Conversely, other forms of selective autophagy (e.g. reticulophagy and lysophagy) enhance the cellular defense against ferroptotic damage. Dysregulated autophagy-dependent ferroptosis has implications for a diverse range of pathological conditions. This review aims to present an updated definition of autophagy-dependent ferroptosis, discuss influential substrates and receptors, outline experimental methods, and propose guidelines for interpreting the results.
    Keywords:  Cell death; ferritinophagy; iron; lipid peroxidation; lipophagy; lysosome
    DOI:  https://doi.org/10.1080/15548627.2024.2319901
  10. Brain Behav Immun. 2024 Mar 04. pii: S0889-1591(24)00281-2. [Epub ahead of print]
    Compartmentalized role of xCT in supporting pancreatic tumor growth, inflammation and mood disturbance in mice.
    Olaya Lara, Pauline Janssen, Marco Mambretti, Laura De Pauw, Gamze Ates, Liselotte Mackens, Jolien De Munck, Jarne Walckiers, Zhaolong Pan, Pauline Beckers, Elisa Espinet, Hideyo Sato, Mark De Ridder, Daniel L Marks, Kurt Barbé, Joeri L Aerts, Emmanuel Hermans, Ilse Rooman, Ann Massie.
      xCT (Slc7a11), the specific subunit of the cystine/glutamate antiporter, is present in the brain and on immune cells, where it is known to modulate behavior and inflammatory responses. In a variety of cancers -including pancreatic ductal adenocarcinoma (PDAC)-, xCT is upregulated by tumor cells to support their growth and spread. Therefore, we studied the impact of xCT deletion in pancreatic tumor cells (Panc02) and/or the host (xCT-/- mice) on tumor burden, inflammation, cachexia and mood disturbances. Deletion of xCT in the tumor strongly reduced tumor growth. Targeting xCT in the host and not the tumor resulted only in a partial reduction of tumor burden, while it did attenuate tumor-related systemic inflammation and prevented an increase in immunosuppressive regulatory T cells. The latter effect could be replicated by specific xCT deletion in immune cells. xCT deletion in the host or the tumor differentially modulated neuroinflammation. When mice were grafted with xCT-deleted tumor cells, hypothalamic inflammation was reduced and, accordingly, food intake improved. Tumor bearing xCT-/- mice showed a trend of reduced hippocampal neuroinflammation with less anxiety- and depressive-like behavior. Taken together, targeting xCT may have beneficial effects on pancreatic cancer-related comorbidities, beyond reducing tumor burden. The search for novel and specific xCT inhibitors is warranted as they may represent a holistic therapy in pancreatic cancer.
    Keywords:  (neuro)inflammation; Cystine/glutamate antiporter system xc-; cachexia; mood disturbances; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.bbi.2024.03.001
  11. Cold Spring Harb Perspect Med. 2024 Mar 04. pii: a041543. [Epub ahead of print]
    Growth Signaling Networks Orchestrate Cancer Metabolic Networks.
    Brendan D Manning, Christian C Dibble.
      Normal cells grow and divide only when instructed to by signaling pathways stimulated by exogenous growth factors. A nearly ubiquitous feature of cancer cells is their capacity to grow independent of such signals, in an uncontrolled, cell-intrinsic manner. This property arises due to the frequent oncogenic activation of core growth factor signaling pathway components, including receptor tyrosine kinases, PI3K-AKT, RAS-RAF, mTORC1, and MYC, leading to the aberrant propagation of pro-growth signals independent of exogenous growth factors. The growth of both normal and cancer cells requires the acquisition of nutrients and their anabolic conversion to the primary macromolecules underlying biomass production (protein, nucleic acids, and lipids). The core growth factor signaling pathways exert tight regulation of these metabolic processes and the oncogenic activation of these pathways drive the key metabolic properties of cancer cells and tumors. Here, we review the molecular mechanisms through which these growth signaling pathways control and coordinate cancer metabolism.
    DOI:  https://doi.org/10.1101/cshperspect.a041543
  12. Trends Endocrinol Metab. 2024 Mar 06. pii: S1043-2760(24)00037-7. [Epub ahead of print]
    Metabolic remodeling in cancer and senescence and its therapeutic implications.
    Yeonju Kim, Yeji Jang, Mi-Sung Kim, Chanhee Kang.
      Cellular metabolism is a flexible and plastic network that often dictates physiological and pathological states of the cell, including differentiation, cancer, and aging. Recent advances in cancer metabolism represent a tremendous opportunity to treat cancer by targeting its altered metabolism. Interestingly, despite their stable growth arrest, senescent cells - a critical component of the aging process - undergo metabolic changes similar to cancer metabolism. A deeper understanding of the similarities and differences between these disparate pathological conditions will help identify which metabolic reprogramming is most relevant to the therapeutic liabilities of senescence. Here, we compare and contrast cancer and senescence metabolism and discuss how metabolic therapies can be established as a new modality of senotherapy for healthy aging.
    Keywords:  aging; cancer; metabolism; senescence; senotherapy
    DOI:  https://doi.org/10.1016/j.tem.2024.02.008
  13. Mol Metab. 2024 Mar 06. pii: S2212-8778(24)00043-7. [Epub ahead of print] 101912
    Mustn1 is a smooth muscle cell-secreted microprotein that modulates skeletal muscle extracellular matrix composition.
    Serge Ducommun, Paulo R Jannig, Igor Cervenka, Marta Murgia, Melanie J Mittenbühler, Ekaterina Chernogubova, José M Dias, Baptiste Jude, Jorge C Correia, Jonathan G Van Vranken, Gabriel Ocana-Santero, Margareta Porsmyr-Palmertz, Sarah McCann Haworth, Vicente Martínez-Redondo, Zhengye Liu, Mattias Carlström, Matthias Mann, Johanna T Lanner, Ana I Teixeira, Lars Maegdefessel, Bruce M Spiegelman, Jorge L Ruas.
      OBJECTIVE: Skeletal muscle plasticity and remodeling are critical for adapting tissue function to use, disuse, and regeneration. The aim of this study was to identify genes and molecular pathways that regulate the transition from atrophy to compensatory hypertrophy or recovery from injury. Here, we have used a mouse model of hindlimb unloading and reloading, which causes skeletal muscle atrophy, and compensatory regeneration and hypertrophy, respectively.METHODS: We analyzed mouse skeletal muscle at the transition from hindlimb unloading to reloading for changes in transcriptome and extracellular fluid proteome. We then used qRT-PCR, immunohistochemistry, and bulk and single-cell RNA sequencing data to determine Mustn1 gene and protein expression, including changes in gene expression in mouse and human skeletal muscle with different challenges such as exercise and muscle injury. We generated Mustn1-deficient genetic mouse models and characterized them in vivo and ex vivo with regard to muscle function and whole-body metabolism. We isolated smooth muscle cells and functionally characterized them, and performed transcriptomics and proteomics analysis of skeletal muscle and aorta of Mustn1-deficient mice.
    RESULTS: We show that Mustn1 (Musculoskeletal embryonic nuclear protein 1, also known as Mustang) is highly expressed in skeletal muscle during the early stages of hindlimb reloading. Mustn1 expression is transiently elevated in mouse and human skeletal muscle in response to intense exercise, resistance exercise, or injury. We find that Mustn1 expression is highest in smooth muscle-rich tissues, followed by skeletal muscle fibers. Muscle from heterozygous Mustn1-deficient mice exhibit differences in gene expression related to extracellular matrix and cell adhesion, compared to wild-type littermates. Mustn1-deficient mice have normal muscle and aorta function and whole-body glucose metabolism. Loss of Mustn1 in vascular smooth muscle cells does not affect their proliferative or migratory functions. We show that Mustn1 can be secreted from smooth muscle cells, and that it is present in arterioles of the muscle microvasculature and in muscle extracellular fluid, particularly during the hindlimb reloading phase. Proteomics analysis of muscle from Mustn1-deficient mice confirms differences in extracellular matrix composition, and female mice display higher collagen content after chemically induced muscle injury compared to wild-type littermates.
    CONCLUSIONS: We show that, in addition to its previously reported intracellular localization, Mustn1 is a microprotein secreted from smooth muscle cells into the muscle extracellular space. We explore its role in muscle ECM deposition and remodeling in homeostasis and upon muscle injury. The role of Mustn1 in fibrosis and immune infiltration upon muscle injury and dystrophies remains to be investigated, as does its potential for therapeutic interventions.
    Keywords:  Extracellular Matrix; Leiokine; Microprotein; Muscle regeneration; Mustn1; Smooth Muscle
    DOI:  https://doi.org/10.1016/j.molmet.2024.101912
  14. Adv Healthc Mater. 2024 Mar 08. e2400241
    Identification of Pancreatic Metastasis Cells and Cell Spheroids by the Organelle-Targeting Sensor Array.
    Guoyang Zhang, Zirui Wang, Lijun Ma, Jiguang Li, Jiahao Han, Mingguang Zhu, Zixuan Zhang, Shilong Zhang, Xin Zhang, Zhuo Wang.
      Pancreatic cancer is a highly malignant and metastatic cancer. Pancreatic cancer can lead to liver metastases, gallbladder metastases, and duodenum metastases. The identification of pancreatic cancer cells is essential for the diagnosis of metastatic cancer and exploration of carcinoma in situ. Organelles play an important role in maintaining the function of cells, the various cells show significant difference in organelle microenvironment. Herein, six probes were synthesized for targeting mitochondria, lysosomes, cell membranes, endoplasmic reticulum, Golgi apparatus, and lipid droplets. The six fluorescent probes formed OT-SA (an organelles-targeted sensor array) to image pancreatic metastatic cancer cells and cell spheroids. The homology of metastatic cancer cells brings the challenge for identification of these cells. The residual network (ResNet) model has been proven to automatically extract and select image features, which can figure out a subtle difference among the similar samples. Hence, OT-SA was developed to identify pancreatic metastasis cells and cell spheroids combination with ResNet analysis. The identification accuracy for the pancreatic metastasis cells (> 99%) and pancreatic metastasis cell spheroids (> 99%) in test set was successfully achieved respectively. The organelles-targeting sensor array provided a method for the identification of pancreatic cancer metastasis in cells and cell spheroids. This article is protected by copyright. All rights reserved.
    Keywords:  cell spheroids; deep learning; organelle-targeted sensor array; pancreatic cancer cells; recognization
    DOI:  https://doi.org/10.1002/adhm.202400241
  15. J Clin Invest. 2024 Mar 07. pii: e173371. [Epub ahead of print]
    An in vivo screening platform identifies senolytic compounds that target p16INK4a+ fibroblasts in lung fibrosis.
    Jin Young Lee, Nabora S Reyes, Supriya Ravishankar, Minqi Zhou, Maria Krasilnikov, Christian Ringler, Grace Pohan, Chris Wilson, Kenny Kean-Hooi Ang, Paul J Wolters, Tatsuya Tsukui, Dean Sheppard, Michelle R Arkin, Tien Peng.
      The appearance of senescent cells in age-related diseases has spurred the search for compounds that can target senescent cells in tissues ("senolytics"). However, a major caveat with current senolytic screens is the use of cell lines as targets where senescence is induced in vitro, which does not necessarily reflect the identity and function of pathogenic senescent cells in vivo. Here, we developed a new pipeline leveraging a fluorescent murine reporter that allows for isolation and quantification of p16Ink4a+ cells in diseased tissues. By high-throughput screening in vitro, precision cut lung slice (PCLS) screening ex vivo, and phenotypic screening in vivo, we identified a HSP90 inhibitor (XL888) as a potent senolytic in tissue fibrosis. XL888 treatment eliminated pathogenic p16Ink4a+ fibroblasts in a murine model of lung fibrosis and reduced fibrotic burden. Finally, XL888 preferentially targeted p16INK4a-high human lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis (IPF), and reduced p16INK4a+ fibroblasts from IPF PCLS ex vivo. This study provides proof of concept for a platform where p16INK4a+ cells are directly isolated from diseased tissues to identify compounds with in vivo and ex vivo efficacy in mouse and human respectively and provides a senolytic screening platform for other age-related diseases.
    Keywords:  Aging; Cellular senescence; Drug screens; Fibrosis; Pulmonology
    DOI:  https://doi.org/10.1172/JCI173371
  16. Methods Mol Biol. 2024 Mar 07.
    Measurement of Autophagic Activity in Cancer Cells with Flow Cytometric Analysis Using Cyto-ID Staining.
    Merve Şansaçar, Emel Başak Gencer Akçok.
      Autophagy is an evolutionarily conserved process providing the energy that cells need to survive, especially in stress situations, through catabolic processes. Considering the dual role of autophagy in cancer cells depending on the cellular context, it is crucial to comprehend the effect of drug candidates put forward to prevent cancer through the autophagy pathway. The CYTO-ID® Autophagy Detection Kit allows a rapid, specific and quantitative measurement of autophagic activity at the cellular level using a 488 nm-excitable green fluorescent detection reagent via flow cytometer. In this chapter, we present the CYTO-ID® Autophagy Detection method with a stepwise protocol to monitor the autophagy flux after the application of any compound to suspension cancer cell lines with flow cytometric analysis.
    Keywords:  Autophagic compartments; Autophagic flux; Autophagosome; Autophagy; Cancer; Cyto-ID; Flow cytometry
    DOI:  https://doi.org/10.1007/7651_2024_526
  17. J Clin Oncol. 2024 Mar 08. JCO2301573
    Using Tumor Marker Gene Variants to Improve the Diagnostic Accuracy of DUPAN-2 and Carbohydrate Antigen 19-9 for Pancreatic Cancer.
    Yohei Ando, Mohamad Dbouk, Takeichi Yoshida, Helena Saba, Elizabeth Abou Diwan, Kanako Yoshida, Ali Dbouk, Amanda L Blackford, Ming-Tseh Lin, Anne Marie Lennon, Richard A Burkhart, Jin He, Lori Sokoll, James R Eshleman, Marcia Irene Canto, Michael Goggins.
      PURPOSE: Circulating carbohydrate antigen 19-9 (CA19-9) levels reflect FUT3 and FUT2 fucosyltransferase activity. Measuring the related glycan, DUPAN-2, can be useful in individuals unable to synthesize CA19-9. We hypothesized that similar to CA19-9, FUT functional groups determined by variants in FUT3 and FUT2 influence DUPAN-2 levels, and having tumor marker reference ranges for each functional group would improve diagnostic performance.MATERIALS AND METHODS: Using a training/validation study design, FUT2/FUT3 genotypes were determined in 938 individuals from Johns Hopkins Hospital: 607 Cancer of the Pancreas Screening (CAPS) study subjects with unremarkable pancreata and 331 with pancreatic ductal adenocarcinoma (PDAC). Serum DUPAN-2 and CA19-9 levels were measured by immunoassay.
    RESULTS: In controls, three functional FUT groups were identified with significant differences in DUPAN-2 levels: FUT3-intact, FUT3-null/FUT2-intact, and FUT3-null/FUT2-null. DUPAN-2 training set diagnostic cutoffs for each FUT group yielded higher diagnostic sensitivity in the validation set for patients with stage I/II PDAC than uniform cutoffs (60.4% [95% CI, 50.2 to 70.0] v 39.8% [30.0 to 49.8]), at approximately 99% (96.7 to 99.6) specificity. Combining FUT/CA19-9 and FUT/DUPAN-2 tests yielded 78.4% (72.3 to 83.7) sensitivity for stage I/II PDAC, at 97.7% (95.3 to 99.1) specificity in the combined sets, with higher AUC (stage I/II: 0.960 v 0.935 for CA19-9 + DUPAN-2 without the FUT test; P < .001); for stage I PDAC, sensitivity was 62.0% (49.1 to 73.2; AUC, 0.919 v 0.883; P = .03). CA19-9 levels in FUT3-null/FUT2-null PDAC subjects were higher than in FUT3-null/FUT2-intact subjects (median/IQR; 24.9/57.4 v <1/2.3 U/mL; P = .0044). In a simulated CAPS cohort, AUC precision recall (AUCPR) scores were 0.51 for CA19-9 alone, 0.64 for FUT/CA19-9, 0.73 for CA19-9/DUPAN-2, and 0.84 for FUT/CA19-9/DUPAN-2.
    CONCLUSION: Using a tumor marker gene test to individualize CA19-9 and DUPAN-2 reference ranges achieves high diagnostic performance for stage I/II pancreatic cancer.
    DOI:  https://doi.org/10.1200/JCO.23.01573
  18. Nat Commun. 2024 Mar 05. 15(1): 2011
    Riboformer: a deep learning framework for predicting context-dependent translation dynamics.
    Bin Shao, Jiawei Yan, Jing Zhang, Lili Liu, Ye Chen, Allen R Buskirk.
      Translation elongation is essential for maintaining cellular proteostasis, and alterations in the translational landscape are associated with a range of diseases. Ribosome profiling allows detailed measurements of translation at the genome scale. However, it remains unclear how to disentangle biological variations from technical artifacts in these data and identify sequence determinants of translation dysregulation. Here we present Riboformer, a deep learning-based framework for modeling context-dependent changes in translation dynamics. Riboformer leverages the transformer architecture to accurately predict ribosome densities at codon resolution. When trained on an unbiased dataset, Riboformer corrects experimental artifacts in previously unseen datasets, which reveals subtle differences in synonymous codon translation and uncovers a bottleneck in translation elongation. Further, we show that Riboformer can be combined with in silico mutagenesis to identify sequence motifs that contribute to ribosome stalling across various biological contexts, including aging and viral infection. Our tool offers a context-aware and interpretable approach for standardizing ribosome profiling datasets and elucidating the regulatory basis of translation kinetics.
    DOI:  https://doi.org/10.1038/s41467-024-46241-8
  19. ESMO Open. 2024 Mar 04. pii: S2059-7029(24)00009-7. [Epub ahead of print]9(3): 102241
    Body mass index, weight change, and cancer prognosis: a meta-analysis and systematic review of 73 cohort studies.
    H Wen, G Deng, X Shi, Z Liu, A Lin, Q Cheng, J Zhang, P Luo.
      BACKGROUND: Identifying the association between body mass index (BMI) or weight change and cancer prognosis is essential for the development of effective cancer treatments. We aimed to assess the strength and validity of the evidence of the association between BMI or weight change and cancer prognosis by a systematic evaluation and meta-analysis of relevant cohort studies.METHODS: We systematically searched the PubMed, Web of Science, EconLit, Embase, Food Sciences and Technology Abstracts, PsycINFO, and Cochrane databases for literature published up to July 2023. Inclusion criteria were cohort studies with BMI or weight change as an exposure factor, cancer as a diagnostic outcome, and data type as an unadjusted hazard ratio (HR) or headcount ratio. Random- or fixed-effects models were used to calculate the pooled HR along with the 95% confidence interval (CI).
    RESULTS: Seventy-three cohort studies were included in the meta-analysis. Compared with normal weight, overweight or obesity was a risk factor for overall survival (OS) in patients with breast cancer (HR 1.37, 95% CI 1.22-1.53; P < 0.0001), while obesity was a protective factor for OS in patients with gastrointestinal tumors (HR 0.67, 95% CI 0.56-0.80; P < 0.0001) and lung cancer (HR 0.67, 95% CI 0.48-0.92; P = 0.01) compared with patients without obesity. Compared with normal weight, underweight was a risk factor for OS in patients with breast cancer (HR 1.15, 95% CI 0.98-1.35; P = 0.08), gastrointestinal tumors (HR 1.54, 95% CI 1.32-1.80; P < 0.0001), and lung cancer (HR 1.28, 95% CI 1.22-1.35; P < 0.0001). Compared with nonweight change, weight loss was a risk factor for OS in patients with gastrointestinal cancer.
    CONCLUSIONS: Based on the results of the meta-analysis, we concluded that BMI, weight change, and tumor prognosis were significantly correlated. These findings may provide a more reliable argument for the development of more effective oncology treatment protocols.
    Keywords:  body mass index (BMI); cancer; meta-analysis; obesity; survival; weight change
    DOI:  https://doi.org/10.1016/j.esmoop.2024.102241
  20. ACS Sens. 2024 Mar 07.
    Live Cell Imaging and Real-Time Monitoring of Nucleolus Morphology and Mitophagy with a Red Fluorescent and Photostable rRNA-Specific Probe in Human Cancer Cells.
    Jun-Ren Luo, Wei Long, Ze-Xin Chen, Shi-Min Wang, Yao-Xun Zeng, Yu-Jing Lu, Bo-Xin Zheng, Meng-Ting She, Wing-Leung Wong.
      rRNAs are prevalent in living organisms. They are produced in nucleolus and mitochondria and play essential cellular functions. In addition to the primary biofunction in protein synthesis, rRNAs have been recognized as the emerging signaling molecule and drug target for studies on nucleolus morphology, mitochondrial autophagy, and tumor cell malignancy. Currently, only a few rRNA-selective probes have been developed, and most of them encounter the drawbacks of low water solubility, poor nuclear membrane permeability, short emission wavelength, low stability against photobleaching, and high cytotoxicity. These unfavorable properties of rRNA probes limit their potential applications. In the present study, we reported a new rRNA-selective and near-infrared fluorescent turn-on probe, 4MPS-TO, capable of tracking rRNA in live human cancer cells. The real-time monitoring performance in nucleolus morphology and mitochondrial autophagy is demonstrated in HeLa cells. The probe shows great application potential for being used as a rRNA-selective, sensitive, and photostable imaging tool in chemical biology study and drug screening.
    Keywords:  autophagy; live-cell imaging; molecular rRNA sensor; nucleolus morphology; red fluorescent probe
    DOI:  https://doi.org/10.1021/acssensors.3c02764
  21. JCI Insight. 2024 Mar 07. pii: e175462. [Epub ahead of print]
    Lack of SPNS1 results in accumulation of lysolipids and lysosomal storage disease in mouse models.
    Hoa Tt Ha, SiYi Liu, Xuan Ta Nguyen, Linh K Vo, Nancy Cp Leong, Dat T Nguyen, Shivaranjani Balamurugan, Pei Yen Lim, YaJun Wu, Eunju Seong, Toan Q Nguyen, Jeongah Oh, Markus R Wenk, Amaury Cazenave-Gassiot, Zuhal Yapici, Wei-Yi Ong, Margit Burmeister, Long N Nguyen.
      Accumulation of sphingolipids, especially sphingosines, in the lysosomes is a key driver of several lysosomal storage diseases. The transport mechanism for sphingolipids from the lysosome remains unclear. Here, we identified SPNS1, which shares the highest homology to SPNS2 - a sphingosine-1-phosphate (S1P) transporter, functions as a transporter for lysolipids from the lysosome. We generated Spns1 knockout cells and mice and employed lipidomic and metabolomic approaches to reveal SPNS1 ligand identity. Global knockout of Spns1 caused embryonic lethality between E12.5-E13.5 and an accumulation of sphingosine, lysophosphatidylcholines (LPC) and lysophosphatidylethanolamines (LPE) in the fetal livers. Similarly, metabolomic analysis of livers from postnatal Spns1 knockout (Spns1-KO) mice presented an accumulation of sphingosines and lysoglycerophospholipids including LPC and LPE. Subsequently, biochemical assays showed that SPNS1 is required for LPC and sphingosine release from lysosomes. The accumulation of these lysolipids in the lysosomes of Spns1-KO mice affected liver functions and altered the PI3K-AKT signaling pathway. Furthermore, we identified three human siblings with a homozygous variant in the SPNS1 gene. These patients suffer from developmental delay, neurological impairment, intellectual disability, and exhibiting cerebellar hypoplasia. These results reveal a critical role of SPNS1 as a promiscuous lysolipid transporter in the lysosomes and link its physiological functions with lysosomal storage diseases.
    Keywords:  Aging; Autophagy; Embryonic development; Metabolism; Mouse models
    DOI:  https://doi.org/10.1172/jci.insight.175462
  22. Mol Cell. 2024 Feb 29. pii: S1097-2765(24)00129-1. [Epub ahead of print]
    CDK-independent role of D-type cyclins in regulating DNA mismatch repair.
    Gergely Rona, Bearach Miwatani-Minter, Qingyue Zhang, Hailey V Goldberg, Marc A Kerzhnerman, Jesse B Howard, Daniele Simoneschi, Ethan Lane, John W Hobbs, Elizabeth Sassani, Andrew A Wang, Sarah Keegan, Daniel J Laverty, Cortt G Piett, Lorinc S Pongor, Miranda Li Xu, Joshua Andrade, Anish Thomas, Piotr Sicinski, Manor Askenazi, Beatrix Ueberheide, David Fenyö, Zachary D Nagel, Michele Pagano.
      Although mismatch repair (MMR) is essential for correcting DNA replication errors, it can also recognize other lesions, such as oxidized bases. In G0 and G1, MMR is kept in check through unknown mechanisms as it is error-prone during these cell cycle phases. We show that in mammalian cells, D-type cyclins are recruited to sites of oxidative DNA damage in a PCNA- and p21-dependent manner. D-type cyclins inhibit the proteasomal degradation of p21, which competes with MMR proteins for binding to PCNA, thereby inhibiting MMR. The ability of D-type cyclins to limit MMR is CDK4- and CDK6-independent and is conserved in G0 and G1. At the G1/S transition, the timely, cullin-RING ubiquitin ligase (CRL)-dependent degradation of D-type cyclins and p21 enables MMR activity to efficiently repair DNA replication errors. Persistent expression of D-type cyclins during S-phase inhibits the binding of MMR proteins to PCNA, increases the mutational burden, and promotes microsatellite instability.
    Keywords:  AMBRA1; CDK4; D-type cyclins; DNA repair; DNA repair pathway choice; G0 DNA repair; G1 DNA repair; PCNA; base excision repair; cell cycle; cullin-RING ubiquitin ligases; cyclin D1; genome stability; mismatch repair; oxidative DNA damage
    DOI:  https://doi.org/10.1016/j.molcel.2024.02.010
  23. Mol Pharm. 2024 Mar 08.
    KRAS Mutation Detection with (2S,4R)-4-[18F]FGln for Noninvasive PDAC Diagnosis.
    Song Liu, Futao Liu, Xingguo Hou, Qian Zhang, Ya'nan Ren, Hua Zhu, Zhi Yang, Xiaoxia Xu.
      Pancreatic ductal adenocarcinoma (PDAC), which has a poor prognosis and nonspecific symptoms and progresses rapidly, is the most common pancreatic cancer type. Inhibitors targeting KRAS G12D and G12C mutations have been pivotal in PDAC treatment. Cancer cells with different KRAS mutations exhibit various degrees of glutamine dependency; in particular, cells with KRAS G12D mutations exhibit increased glutamine uptake. (2S,4R)-4-[18F]FGln has recently been developed for clinical cancer diagnosis and tumor cell metabolism analysis. Thus, we verified the heterogeneity of glutamine dependency in PDAC models with different KRAS mutations by a visual and noninvasive method with (2S,4R)-4-[18F]FGln. Two tumor-bearing mouse models (bearing the KRAS G12D or G12C mutation) were injected with (2S,4R)-4-[18F]FGln, and positron emission tomography (PET) imaging features and biodistribution were observed and analyzed. The SUVmax in the regions of interest (ROI) was significantly higher in PANC-1 (G12D) tumors than in MIA PaCa-2 (G12C) tumors. Biodistribution analysis revealed higher tumor accumulation of (2S,4R)-4-[18F]FGln and other metrics, such as T/M and T/B, in the PANC-1 mouse models compared to those in the MIAPaCa-2 mouse models. In conclusion, PDAC cells with the KRAS G12D and G12C mutations exhibit various degrees of (2S,4R)-4-[18F]FGln uptake, indicating that (2S,4R)-4-[18F]FGln might be applied to detect KRAS G12C and G12D mutations and provide treatment guidance.
    Keywords:  (2S,4R)-4-[18F]FGln; KRAS mutation; PET imaging
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.4c00082
  24. Cell. 2024 Mar 01. pii: S0092-8674(24)00180-6. [Epub ahead of print]
    Proteome-scale movements and compartment connectivity during the eukaryotic cell cycle.
    Athanasios Litsios, Benjamin T Grys, Oren Z Kraus, Helena Friesen, Catherine Ross, Myra Paz David Masinas, Duncan T Forster, Mary T Couvillion, Stefanie Timmermann, Maximilian Billmann, Chad Myers, Nils Johnsson, L Stirling Churchman, Charles Boone, Brenda J Andrews.
      Cell cycle progression relies on coordinated changes in the composition and subcellular localization of the proteome. By applying two distinct convolutional neural networks on images of millions of live yeast cells, we resolved proteome-level dynamics in both concentration and localization during the cell cycle, with resolution of ∼20 subcellular localization classes. We show that a quarter of the proteome displays cell cycle periodicity, with proteins tending to be controlled either at the level of localization or concentration, but not both. Distinct levels of protein regulation are preferentially utilized for different aspects of the cell cycle, with changes in protein concentration being mostly involved in cell cycle control and changes in protein localization in the biophysical implementation of the cell cycle program. We present a resource for exploring global proteome dynamics during the cell cycle, which will aid in understanding a fundamental biological process at a systems level.
    Keywords:  Saccharomyces cerevisiae; automated image analysis; cell cycle; deep learning; differential scaling; high-content screening; protein localization; proteomics; spatiotemporal proteome; systems biology
    DOI:  https://doi.org/10.1016/j.cell.2024.02.014
  25. Trends Immunol. 2024 Mar 02. pii: S1471-4906(24)00022-X. [Epub ahead of print]
    Targeting MHC-I inhibitory pathways for cancer immunotherapy.
    Jun Wang, Qiao Lu, Xufeng Chen, Iannis Aifantis.
      The MHC-I antigen presentation (AP) pathway is key to shaping mammalian CD8+ T cell immunity, with its aberrant expression closely linked to low tumor immunogenicity and immunotherapy resistance. While significant attention has been given to genetic mutations and downregulation of positive regulators that are essential for MHC-I AP, there is a growing interest in understanding how tumors actively evade MHC-I expression and/or AP through the induction of MHC-I inhibitory pathways. This emerging field of study may offer more viable therapeutic targets for future cancer immunotherapy. Here, we explore potential mechanisms by which cancer cells evade MHC-I AP and function and propose therapeutic strategies that might target these MHC-I inhibitors to restore impaired T cell immunity within the tumor microenvironment (TME).
    Keywords:  CD8 T cell; Immune inhibitory mechanisms; MHC-I; antigen presentation; cancer immune evasion; cancer immunotherapy
    DOI:  https://doi.org/10.1016/j.it.2024.01.009
  26. NPJ Breast Cancer. 2024 Mar 04. 10(1): 19
    The search for CDK4/6 inhibitor biomarkers has been hampered by inappropriate proliferation assays.
    Reece Foy, Kah Xin Lew, Adrian T Saurin.
      CDK4/6 inhibitors are effective at treating advanced HR+ /HER2- breast cancer, however biomarkers that can predict response are urgently needed. We demonstrate here that previous large-scale screens designed to identify which tumour types or genotypes are most sensitive to CDK4/6 inhibitors have misrepresented the responsive cell lines because of a reliance on metabolic proliferation assays. CDK4/6-inhibited cells arrest in G1 but continue to grow in size, thereby producing more mitochondria. We show that this growth obscures the arrest using ATP-based proliferation assays but not if DNA-based assays are used instead. Furthermore, lymphoma lines, previously identified as the most sensitive, simply appear to respond the best using ATP-based assays because they fail to overgrow during the G1 arrest. Similarly, the CDK4/6 inhibitor abemaciclib appears to inhibit proliferation better than palbociclib because it also restricts cellular overgrowth through off-target effects. DepMap analysis of screening data using reliable assay types, demonstrates that palbociclib-sensitive cell types are also sensitive to Cyclin D1, CDK4 and CDK6 knockout/knockdown, whereas the palbociclib-resistant lines are sensitive to Cyclin E1, CDK2 and SKP2 knockout/knockdown. Potential biomarkers of palbociclib-sensitive cells are increased expression of CCND1 and RB1, and reduced expression of CCNE1 and CDKN2A. Probing DepMap with similar data from metabolic assays fails to reveal these associations. Together, this demonstrates why CDK4/6 inhibitors, and any other anti-cancer drugs that arrest the cell cycle but permit continued cell growth, must now be re-screened against a wide-range of cell types using an appropriate proliferation assay. This would help to better inform clinical trials and to identify much needed biomarkers of response.
    DOI:  https://doi.org/10.1038/s41523-024-00624-8
  27. APL Bioeng. 2024 Mar;8(1): 011502
    Advances in cancer mechanobiology: Metastasis, mechanics, and materials.
    Abigail J Clevenger, Maygan K McFarlin, John Paul M Gorley, Spencer C Solberg, Anirudh K Madyastha, Shreya A Raghavan.
      Within the tumor microenvironment (TME), tumor cells are exposed to numerous mechanical forces, both internally and externally, which contribute to the metastatic cascade. From the initial growth of the tumor to traveling through the vasculature and to the eventual colonization of distant organs, tumor cells are continuously interacting with their surroundings through physical contact and mechanical force application. The mechanical forces found in the TME can be simplified into three main categories: (i) shear stress, (ii) tension and strain, and (iii) solid stress and compression. Each force type can independently impact tumor growth and progression. Here, we review recent bioengineering strategies, which have been employed to establish the connection between mechanical forces and tumor progression. While many cancers are explored in this review, we place great emphasis on cancers that are understudied in their response to mechanical forces, such as ovarian and colorectal cancers. We discuss the major steps of metastatic transformation and present novel, recent advances in model systems used to study how mechanical forces impact the study of the metastatic cascade. We end by summarizing systems that incorporate multiple forces to expand the complexity of our understanding of how tumor cells sense and respond to mechanical forces in their environment. Future studies would also benefit from the inclusion of time or the aspect of mechanical memory to further enhance this field. While the knowledge of mechanical forces and tumor metastasis grows, developing novel materials and in vitro systems are essential to providing new insight into predicting, treating, and preventing cancer progression and metastasis.
    DOI:  https://doi.org/10.1063/5.0186042
  28. Protein Cell. 2024 Mar 02. pii: pwae004. [Epub ahead of print]
    Proteomic analysis of ferroptosis pathways reveals a role of CEPT1 in suppressing ferroptosis.
    Xiaoguang Liu, Zhen Chen, Yuelong Yan, Fereshteh Zandkarimi, Litong Nie, Qidong Li, Amber Horbath, Kellen Olszewski, Lavanya Kondiparthi, Chao Mao, Hyemin Lee, Li Zhuang, Masha Poyurovsky, Brent R Stockwell, Junjie Chen, Boyi Gan.
      Ferroptosis has been recognized as a unique cell death modality driven by excessive lipid peroxidation and unbalanced cellular metabolism. In this study, we established a protein interaction landscape for ferroptosis pathways through proteomic analyses, and identified choline/ethanolamine phosphotransferase 1 (CEPT1) as a lysophosphatidylcholine acyltransferase 3 (LPCAT3)-interacting protein that regulates LPCAT3 protein stability. In contrast to its known role in promoting phospholipid synthesis, we showed that CEPT1 suppresses ferroptosis potentially by interacting with phospholipases and breaking down certain pro-ferroptotic polyunsaturated fatty acid (PUFA)-containing phospholipids. Together, our study reveals a previously unrecognized role of CEPT1 in suppressing ferroptosis.
    Keywords:  CEPT1; LPCAT3; ferroptosis; proteomics
    DOI:  https://doi.org/10.1093/procel/pwae004
  29. Ann Surg Oncol. 2024 Mar 08.
    Adjuvant Gemcitabine Versus Neoadjuvant/Adjuvant FOLFIRINOX in Resectable Pancreatic Cancer: The Randomized Multicenter Phase II NEPAFOX Trial.
    Thorsten O Goetze, Alexander Reichart, Ulli S Bankstahl, Claudia Pauligk, Maria Loose, Thomas W Kraus, Moustafa Elshafei, Wolf O Bechstein, Jörg Trojan, Matthias Behrend, Nils Homann, Marino Venerito, Wolfram Bohle, Michael Varvenne, Claus Bolling, Dirk M Behringer, Karsten Kratz-Albers, Gabriele M Siegler, Wael Hozaeel, Salah-Eddin Al-Batran.
      BACKGROUND: Although addition of adjuvant chemotherapy is the current standard, the prognosis of pancreatic cancers still remains poor. The NEPAFOX trial evaluated perioperative treatment with FOLFIRINOX in resectable pancreatic cancer.PATIENTS AND METHODS: This multicenter phase II trial randomized patients with resectable or borderline resectable pancreatic cancer without metastases into arm (A,) upfront surgery plus adjuvant gemcitabine, or arm (B,) perioperative FOLFIRINOX. The primary endpoint was overall survival (OS).
    RESULTS: Owing to poor accrual, recruitment was prematurely stopped after randomization of 40 of the planned 126 patients (A: 21, B: 19). Overall, approximately three-quarters were classified as primarily resectable (A: 16, B: 15), and the remaining patients were classified as borderline resectable (A: 5, B: 4). Of the 12 evaluable patients, 3 achieved partial response under neoadjuvant FOLFIRINOX. Of the 21 patients in arm A and 19 patients in arm B, 17 and 7 underwent curative surgery, and R0-resection was achieved in 77% and 71%, respectively. Perioperative morbidity occurred in 72% in arm A and 46% in arm B, whereas non-surgical toxicity was comparable in both arms. Median RFS/PFS was almost doubled in arm B (14.1 months) compared with arm A (8.4 months) in the population with surgical resection, whereas median OS was comparable between both arms.
    CONCLUSIONS: Although the analysis was only descriptive owing to small patient numbers, no safety issues regarding surgical complications were observed in the perioperative FOLFIRINOX arm. Thus, considering the small number of patients, perioperative treatment approach appears feasible and potentially effective in well-selected cohorts of patients. In pancreatic cancer, patient selection before initiation of neoadjuvant therapy appears to be critical.
    Keywords:  Adjuvant; FOLFIRINOX; Neoadjuvant; Resectable pancreatic cancer
    DOI:  https://doi.org/10.1245/s10434-024-15011-7
  30. Nat Genet. 2024 Mar 07.
    Improved identification of cancer mutational processes.
    Tom L Kaufmann, Roland F Schwarz.
      
    DOI:  https://doi.org/10.1038/s41588-024-01679-w
  31. Autophagy. 2024 Mar 08. 1-2
    Pink1 balances reticulophagy and mitophagy by regulating distinct E3 ubiquitin ligases.
    Zhangyuan Yin, Daniel J Klionsky.
      The selective clearance of unwanted, damaged or dangerous components by macroautophagy/autophagy is critical for maintaining cellular homeostasis in organisms from yeast to humans. In recent years, significant progress has been made in understanding how phagophores selectively sequester specific cargo. Nevertheless, a fundamental question remains: Can distinct selective autophagy programs simultaneously operate within the same cell? A recent study from the Baehrecke lab has unveiled a developmentally programmed Pink1-dependent reticulophagy process in the Drosophila intestine. Furthermore, this study demonstrated that autophagy differentially clears mitochondria and ER in the same cell under the regulation of Pink1 through different E3 ubiquitin ligases, highlighting the need for further exploration in understanding the complexity of autophagic substrate selection and crosstalk between diverse autophagy programs.
    Keywords:  Autophagy receptor; Keap1; Pink1; mitophagy; selective autophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2323294
  32. Nat Cancer. 2024 Mar 05.
    A deep learning model of tumor cell architecture elucidates response and resistance to CDK4/6 inhibitors.
    Sungjoon Park, Erica Silva, Akshat Singhal, Marcus R Kelly, Kate Licon, Isabella Panagiotou, Catalina Fogg, Samson Fong, John J Y Lee, Xiaoyu Zhao, Robin Bachelder, Barbara A Parker, Kay T Yeung, Trey Ideker.
      Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have revolutionized breast cancer therapy. However, <50% of patients have an objective response, and nearly all patients develop resistance during therapy. To elucidate the underlying mechanisms, we constructed an interpretable deep learning model of the response to palbociclib, a CDK4/6i, based on a reference map of multiprotein assemblies in cancer. The model identifies eight core assemblies that integrate rare and common alterations across 90 genes to stratify palbociclib-sensitive versus palbociclib-resistant cell lines. Predictions translate to patients and patient-derived xenografts, whereas single-gene biomarkers do not. Most predictive assemblies can be shown by CRISPR-Cas9 genetic disruption to regulate the CDK4/6i response. Validated assemblies relate to cell-cycle control, growth factor signaling and a histone regulatory complex that we show promotes S-phase entry through the activation of the histone modifiers KAT6A and TBL1XR1 and the transcription factor RUNX1. This study enables an integrated assessment of how a tumor's genetic profile modulates CDK4/6i resistance.
    DOI:  https://doi.org/10.1038/s43018-024-00740-1
  33. Adv Mater. 2024 Mar 08. e2312898
    Phospholipid Membranes as Chemically and Functionally Tunable Materials.
    Daniel Huster, Sudipta Maiti, Andreas Herrmann.
      The sheet-like lipid bilayer is the fundamental structural component of all cell membranes. Its building blocks are phospholipids and cholesterol. Their amphiphilic structure spontaneously leads to the formation of a bilayer in aqueous environment. Lipids are not just structural elements. Individual lipid species, the lipid membrane structure, and lipid dynamics influence and regulate membrane protein function. An exciting field is emerging where the membrane-associated material properties of different bilayer systems are used in designing innovative solutions for widespread applications across various fields, such as the food industry, cosmetics, nano- and biomedicine, drug storage and delivery, biotechnology, nano- and biosensors, and computing. Here, the authors summarize what is known about how lipids determine the properties and functions of biological membranes and how this has been or can be translated into innovative applications. Based on recent progress in the understanding of membrane structure, dynamics, and physical properties, a perspective is provided on how membrane-controlled regulation of protein functions can extend current applications and even offer new applications.
    Keywords:  allosteric modulation from the membrane; functional modulations; lipid bilayers; liposomes; membrane dynamics
    DOI:  https://doi.org/10.1002/adma.202312898
  34. Nat Chem Biol. 2024 Mar 06.
    Mitochondrial ATP generation is more proteome efficient than glycolysis.
    Yihui Shen, Hoang V Dinh, Edward R Cruz, Zihong Chen, Caroline R Bartman, Tianxia Xiao, Catherine M Call, Rolf-Peter Ryseck, Jimmy Pratas, Daniel Weilandt, Heide Baron, Arjuna Subramanian, Zia Fatma, Zong-Yen Wu, Sudharsan Dwaraknath, John I Hendry, Vinh G Tran, Lifeng Yang, Yasuo Yoshikuni, Huimin Zhao, Costas D Maranas, Martin Wühr, Joshua D Rabinowitz.
      Metabolic efficiency profoundly influences organismal fitness. Nonphotosynthetic organisms, from yeast to mammals, derive usable energy primarily through glycolysis and respiration. Although respiration is more energy efficient, some cells favor glycolysis even when oxygen is available (aerobic glycolysis, Warburg effect). A leading explanation is that glycolysis is more efficient in terms of ATP production per unit mass of protein (that is, faster). Through quantitative flux analysis and proteomics, we find, however, that mitochondrial respiration is actually more proteome efficient than aerobic glycolysis. This is shown across yeast strains, T cells, cancer cells, and tissues and tumors in vivo. Instead of aerobic glycolysis being valuable for fast ATP production, it correlates with high glycolytic protein expression, which promotes hypoxic growth. Aerobic glycolytic yeasts do not excel at aerobic growth but outgrow respiratory cells during oxygen limitation. We accordingly propose that aerobic glycolysis emerges from cells maintaining a proteome conducive to both aerobic and hypoxic growth.
    DOI:  https://doi.org/10.1038/s41589-024-01571-y
  35. Biophys J. 2024 Mar 02. pii: S0006-3495(24)00164-4. [Epub ahead of print]
    TRPV4-dependent Ca2+ influx determines cholesterol dynamics at the plasma membrane.
    Yutaro Kuwashima, Masataka Yanagawa, Masashi Maekawa, Mitsuhiro Abe, Yasushi Sako, Makoto Arita.
      The activities of the transient receptor potential vanilloid 4 (TRPV4), a Ca2+-permeable non-selective cation channel, are controlled by its surrounding membrane lipids (e.g., cholesterol, phosphoinositides). The transmembrane region of TRPV4 contains a cholesterol recognition amino acid consensus (CRAC) motif and its inverted (CARC) motif located in the plasmalemmal cytosolic leaflet. TRPV4 localizes in caveolae, a bulb-shaped cholesterol-rich domain at the plasma membrane. Here, we visualized the spatiotemporal interactions between TRPV4 and cholesterol at the plasma membrane in living cells by dual-color single-molecule imaging using total internal reflection fluorescence microscopy (TIRFM). To this aim, we labelled cholesterol at the cytosolic leaflets of the plasma membrane using a cholesterol biosensor, D4H. Our single-molecule tracking analysis showed that the TRPV4 molecules colocalize with D4H-accessible cholesterol molecules mainly in the low fluidity membrane domains in which both molecules are highly-clustered. Colocalization of TRPV4 and D4H-accessible cholesterol was observed both inside and outside of caveolae. Agonist-evoked TRPV4 activation remarkably decreased colocalization probability and association rate between TRPV4 and D4H-accessible cholesterol molecules. Interestingly, upon TRPV4 activation, the particle density of D4H-accessible cholesterol molecules was decreased and the D4H-accessible cholesterol molecules in the fast-diffusing state were increased at the plasma membrane. The introduction of skeletal dysplasia-associated R616Q mutation into the CRAC/CARC motif of TRPV4, which reduced the interaction with cholesterol clusters, could not alter the D4H-accessible cholesterol dynamics. Mechanistically, TRPV4-mediated Ca2+ influx and the C-terminal calmodulin-binding site of TRPV4 are essential for modulating the plasmalemmal D4H-accessible cholesterol dynamics. We propose that TRPV4 remodels its surrounding plasmalemmal environment by manipulating cholesterol dynamics through Ca2+ influx.
    DOI:  https://doi.org/10.1016/j.bpj.2024.02.030
  36. J Biol Chem. 2024 Mar 04. pii: S0021-9258(24)01631-4. [Epub ahead of print] 107136
    Transcriptome analysis of polyploid giant cancer cells and their progeny reveals a functional role for p21 in polyploidization and depolyploidization.
    Shai White-Gilbertson, Ping Lu, Ozge Saatci, Ozgur Sahin, Joe R Delaney, Besim Ogretmen, Christina Voelkel-Johnson.
      Polyploid giant cancer cells (PGCC) are frequently detected in tumors and are increasingly recognized for their roles in chromosomal instability and associated genome evolution that leads to cancer recurrence. We previously reported that therapy stress promotes polyploidy, and that acid ceramidase plays a role in depolyploidization. In this study, we used an RNA-seq approach to gain a better understanding of the underlying transcriptomic changes that occur as cancer cells progress through polyploidization and depolyploidization. Our results revealed gene signatures that are associated with disease-free and/or overall survival in several cancers and identified the cell cycle inhibitor CDKN1A/p21 as the major hub in PGCC and early progeny. Increased expression of p21 in PGCC was limited to the cytoplasm. We previously demonstrated that the sphingolipid enzyme acid ceramidase is dispensable for polyploidization upon therapy stress but plays a crucial role in depolyploidization. The current study demonstrates that treatment of cells with ceramide is not sufficient for p53-independent induction of p21 and that knockdown of acid ceramidase, which hydrolyzes ceramide, does not interfere with upregulation of p21. In contrast, blocking expression of p21 with UC2288 prevented the induction of acid ceramidase and inhibited both the formation of PGCC from parental cells as well as the generation of progeny from PGCC. Taken together, our data suggest that p21 functions upstream of acid ceramidase and plays an important role in polyploidization and depolyploidization.
    Keywords:  Cancer biology; bioinformatics; cell signaling; ceramide; sphingolipid; stress response
    DOI:  https://doi.org/10.1016/j.jbc.2024.107136
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