bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2022‒05‒15
39 papers selected by
Kıvanç Görgülü
Technical University of Munich
  1. ST6Gal1 Contributes to Pancreatic Cancer Initiation by Promoting Pancreatitis-Induced Acinar to Ductal Metaplasia.
  2. ATG9A-mediated turnover of p62 condensates requires ubiquitin and occurs independently of the LC3-lipidation machinery.
  3. The interactive role of inflammatory mediators and metabolic reprogramming in pancreatic cancer.
  4. Pro-survival lipid metabolism activates intracellular complement signaling to induce inflammasome-mediated tumor metastasis.
  5. The glycocalyx in tumor progression and metastasis.
  6. Autophagy in PDGFRα+ mesenchymal cells is essential for intestinal stem cell survival.
  7. Roles for inter-organelle contacts in organizing metabolism.
  8. Tracing copper utilization by kinase signal transduction pathways: Implications for cancer cell processes.
  9. Metaplasia-induced Epithelial Heterogeneity Directs Pancreatic Injury and Tumorigenesis.
  10. Rapid acceleration of KRAS-mutant pancreatic carcinogenesis via remodeling of tumor immune microenvironment by PPARδ.
  11. Protein restriction and branched-chain amino acid restriction promote geroprotective shifts in metabolism.
  12. Lymph node colonization induces tumor-immune tolerance to promote distant metastasis.
  13. Candidate diagnostic and prognostic markers for pancreatitis and pancreatic ductal adenocarcinoma.
  14. The multifaceted role of autophagy in cancer.
  15. PRMT5 regulates lipid metabolism in skeletal muscle via epigenetic suppression of Pnpla2.
  16. The lactate-NAD+ axis activates cancer-associated fibroblasts by downregulating p62.
  17. ATG9 Vesicles Are Incorporated Into Nascent Autophagosome Membranes.
  18. Enhancing CRISPR/Cas gene editing through modulating cellular mechanical properties for cancer therapy.
  19. Metabolic oscillations during cell-cycle progression.
  20. Fundamental immune-oncogenicity trade-offs define driver mutation fitness.
  21. Profiling Oncogenic Ras Mutant Drugs with Homogeneous Bioluminescent Immunoassays.
  22. CLUH controls astrin-1 expression to couple mitochondrial metabolism to cell cycle progression.
  23. Spherical Invasion Assay: A novel method to measure the pro-invasive activity of cancer cells.
  24. MUC16 Promotes Liver Metastasis of Pancreatic Ductal Adenocarcinoma by Upregulating NRP2 Associated Cell Adhesion.
  25. Evidence for widespread cytoplasmic structuring into mesoscopic condensates.
  26. Cross-tissue immune cell analysis reveals tissue-specific features in humans.
  27. Genome-wide CRISPR screens using isogenic cells reveal vulnerabilities conferred by loss of tumor suppressors.
  28. Hallmarks of cancer and hallmarks of aging.
  29. Lipogenesis mediated by OGR1 regulates metabolic adaptation to acid stress in cancer cells via autophagy.
  30. Autophagy Impairment and Sarcopenia in Type-Identified Muscle Fibers of Aging Extensor Digitorum Longus Muscle.
  31. Autophagy power expands: fuse those cells!
  32. Topical therapy for regression and melanoma prevention of congenital giant nevi.
  33. A hitchhiker's guide to cancer models.
  34. Molecular architecture of the human caveolin-1 complex.
  35. Cancer-associated fibroblasts in pancreatic cancer: new subtypes, new markers, new targets.
  36. Calorie restriction in cancer patients undergoing chemotherapy: Facts, phantasy or misunderstanding.
  37. Mapping the developing human immune system across organs.
  38. Molecular Mechanisms and Current Treatment Options for Cancer Cachexia.
  39. Obesity-Associated Cancers: Evidence from Studies in Mouse Models.
  1. FASEB J. 2022 May;36 Suppl 1
    ST6Gal1 Contributes to Pancreatic Cancer Initiation by Promoting Pancreatitis-Induced Acinar to Ductal Metaplasia.
    Michael P Marciel, Asmi Chakraborty, Nikita U Bhalerao, Susan L Bellis.
      Aberrant glycosylation is one of the earliest known hallmarks of cancer. Amongst the predominate changes in tumor cell glycosylation is an increase in α2-6 sialylation on N-glycans, a modification elaborated by the ST6Gal1 sialyltransferase. ST6Gal1 activity dramatically alters cellular function via the sialylation of various surface receptors such as EGFR and TNFR1, resulting in altered signal transduction and gene expression. ST6Gal1 expression is upregulated in multiple cancers, including pancreatic ductal adenocarcinoma (PDAC). Recent studies from our group suggest that the upregulation of ST6Gal1 in pancreatic acinar cells may promote PDAC initiation by facilitating acinar to ductal metaplasia (ADM), a process in which acinar cells de-differentiate into ductal-like, progenitor cells. In the nonmalignant pancreas, ADM is induced primarily by pancreatitis, a known risk factor for PDAC. Pancreatitis causes acinar cell apoptosis, however some cells undergo ADM and acquire regenerative capabilities essential for tissue healing. Notably, ADM-like cells are particularly susceptible to oncogenic transformation. In the current study we determined that ST6Gal1 was strikingly upregulated in pancreatic tissues from chronic pancreatitis patients and mice with experimental pancreatitis. Furthermore, ST6Gal1 was selectively expressed in the ADM-like cells, as identified both morphologically and by staining for ADM-specific markers. ST6Gal1 activity was associated with a proliferative phenotype. More than 50% of cells with upregulated ST6Gal1 co-expressed the proliferative marker, Ki67, whereas activated caspase 8 was undetectable in ST6Gal1-positive cells. To interrogate a functional role for ST6Gal1 in ADM, we developed genetically-engineered mice with ST6Gal1 expression in the pancreas ("SC" mice). Importantly, acinar cells from SC mice exhibited ADM-like characteristics, indicated by increased expression of classic stem and ductal genes. RNASeq analyses comparing SC and WT pancreata indicated that SC cells had an enrichment in: stem cell pathways; a pancreatic ductal cell program; and gene networks associated with pancreatic cancer. Additionally, organoids derived from SC pancreata displayed increased expression of stem and ductal genes relative to WT organoids, as well as greater organoid-forming potential and growth. To evaluate inflammation-induced ADM, SC and WT mice were injected with cerulein to induce pancreatitis, and the ADM-like cells were quantified by examining surface ADM markers by flow cytometry. Following induction of pancreatitis, more ADM-like cells were present in SC versus WT pancreata. Finally, we crossbred SC mice to the "KC" PDAC model, which expresses oncogenic KRas (KrasG12D ) in the pancreas. Mice with dual expression of ST6Gal1 and KrasG12D had greatly accelerated PDAC initiation, progression and mortality as compared with KC mice. Together these data suggest that the upregulation of ST6Gal1 during chronic pancreatitis may prime acinar cells for neoplastic transformation by facilitating ADM.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R3992
  2. FASEB J. 2022 May;36 Suppl 1
    ATG9A-mediated turnover of p62 condensates requires ubiquitin and occurs independently of the LC3-lipidation machinery.
    Colten M McEwan, David G Broadbent, Daniel M Poole, Brad C Naylor, John C Price, Jens C Schmidt, Josh L Andersen.
      Autophagy is a tightly controlled cellular recycling process that requires a host of autophagy machinery to form a double membraned vesicle called the autophagosome. This process is most understood in the context of stress-induced autophagy, with little known about autophagosome biogenesis in basal (nutrient replete) conditions. To understand the regulation of basal autophagy, our work has focused on the poorly understood protein ATG9A, a multi-pass transmembrane lipid scramblase that is essential for basal autophagy. To broadly understand the role ATG9A plays in basal autophagy, we utilized a quantitative proteome-level MS/MS approach to measure how ATG9A affects protein flux. We show that loss of ATG9A in basal conditions impairs the degradation of autophagy adaptors, particularly p62/SQSTM1. Using a panel of ATG knock-out cells, we demonstrate that the lipid transferase proteins ATG2A, ATG2B, and ATG9A promote the basal autophagic turnover of p62 and TAX1BP1 over other autophagy adaptors and do so independently of the LC3-lipidation machinery. Furthermore, we demonstrate that ATG2A and ATG9A lipid transferase activity regulates the rate of p62 condensate degradation. Finally, we show in CRISPR knock-in cell lines that ubiquitin is required for recruiting ATG9A to p62 condensates. Taken together, our data suggest that the lipid transferase activity of ATG9A and ATG2A is vital to basal autophagic regulation of protein homeostasis, and that ubiquitination is an apical signal that initiates recruitment of ATG9A to p62 condensates.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R5717
  3. Trends Cancer. 2022 May 04. pii: S2405-8033(22)00070-X. [Epub ahead of print]
    The interactive role of inflammatory mediators and metabolic reprogramming in pancreatic cancer.
    Yuuki Ohara, Paloma Valenzuela, S Perwez Hussain.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by its highly reactive inflammatory desmoplastic stroma with evidence of an extensive tumor stromal interaction largely mediated by inflammatory factors. KRAS mutation and inflammatory signaling promote protumorigenic events, including metabolic reprogramming with several inter-regulatory crosstalks to fulfill the high demand of energy and regulate oxidative stress for tumor growth and progression. Notably, the more aggressive molecular subtype of PDAC enhances influx of glycolytic intermediates. This review focuses on the interactive role of inflammatory signaling and metabolic reprogramming with emerging evidence of crosstalk, which supports the development, progression, and therapeutic resistance of PDAC. Understanding the emerging crosstalk between inflammation and metabolic adaptations may identify potential targets and develop novel therapeutic approaches for PDAC.
    Keywords:  autophagy; inflammatory mediators; metabolic reprogramming; molecular subtype; pancreatic ductal adenocarcinoma (PDAC)
    DOI:  https://doi.org/10.1016/j.trecan.2022.03.004
  4. FASEB J. 2022 May;36 Suppl 1
    Pro-survival lipid metabolism activates intracellular complement signaling to induce inflammasome-mediated tumor metastasis.
    Alhaji H Janneh, Besim Ogretmen.
      Tumor metastasis remains one of the major causes of cancer-related deaths in patients with solid tumors. Mechanisms by which metabolic alterations regarding pro-survival lipid signaling activation in inducing cancer cell migration and metastasis are largely unknown. Here, we demonstrate that sphingosine 1-phosphate (S1P) metabolism activates endogenous complement signaling for inducing tumor metastasis via inducing inflammasome-mediated pro-inflammation. Our studies using molecular, pharmacologic, and genetic tools showed that activation of S1P and S1P receptor 1 (S1P/S1PR1) induces tumor metastasis via enhanced intracellular complement signaling by the regulation of the C3-PPIL1 complex and subsequent inflammasome activation in cancer cells and in vivo xenograft-derived tumors.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.0R365
  5. FASEB J. 2022 May;36 Suppl 1
    The glycocalyx in tumor progression and metastasis.
    Valerie M Weaver.
      Tumors develop a desmoplastic response that creates a tissue microenvironment that is complicit in malignant transformation and metastasis. Tumor desmoplasia is characterized by fibrosis that is mediated by elevated extracellular matrix deposition, remodeling and cross-linking that stiffen the tumor stroma. We have been studying how these aberrant cell and tissue level forces promote malignant transformation and drive tumor metastasis, and how they modulate tumor recurrence and treatment resistance in breast and pancreatic cancer and glioblastoma. We use two and three dimensional culture models with tuned extracellular matrix stiffness, as well as transgenic and syngeneic mouse models, human PDX models and human biospecimens, in which ECM crosslinking and stiffness and integrin mechanosignaling can be quantified and modified. Our studies have thus far revealed that the ECM in all tumors becomes progressively remodeled and stiffened by the resident stromal fibroblasts and revealed that this occurs prior to malignant transformation. The stromal-fibroblast stiffened ECM disrupts tissue organization, promotes tumor cell growth, survival and invasion, induces angiogenesis, and promotes a pro-tumor immunity that drives tumor aggression and metastasis. We recently found that the fibrotic stroma drives the metabolic rewiring of the tumor cells and determined that this associates with elevated expression of key enzymes that regulate the cellular glycoproteome. A stiffened fibrotic stroma stimulated sialoglycan expression through tension-induced integrin signaling. The elevated mechanosignaling induced in the tumor cells by the stiffened stroma increased the level of secreted proteoglycans deposited at the tumor-ECM interface where a high density of protumorigenic immune suppressive infiltrating myeloid cells were detected. The association between a stiff, fibrotic tumor stroma, elevated secreted proteoglycans and a pro tumor immune infiltrate was very predominant in the more aggressive human breast tumors. I will discuss the dynamic and reciprocal interplay between tissue tension, metabolic reprogramming and glycoprotein regulation and innate and acquired immunity in tumor aggression and progression.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.0I189
  6. Proc Natl Acad Sci U S A. 2022 May 24. 119(21): e2202016119
    Autophagy in PDGFRα+ mesenchymal cells is essential for intestinal stem cell survival.
    Yang Yang, Maria Gomez, Timothy Marsh, Laura Poillet-Perez, Akshada Sawant, Lei Chen, Noel R Park, S RaElle Jackson, Zhixian Hu, Noa Alon, Chen Liu, Jayanta Debnath, Jun-Lin Guan, Shawn Davidson, Michael Verzi, Eileen White.
      SignificanceAutophagy defects are a risk factor for inflammatory bowel diseases (IBDs), but the mechanism remains unknown. We show here that conditional whole-body deletion of Atg5 or Fip200, but not Atg7, is lethal due to loss of ileum stem cells and barrier function likely caused by different kinetics of autophagy loss, which was rescued by slow deletion. Specific autophagy loss in PDGFRα+ mesenchymal cells (PMCs) resulted in loss of Wnt signaling responsible for failed stem cell renewal. We also observed depletion of aspartate and nucleotides throughout the ileum. Our results illustrate that autophagy is required for PMC metabolism and survival necessary to sustain intestinal stem cells and mouse survival, and failure to maintain PMCs through autophagy contributes to IBD.
    Keywords:  IBD; autophagy; intestine; metabolism; stem cells
    DOI:  https://doi.org/10.1073/pnas.2202016119
  7. FASEB J. 2022 May;36 Suppl 1
    Roles for inter-organelle contacts in organizing metabolism.
    W M Henne.
      When faced with nutrient shortage, cells adapt by remodeling their metabolic pathways and organelles. I will discuss our work using budding yeast to dissect how nutrient shortage impacts the spatial organization of metabolism and lipid droplets. We find that in response to glucose restriction, yeast remodel their mevalonate pathway by spatially compartmentalizing its rate-limiting enzyme, HMG-CoA Reductase (HMGCR). HMGCR spatial compartmentalization occurs at a unique inter-organelle contact site called the nucleus-vacuole junction (NVJ). This spatial partitioning enhances HMGCR activity, driving mevalonate synthesis to enable cellular adaptation. Our work suggests a new use for an inter-organelle contact site in the fine-tuning of mevalonate metabolism during nutrient stress. Remarkably, we also find that glucose restriction drives the phase transition of lipids within lipid droplets (LDs), causing them to convert from a disordered to liquid-crystalline phase. Mechanistically, we find that these liquid crystalline lattices (LCLs) within LDs require triglyceride lipolysis. We also find that LCL-LDs exhibit changes to the LD surface proteome. Several known LD proteins redistribute from LDs to the ER network, whereas others remain on LCL-LDs, suggesting phase transitions of LD lipids influences LD protein targeting. Global proteomics also reveals that triglycerides harvested from LDs fuel cellular energetics at peroxisomes and mitochondria. This indicates that glucose starvation induces inter-organelle lipid flux while promoting lipid phase transitions within LDs.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.0I151
  8. FASEB J. 2022 May;36 Suppl 1
    Tracing copper utilization by kinase signal transduction pathways: Implications for cancer cell processes.
    Donita C Brady.
      Akin to organic nutrients, such as oxygen, lipids, amino acids, and carbohydrates, the transition metal copper (Cu) is an essential dietary nutrient for normal physiology and development. Decades of research highlight the physiological and disease associated consequences of disrupting homeostatic mechanisms that ensure proper Cu acquisition, storage, and distribution to Cu-dependent enzymes. However, phenotypes associated with alterations in Cu availability cannot be fully explained by the limited number of enzymes that traditionally harness the redox potential of Cu as a catalytic cofactor. Recent discoveries in Cu biology have revealed direct Cu binding at non-catalytic sites within signaling molecules that modulate cell proliferation via the protein kinases MEK1/2, lipid metabolism via the phosphodiesterase PDE3B, and nutrient recycling via the autophagic kinases ULK1/2. The emergence of this new paradigm in nutrient sensing and protein regulation has established that Cu is a critical mediator of intracellular signaling, provided evidence for the existence of molecular mechanisms for sensing changes in Cu abundance, and expanded the contribution of Cu to cellular processes necessary for adaptation to nutrient scarcity. Our presentation will focus on the intersections between Cu homeostasis, nutrient signaling, and metabolism by examining the interplay between mechanisms of Cu-sensing necessary for cellular energy homeostasis and evaluating the necessity of Cu for metabolic flexibility under nutrient and oxygen stress. We will present novel findings on Cu-controlled autophagy-lysosomal biogenesis and function, and interconnectivity between mitochondrial Cu transport and cytosolic nutrient sensing signaling pathways necessary for metabolism. These studies increase our fundamental knowledge of the molecular and cellular features of Cu-dependent enzymes and cellular processes and enable therapeutic targeting of Cu-dependent disease vulnerabilities.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.0I105
  9. FASEB J. 2022 May;36 Suppl 1
    Metaplasia-induced Epithelial Heterogeneity Directs Pancreatic Injury and Tumorigenesis.
    Kathleen DelGiorno, Zhibo Ma, Nikki Lytle, Bob Chen, Nidhi Jyotsana, Sammy Weiser Novak, Charles Cho, Leah Caplan, Olivia Ben-Levy, Abigail Neininger, Dylan Burnette, Vincent Trinh, Marcus Tan, Uri Manor, Jason Mills, James Goldenring, Ken Lau, Geoffrey Wahl.
      BACKGROUND AND AIMS: Despite years of research, mechanisms of pancreatic injury and healing remain poorly understood. Acute pancreatitis is a painful and debilitating condition; chronic pancreatitis may be asymptomatic, but greatly enhances the risk of pancreatic ductal adenocarcinoma (PDAC). Acinar to ductal metaplasia (ADM), or the transdifferentiation of digestive enzyme producing acinar cells to ductal cells, is an early event in both conditions. While ADM is thought to function in healing and regeneration, it also represents a first step in tumorigenesis, demonstrating the duplicitous nature of this inherent plasticity. The goal of these studies was to define the populations arising in ADM, associated transcriptional changes, and their role in disease progression.METHODS: Acinar cells were lineage traced to follow their fate upon injury. Transcripts of more than 13,000 EYFP+ cells were determined using single cell RNA sequencing (scRNA-seq). Developmental trajectories were generated using several computational biology approaches that rely on non-overlapping assumptions. Data were compared to scRNA-seq studies of gastric metaplasia, oncogenic KrasG12D -induced ADM, and human pancreatitis. Results were confirmed using immunostaining and electron microscopy. Tuft and enteroendocrine cell (EEC) populations were quantified throughout tumorigenesis. KrasG12D was expressed in injury-induced ADM populations using several inducible Cre drivers.
    RESULTS: scRNA-seq of ADM from chronically injured pancreata revealed emergence of a mucin/ductal population that resembles gastric pyloric metaplasia. Developmental trajectories suggest that some pyloric metaplasia cells generate tuft or EEC populations as distinct lineages. Comparison to KrasG12D -induced ADM reveals populations associated with disease progression. Immunostaining demonstrates that tuft and EEC formation is an early event in tumorigenesis. Activation of KrasG12D in ADM populations results in neoplastic transformation and the formation of MUC5AC+ pit cells. Human pancreatitis samples reflect a pyloric metaplasia phenotype as well as the formation of tuft and EEC populations.
    CONCLUSIONS: ADM under conditions of chronic injury results in the formation of a pyloric-type metaplasia which seeds disparate tuft and EEC lineages. This carefully orchestrated plasticity generates myriad epithelial cell types which likely mitigate injury, providing protection from the formation of pancreatitis and PDAC. KrasG12D expression is sufficient to drive neoplasia when targeted to injury-induced ADM populations offering an alternative origin for tumorigenesis. This program is conserved in human pancreatitis and provides insight into early events in pancreas diseases.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.0I661
  10. Nat Commun. 2022 May 13. 13(1): 2665
    Rapid acceleration of KRAS-mutant pancreatic carcinogenesis via remodeling of tumor immune microenvironment by PPARδ.
    Yi Liu, Yasunori Deguchi, Daoyan Wei, Fuyao Liu, Micheline J Moussalli, Eriko Deguchi, Donghui Li, Huamin Wang, Lovie Ann Valentin, Jennifer K Colby, Jing Wang, Xiaofeng Zheng, Haoqiang Ying, Mihai Gagea, Baoan Ji, Jiaqi Shi, James C Yao, Xiangsheng Zuo, Imad Shureiqi.
      Pancreatic intraepithelial neoplasia (PanIN) is a precursor of pancreatic ductal adenocarcinoma (PDAC), which commonly occurs in the general populations with aging. Although most PanIN lesions (PanINs) harbor oncogenic KRAS mutations that initiate pancreatic tumorigenesis; PanINs rarely progress to PDAC. Critical factors that promote this progression, especially targetable ones, remain poorly defined. We show that peroxisome proliferator-activated receptor-delta (PPARδ), a lipid nuclear receptor, is upregulated in PanINs in humans and mice. Furthermore, PPARδ ligand activation by a high-fat diet or GW501516 (a highly selective, synthetic PPARδ ligand) in mutant KRASG12D (KRASmu) pancreatic epithelial cells strongly accelerates PanIN progression to PDAC. This PPARδ activation induces KRASmu pancreatic epithelial cells to secrete CCL2, which recruits immunosuppressive macrophages and myeloid-derived suppressor cells into pancreas via the CCL2/CCR2 axis to orchestrate an immunosuppressive tumor microenvironment and subsequently drive PanIN progression to PDAC. Our data identify PPARδ signaling as a potential molecular target to prevent PDAC development in subjects harboring PanINs.
    DOI:  https://doi.org/10.1038/s41467-022-30392-7
  11. Aging Cell. 2022 May 08. e13626
    Protein restriction and branched-chain amino acid restriction promote geroprotective shifts in metabolism.
    Michaela E Trautman, Nicole E Richardson, Dudley W Lamming.
      The proportion of humans suffering from age-related diseases is increasing around the world, and creative solutions are needed to promote healthy longevity. Recent work has clearly shown that a calorie is not just a calorie-and that low protein diets are associated with reduced mortality in humans and promote metabolic health and extended lifespan in rodents. Many of the benefits of protein restriction on metabolism and aging are the result of decreased consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we discuss the emerging evidence that BCAAs are critical modulators of healthy metabolism and longevity in rodents and humans, as well as the physiological and molecular mechanisms that may drive the benefits of BCAA restriction. Our results illustrate that protein quality-the specific composition of dietary protein-may be a previously unappreciated driver of metabolic dysfunction and that reducing dietary BCAAs may be a promising new approach to delay and prevent diseases of aging.
    Keywords:  FGF21; amino acids; branched-chain amino acids; isoleucine; lifespan; mTOR
    DOI:  https://doi.org/10.1111/acel.13626
  12. Cell. 2022 May 01. pii: S0092-8674(22)00466-4. [Epub ahead of print]
    Lymph node colonization induces tumor-immune tolerance to promote distant metastasis.
    Nathan E Reticker-Flynn, Weiruo Zhang, Julia A Belk, Pamela A Basto, Nichole K Escalante, Genay O W Pilarowski, Alborz Bejnood, Maria M Martins, Justin A Kenkel, Ian L Linde, Sreya Bagchi, Robert Yuan, Serena Chang, Matthew H Spitzer, Yaron Carmi, Jiahan Cheng, Lorna L Tolentino, Okmi Choi, Nancy Wu, Christina S Kong, Andrew J Gentles, John B Sunwoo, Ansuman T Satpathy, Sylvia K Plevritis, Edgar G Engleman.
      For many solid malignancies, lymph node (LN) involvement represents a harbinger of distant metastatic disease and, therefore, an important prognostic factor. Beyond its utility as a biomarker, whether and how LN metastasis plays an active role in shaping distant metastasis remains an open question. Here, we develop a syngeneic melanoma mouse model of LN metastasis to investigate how tumors spread to LNs and whether LN colonization influences metastasis to distant tissues. We show that an epigenetically instilled tumor-intrinsic interferon response program confers enhanced LN metastatic potential by enabling the evasion of NK cells and promoting LN colonization. LN metastases resist T cell-mediated cytotoxicity, induce antigen-specific regulatory T cells, and generate tumor-specific immune tolerance that subsequently facilitates distant tumor colonization. These effects extend to human cancers and other murine cancer models, implicating a conserved systemic mechanism by which malignancies spread to distant organs.
    Keywords:  ISGs; MHC-I; NK cells; PD-L1; Tregs; interferon; lymph nodes; metastasis; regulatory T cells; tolerance
    DOI:  https://doi.org/10.1016/j.cell.2022.04.019
  13. FASEB J. 2022 May;36 Suppl 1
    Candidate diagnostic and prognostic markers for pancreatitis and pancreatic ductal adenocarcinoma.
    Thomas M Wilkie, Havish Kantheti.
      Diagnostic markers are desperately needed for early detection of pancreatic ductal adenocarcinoma (PDA). We describe sets of markers expressed in temporal order in mouse models during pancreatitis, PDA initiation and progression. Cell type specificity of PDA marker expression was analyzed by interrogating quantitative dot plots of single cell (sc) RNAseq for 3021 candidate genes in tumor samples from a mouse model for PDA (KIC) at early and late stages of PDA progression compared to normal pancreas. Protein markers were identified by differential mass spectrometry (MS) of mouse tumors and conditioned media from human cancer cell lines. Additional candidate genes were identified from signaling pathways that drive PDA, including the Ras pathway, calcium signaling, and known cancer genes. Developmental progression of cancer was revealed in seven classes of PDA markers expressed in cancer cells and stroma. The earliest diagnostic markers (47 genes) were specifically expressed in epithelial cancer cells in early, but not late, PDA tumors. Other markers were first elevated in epithelial cancer cells of late stage tumors (288 genes), or in both epithelial and mesenchymal cells (740 genes), or only in mesenchymal cells (216 genes). Stromal markers were differentially expressed in early- and/or late-PDA neoplasia (594 genes). Pancreatitis is a risk factor for PDA in humans. Mouse models of pancreatitis, including caerulein treatment and acinar-specific homozygous deletion of differentiation transcription factors (dTFs), were screened for early expression of all PDA markers identified in KIC neoplasia. Select diagnostic markers were validated by immunohistochemistry in mouse and human samples of normal pancreas, early- and late-stage PDA. Prognostic markers from TCGA were identified that showed differential and cell type-specific expression in PDA. Here we present diagnostic and prognostic markers for disease progression from pancreatitis to late-stage PDA.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.L8029
  14. EMBO J. 2022 May 10. e110031
    The multifaceted role of autophagy in cancer.
    Ryan C Russell, Kun-Liang Guan.
      Autophagy is a cellular degradative pathway that plays diverse roles in maintaining cellular homeostasis. Cellular stress caused by starvation, organelle damage, or proteotoxic aggregates can increase autophagy, which uses the degradative capacity of lysosomal enzymes to mitigate intracellular stresses. Early studies have shown a role for autophagy in the suppression of tumorigenesis. However, work in genetically engineered mouse models and in vitro cell studies have now shown that autophagy can be either cancer-promoting or inhibiting. Here, we summarize the effects of autophagy on cancer initiation, progression, immune infiltration, and metabolism. We also discuss the efforts to pharmacologically target autophagy in the clinic and highlight future areas for exploration.
    Keywords:  ATG; autophagy; cancer; chloroquine; metabolism
    DOI:  https://doi.org/10.15252/embj.2021110031
  15. FASEB J. 2022 May;36 Suppl 1
    PRMT5 regulates lipid metabolism in skeletal muscle via epigenetic suppression of Pnpla2.
    Kun Ho Kim, Feng Yue, Zhihao Jia, Jingjuan Chen, Jiamin Qiu, Madigan M Strange, Xiyue Chen, Bruno Tesini Roseguini, Changdeng Hu, Shihuan Kuang.
      Skeletal muscle plays a vital role in regulating systemic energy metabolism. Defects in skeletal muscle energy production exacerbate chronic metabolic disorders. Protein arginine methyltransferase 5 (PRMT5) catalyzes arginine methylation and regulates a plethora of cellular processes in many tissues, but its function in skeletal muscle is poorly defined. Using a skeletal muscle specific Prmt5 knockout mouse model (Prmt5MKO ), we observed that Prmt5 KO led to a reduction of myofiber size, compromised contractile function, and exercise performance. In addition, Prmt5KO muscles had fewer oxidative fiber type and correspondingly more glycolytic myofibers. Prmt5MKO mice also exhibit systemic metabolic defects and abnormal lipid droplet biogenesis within skeletal muscle, resulting in reduced fat mass in response to high-fat-diet. Mechanistic studies demonstrated that PRMT5 mediates dimethylation of H4R3 in the promoter region of Pnpla2 (encoding ATGL, the rate-limiting enzyme in lipolysis), and loss of Prmt5 results in elevated level of ATGL. Accordingly, constitutive deletion of Pnpla2in skeletal muscle rescued muscle mass and function of Prmt5MKO mice. Taken together, our findings delineate a novel function of Prmt5 as a regulator of lipid metabolism in myocytes through repressing Pnpla2 expression.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R5961
  16. Cell Rep. 2022 May 10. pii: S2211-1247(22)00559-9. [Epub ahead of print]39(6): 110792
    The lactate-NAD+ axis activates cancer-associated fibroblasts by downregulating p62.
    Juan F Linares, Tania Cid-Diaz, Angeles Duran, Marta Osrodek, Anxo Martinez-Ordoñez, Miguel Reina-Campos, Hui-Hsuan Kuo, Olivier Elemento, M Laura Martin, Thekla Cordes, Timothy C Thompson, Christian M Metallo, Jorge Moscat, Maria T Diaz-Meco.
      Reduced p62 levels are associated with the induction of the cancer-associated fibroblast (CAF) phenotype, which promotes tumorigenesis in vitro and in vivo through inflammation and metabolic reprogramming. However, how p62 is downregulated in the stroma fibroblasts by tumor cells to drive CAF activation is an unresolved central issue in the field. Here we show that tumor-secreted lactate downregulates p62 transcriptionally through a mechanism involving reduction of the NAD+/NADH ratio, which impairs poly(ADP-ribose)-polymerase 1 (PARP-1) activity. PARP-1 inhibition blocks the poly(ADP-ribosyl)ation of the AP-1 transcription factors, c-FOS and c-JUN, which is an obligate step for p62 downregulation. Importantly, restoring p62 levels in CAFs by NAD+ renders CAFs less active. PARP inhibitors, such as olaparib, mimick lactate in the reduction of stromal p62 levels, as well as the subsequent stromal activation both in vitro and in vivo, which suggests that therapies using olaparib would benefit from strategies aimed at inhibiting CAF activity.
    Keywords:  AP-1; CP: Cancer; NAD(+)/NADH; PARP inhibitors; SQSTM1; cancer metabolism; cancer-associated fibroblasts; olaparib; p62; poly(ADP-ribose)-polymerase 1; stroma
    DOI:  https://doi.org/10.1016/j.celrep.2022.110792
  17. FASEB J. 2022 May;36 Suppl 1
    ATG9 Vesicles Are Incorporated Into Nascent Autophagosome Membranes.
    Taryn J Olivas, Shenliang Yu, Yumei Wu, Lin Luan, Peter Choi, Kallol Gupta, Pietro De Camilli, Thomas J Melia.
      The autophagosome is a double-membrane organelle that traps cytoplasmic cargo and traffics it to the lysosome for degradation. How the autophagosome forms is uncertain, but a prevailing model suggests lipids are moved from the ER through the lipid transporter ATG2 to ATG9 vesicles, which then expand to comprise the growing autophagosomal membrane. However, evidence that ATG9 is ever resident within the autophagosome is scant; detection of this putative autophagosome-resident protein is made challenging both because most ATG9 vesicles in the cell are not involved in the biogenesis at any given time and because the dilution of one or a few vesicle membranes by potentially millions of transported lipids would result in a very low density of ATG9 on the mature autophagosome. Here we develop approaches to address each of these limitations. First, we show that in genetic knockouts of ATG2, ATG9 vesicles accumulate to very high numbers at sites of aborted autophagosome formation. Focused-ion beam scanning electron microscopy reveals that without ATG2, these putative autophagosome seed vesicles do not expand, but instead accumulate within a large vesicle cluster surrounded by ER. By fluorescence microscopy, we also detect downstream modifiers of the autophagosome membrane at these sites, including the lipid-anchored form of the LC3 proteins, which suggests that a biochemically competent seed membrane is present. To establish whether ATG9A is found on the same membrane as LC3B, we use styrene maleic acid (SMA) copolymer nanodiscs, to isolate very small intact sections of autophagosome membrane away from all other potential contaminants. Through rigorous combinations of isolation and purification, we reveal that ATG9A and LC3B are co-resident within the same 10 nm diameter membrane segment and likely engage in a protein-protein complex. We then apply the same SMA-based approach to show that even in wildtype autophagosomes, ATG9 and LC3 are co-resident. Thus, we assert that ATG9 vesicles are the seed membrane for the autophagosome.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.0R457
  18. Nat Nanotechnol. 2022 May 12.
    Enhancing CRISPR/Cas gene editing through modulating cellular mechanical properties for cancer therapy.
    Di Zhang, Guoxun Wang, Xueliang Yu, Tuo Wei, Lukas Farbiak, Lindsay T Johnson, Alan Mark Taylor, Jiazhu Xu, Yi Hong, Hao Zhu, Daniel J Siegwart.
      Genome editing holds great potential for cancer treatment due to the ability to precisely inactivate or repair cancer-related genes. However, delivery of CRISPR/Cas to solid tumours for efficient cancer therapy remains challenging. Here we targeted tumour tissue mechanics via a multiplexed dendrimer lipid nanoparticle (LNP) approach involving co-delivery of focal adhesion kinase (FAK) siRNA, Cas9 mRNA and sgRNA (siFAK + CRISPR-LNPs) to enable tumour delivery and enhance gene-editing efficacy. We show that gene editing was enhanced >10-fold in tumour spheroids due to increased cellular uptake and tumour penetration of nanoparticles mediated by FAK-knockdown. siFAK + CRISPR-PD-L1-LNPs reduced extracellular matrix stiffness and efficiently disrupted PD-L1 expression by CRISPR/Cas gene editing, which significantly inhibited tumour growth and metastasis in four mouse models of cancer. Overall, we provide evidence that modulating the stiffness of tumour tissue can enhance gene editing in tumours, which offers a new strategy for synergistic LNPs and other nanoparticle systems to treat cancer using gene editing.
    DOI:  https://doi.org/10.1038/s41565-022-01122-3
  19. Trends Endocrinol Metab. 2022 May 06. pii: S1043-2760(22)00063-7. [Epub ahead of print]
    Metabolic oscillations during cell-cycle progression.
    Philippe Icard, Luca Simula.
      We discuss how metabolism changes during different phases of the cell cycle to sustain biosynthesis and replication in normal and cancer cells. We also highlight how several master regulators of cell cycle, such as cyclin-cyclin-dependent kinases (cyc-CDK complexes) and E3 proteasome ligases, modulate key metabolic enzymes to support cell-cycle progression.
    Keywords:  Warburg effect; cancer; cell cycle; cell metabolism
    DOI:  https://doi.org/10.1016/j.tem.2022.04.006
  20. Nature. 2022 May 11.
    Fundamental immune-oncogenicity trade-offs define driver mutation fitness.
    David Hoyos, Roberta Zappasodi, Isabell Schulze, Zachary Sethna, Kelvin César de Andrade, Dean F Bajorin, Chaitanya Bandlamundi, Margaret K Callahan, Samuel A Funt, Sine R Hadrup, Jeppe S Holm, Jonathan E Rosenberg, Sohrab P Shah, Ignacio Vázquez-García, Britta Weigelt, Michelle Wu, Dmitriy Zamarin, Laura F Campitelli, Edward J Osborne, Mark Klinger, Harlan S Robins, Payal P Khincha, Sharon A Savage, Vinod P Balachandran, Jedd D Wolchok, Matthew D Hellmann, Taha Merghoub, Arnold J Levine, Marta Łuksza, Benjamin D Greenbaum.
      Missense driver mutations in cancer are concentrated in a few hotspots1. Various mechanisms have been proposed to explain this skew, including biased mutational processes2, phenotypic differences3-6 and immunoediting of neoantigens7,8; however, to our knowledge, no existing model weighs the relative contribution of these features to tumour evolution. We propose a unified theoretical 'free fitness' framework that parsimoniously integrates multimodal genomic, epigenetic, transcriptomic and proteomic data into a biophysical model of the rate-limiting processes underlying the fitness advantage conferred on cancer cells by driver gene mutations. Focusing on TP53, the most mutated gene in cancer1, we present an inference of mutant p53 concentration and demonstrate that TP53 hotspot mutations optimally solve an evolutionary trade-off between oncogenic potential and neoantigen immunogenicity. Our model anticipates patient survival in The Cancer Genome Atlas and patients with lung cancer treated with immunotherapy as well as the age of tumour onset in germline carriers of TP53 variants. The predicted differential immunogenicity between hotspot mutations was validated experimentally in patients with cancer and in a unique large dataset of healthy individuals. Our data indicate that immune selective pressure on TP53 mutations has a smaller role in non-cancerous lesions than in tumours, suggesting that targeted immunotherapy may offer an early prophylactic opportunity for the former. Determining the relative contribution of immunogenicity and oncogenic function to the selective advantage of hotspot mutations thus has important implications for both precision immunotherapies and our understanding of tumour evolution.
    DOI:  https://doi.org/10.1038/s41586-022-04696-z
  21. FASEB J. 2022 May;36 Suppl 1
    Profiling Oncogenic Ras Mutant Drugs with Homogeneous Bioluminescent Immunoassays.
    Hicham Zegzouti, Laurie Engel, Matthew Swiatnicki, Juliano Alves, Said Goueli.
      Activating KRAS mutations present in many cancers are difficult to target with drugs until recently with the FDA approval of sotorasib (AMG-510), a KRAS G12C selective inhibitor. In an effort to study Ras inhibitors in cells and identify new compounds that inhibit Ras and its downstream signaling, assays such as western or ELISA are commonly used. These traditional immunoassays can be tedious, require multiple washing steps, and are not easily adaptable to a high throughput screening (HTS) format. To overcome these limitations, we developed Lumit, a novel immunoassay approach that combines bioluminescent enzyme subunit complementation technology and immunodetection. We applied this bioluminescent and homogeneous "Add and Read" assay to analyze Ras signaling pathway activation and inhibition through multiple nodes of the pathway including detection of phosphorylated ERK. The assay was used to profile different allele specific inhibitors with cell lines harboring different activating KRAS mutations and obtained the predicted pharmacology and selectivity. The potency of PROTAC compound targeting selective degradation of KRAS G12C was also tested using Lumit and the result showed that maximal decrease in RAS signaling was achieved. Unlike current assays that require lengthy sample preparation and multiple washing steps, the Lumit immunoassay provides an alternative platform because it is homogeneous and allows to decipher signaling pathways activities in a fast and simple manner. Our results demonstrate that this bioluminescent technology can be adapted to any signaling pathway node, allowing scientists to streamline the analysis of signaling pathways of interest such as Ras, and identify much needed inhibitors of its mutants.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R4988
  22. Elife. 2022 May 13. pii: e74552. [Epub ahead of print]11
    CLUH controls astrin-1 expression to couple mitochondrial metabolism to cell cycle progression.
    Desiree Schatton, Giada Di Pietro, Karolina Szczepanowska, Matteo Veronese, Marie-Charlotte Marx, Kristina Braunöhler, Esther Barth, Stefan Müller, Patrick Giavalisco, Thomas Langer, Aleksandra Trifunovic, Elena I Rugarli.
      Proliferating cells undergo metabolic changes in synchrony with cell cycle progression and cell division. Mitochondria provide fuel, metabolites, and ATP during different phases of the cell cycle, however it is not completely understood how mitochondrial function and the cell cycle are coordinated. CLUH is a post-transcriptional regulator of mRNAs encoding mitochondrial proteins involved in oxidative phosphorylation and several metabolic pathways. Here, we show a role of CLUH in regulating the expression of astrin, which is involved in metaphase to anaphase progression, centrosome integrity, and mTORC1 inhibition. We find that CLUH binds both the SPAG5 mRNA and its product astrin, and controls the synthesis and the stability of the full-length astrin-1 isoform. We show that CLUH interacts with astrin-1 specifically during interphase. Astrin-depleted cells show mTORC1 hyperactivation and enhanced anabolism. On the other hand, cells lacking CLUH show decreased astrin levels and increased mTORC1 signaling, but cannot sustain anaplerotic and anabolic pathways. In absence of CLUH, cells fail to grow during G1, and progress faster through the cell cycle, indicating dysregulated matching of growth, metabolism and cell cycling. Our data reveal a role of CLUH in coupling growth signaling pathways and mitochondrial metabolism with cell cycle progression.
    Keywords:  cell biology; human
    DOI:  https://doi.org/10.7554/eLife.74552
  23. FASEB J. 2022 May;36 Suppl 1
    Spherical Invasion Assay: A novel method to measure the pro-invasive activity of cancer cells.
    Amanda M Sugrue, Nicholas A Nolan, Stephen D Richbart, Austin T Akers, Kathleen C Brown, Piyali Dasgupta.
      Tumor invasion refers to the process by which cancer cells penetrate the basement membrane into surrounding stroma, neighboring blood vessels and lymph nodes. Tumor invasion is an essential step for metastasis of human cancers. The Boyden Chamber assay is the benchmark technique of measuring the invasion of cancer cells. However, this assay suffers from several caveats. The physiological relevance of transwell inserts (to recapitulate invasion in vivo) is poor. The pore size of the membrane highly influences the number of invaded cells. Another limitation of the Boyden chamber assay is it is very difficult to control the concentration of the chemokine gradient and this may produce aberrant results. All these considerations led us to develop a novel method of measuring tumor invasion namely the SPHERICAL INVASION ASSAY (SIA) in our laboratory. The SIA measures the invasion of human cancer cells as they migrate from the primary Matrigel layer, over the interface and travel into a secondary Matrigel layer. The cells are grown in extracellular matrix (ECM) retain biological characteristics of tumors, such as diffusion gradient of oxygen, nutrients and pH. The growth of the cells inside the ECM allows for complex cell-cell and cell-matrix interaction. Most importantly, the results of the SIA correlate with the data obtained in the Boyden Chamber assay, so the SIA can be used to confirm the results obtained in Boyden Chamber assays1 . The present protocol examines the effect of the Src Kinase inhibitor PP2 on the invasion of A549 human NSCLC cells. We hope that the SIA will be useful tool for researchers working in the field of tumor microenvironment biology and cancer metastasis.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.L6397
  24. Mol Cancer Res. 2022 May 09. pii: molcanres.0888.2021. [Epub ahead of print]
    MUC16 Promotes Liver Metastasis of Pancreatic Ductal Adenocarcinoma by Upregulating NRP2 Associated Cell Adhesion.
    Saravanakumar Marimuthu, Imayavaramban Lakshmanan, Sakthivel Muniyan, Shailendra K Gautam, Rama Krishna Nimmakayala, Sanchita Rauth, Pranita Atri, Ashu Shah, Namita Bhyravbhatla, Kavita Mallya, Paul M Grandgenett, Michael A Hollingsworth, Kaustubh Datta, Maneesh Jain, Moorthy P Ponnusamy, Surinder K Batra.
      Pancreatic ductal adenocarcinoma (PDAC) is the most lethal types of cancer, commonly metastasizes to the liver resulting in an overall poor prognosis. However, the molecular mechanism involved in liver metastasis remains poorly understood. Here, we aimed to identify the MUC16-mediated molecular mechanism of PDAC-liver metastasis. Previous studies demonstrated that MUC16 and its C-terminal (Cter) domain are involved in the aggressiveness of PDAC. In the present study, we observed MUC16 and its Cter expression significantly high in human PDAC tissues, PDAC organoids, and metastatic liver tissues, while no expression was observed in normal pancreatic tissues using immunohistochemistry (IHC) and immunofluorescence (IFC) analyses. MUC16 knockdown in SW1990 and CD18/HPAF PDAC cells significantly decreased the colony formation, migration, and endothelial/p-selectin binding. In contrast, MUC16-Cter ectopic overexpression showed significantly increased colony formation and motility in MiaPaCa2 PC cells. Interestingly, MUC16 promoted cell survival and colonization in the liver, mimicking an ex vivo environment. Furthermore, MUC16 enhanced liver metastasis in the in vivo mouse model. Our integrated analyses of RNA-seq suggested that MUC16 alters Neuropilin-2 (NRP2) and cell adhesion molecules in PC cells. Furthermore, we identified that MUC16 regulated NRP2 via JAK2/STAT1 signaling in PDAC. NRP2 knockdown in MUC16 overexpressed PDAC cells showed significantly decreased cell adhesion and migration. Overall, the findings indicate that MUC16 regulates NRP2 and induces metastasis in PDAC. Implications: This study shows that MUC16 plays a critical role in PDAC liver metastasis by mediating NRP2 regulation by JAK2/STAT1 axis, thereby paving the way for future therapy efforts for metastatic PDAC.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-21-0888
  25. FASEB J. 2022 May;36 Suppl 1
    Evidence for widespread cytoplasmic structuring into mesoscopic condensates.
    Martin Wühr, Felix Keber, Thao Nguyen, Cliff Brangwynne.
      Eukaryotic cytoplasm organizes itself via both membrane-bound organelles and membrane-less biomolecular condensates (BMCs). Known BMCs exhibit liquid-like properties and are typically visualized on the scale of ~1 µm. They have been studied mostly by microscopy, examining select individual proteins. Here, we investigate the global organization of native cytoplasm with quantitative proteomics, using differential pressure filtration, size exclusion, and dilution experiments. These assays reveal that BMCs form throughout the cytosplasm, predominantly at the mesoscale of ~100 nm. Our data indicate that at least 18% of the proteome is organized via such mesoscale BMCs, suggesting that cells widely employ dynamic liquid-like clustering to organize their cytoplasm, at surprisingly small length scales.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.0R768
  26. Science. 2022 May 13. 376(6594): eabl5197
    Cross-tissue immune cell analysis reveals tissue-specific features in humans.
    C Domínguez Conde, C Xu, L B Jarvis, D B Rainbow, S B Wells, T Gomes, S K Howlett, O Suchanek, K Polanski, H W King, L Mamanova, N Huang, P A Szabo, L Richardson, L Bolt, E S Fasouli, K T Mahbubani, M Prete, L Tuck, N Richoz, Z K Tuong, L Campos, H S Mousa, E J Needham, S Pritchard, T Li, R Elmentaite, J Park, E Rahmani, D Chen, D K Menon, O A Bayraktar, L K James, K B Meyer, N Yosef, M R Clatworthy, P A Sims, D L Farber, K Saeb-Parsy, J L Jones, S A Teichmann.
      Despite their crucial role in health and disease, our knowledge of immune cells within human tissues remains limited. We surveyed the immune compartment of 16 tissues from 12 adult donors by single-cell RNA sequencing and VDJ sequencing generating a dataset of ~360,000 cells. To systematically resolve immune cell heterogeneity across tissues, we developed CellTypist, a machine learning tool for rapid and precise cell type annotation. Using this approach, combined with detailed curation, we determined the tissue distribution of finely phenotyped immune cell types, revealing hitherto unappreciated tissue-specific features and clonal architecture of T and B cells. Our multitissue approach lays the foundation for identifying highly resolved immune cell types by leveraging a common reference dataset, tissue-integrated expression analysis, and antigen receptor sequencing.
    DOI:  https://doi.org/10.1126/science.abl5197
  27. Sci Adv. 2022 May 13. 8(19): eabm6638
    Genome-wide CRISPR screens using isogenic cells reveal vulnerabilities conferred by loss of tumor suppressors.
    Xu Feng, Mengfan Tang, Merve Dede, Dan Su, Guangsheng Pei, Dadi Jiang, Chao Wang, Zhen Chen, Mi Li, Litong Nie, Yun Xiong, Siting Li, Jeong-Min Park, Huimin Zhang, Min Huang, Klaudia Szymonowicz, Zhongming Zhao, Traver Hart, Junjie Chen.
      Exploiting cancer vulnerabilities is critical for the discovery of anticancer drugs. However, tumor suppressors cannot be directly targeted because of their loss of function. To uncover specific vulnerabilities for cells with deficiency in any given tumor suppressor(s), we performed genome-scale CRISPR loss-of-function screens using a panel of isogenic knockout cells we generated for 12 common tumor suppressors. Here, we provide a comprehensive and comparative dataset for genetic interactions between the whole-genome protein-coding genes and a panel of tumor suppressor genes, which allows us to uncover known and new high-confidence synthetic lethal interactions. Mining this dataset, we uncover essential paralog gene pairs, which could be a common mechanism for interpreting synthetic lethality. Moreover, we propose that some tumor suppressors could be targeted to suppress proliferation of cells with deficiency in other tumor suppressors. This dataset provides valuable information that can be further exploited for targeted cancer therapy.
    DOI:  https://doi.org/10.1126/sciadv.abm6638
  28. Aging (Albany NY). 2022 May 09. 14(undefined):
    Hallmarks of cancer and hallmarks of aging.
    Mikhail V Blagosklonny.
      A thought-provoking article by Gems and de Magalhães suggests that canonic hallmarks of aging are superficial imitations of hallmarks of cancer. I took their work a step further and proposed hallmarks of aging based on a hierarchical principle and the hyperfunction theory.To do this, I first reexamine the hallmarks of cancer proposed by Hanahan and Weinberg in 2000. Although six hallmarks of cancer are genuine, they are not hierarchically arranged, i.e., molecular, intra-cellular, cellular, tissue, organismal and extra-organismal. (For example, invasion and angiogenesis are manifestations of molecular alterations on the tissue level; metastasis on the organismal level, whereas cell immortality is observed outside the host).The same hierarchical approach is applicable to aging. Unlike cancer, however, aging is not a molecular disease. The lowest level of its origin is normal intracellular signaling pathways such as mTOR that drive developmental growth and, later in life, become hyperfunctional, causing age-related diseases, whose sum is aging. The key hallmark of organismal aging, from worms to humans, are age-related diseases. In addition, hallmarks of aging can be arranged as a timeline, wherein initial hyperfunction is followed by dysfunction, organ damage and functional decline.
    Keywords:  carcinogenesis; geroscience; hyperfunction theory; mTOR; oncology; rapamycin
    DOI:  https://doi.org/10.18632/aging.204082
  29. Cell Rep. 2022 May 10. pii: S2211-1247(22)00563-0. [Epub ahead of print]39(6): 110796
    Lipogenesis mediated by OGR1 regulates metabolic adaptation to acid stress in cancer cells via autophagy.
    Smitha Pillai, Iqbal Mahmud, Rohit Mahar, Crystal Griffith, Michael Langsen, Jonathan Nguyen, Jonathan W Wojtkowiak, Pawel Swietach, Robert A Gatenby, Marilyn M Bui, Matthew E Merritt, Patricia McDonald, Timothy J Garrett, Robert J Gillies.
      Malignant tumors exhibit altered metabolism resulting in a highly acidic extracellular microenvironment. Here, we show that cytoplasmic lipid droplet (LD) accumulation, indicative of a lipogenic phenotype, is a cellular adaption to extracellular acidity. LD marker PLIN2 is strongly associated with poor overall survival in breast cancer patients. Acid-induced LD accumulation is triggered by activation of the acid-sensing G-protein-coupled receptor (GPCR) OGR1, which is expressed highly in breast tumors. OGR1 depletion inhibits acid-induced lipid accumulation, while activation by a synthetic agonist triggers LD formation. Inhibition of OGR1 downstream signaling abrogates the lipogenic phenotype, which can be rescued with OGR1 ectopic expression. OGR1-depleted cells show growth inhibition under acidic growth conditions in vitro and tumor formation in vivo. Isotope tracing shows that the source of lipid precursors is primarily autophagy-derived ketogenic amino acids. OGR1-depleted cells are defective in endoplasmic reticulum stress response and autophagy and hence fail to accumulate LDs affecting survival under acidic stress.
    Keywords:  CP: Cancer; ER stress; OGR1/GPR68; acid-sensing GPCR; acidosis; adiposomes; autophagy; lipid droplets; lipid metabolism; lipogenesis; metabolic adaptation
    DOI:  https://doi.org/10.1016/j.celrep.2022.110796
  30. FASEB J. 2022 May;36 Suppl 1
    Autophagy Impairment and Sarcopenia in Type-Identified Muscle Fibers of Aging Extensor Digitorum Longus Muscle.
    Miguel Pareja-Cajiao, Maria A Barrera, Rachel A Ducaji, Heather M Gransee, Nathan J Hellyer, Gary C Sieck, Carlos B Mantilla.
      Sarcopenia is the aging-related loss of force-generating capacity and atrophy of skeletal muscles and is a major contributor to morbidity and mortality in the elderly. The molecular mechanisms underlying sarcopenia remain to be elucidated. Skeletal muscles exhibit different rates of sarcopenia, generally reflecting their specific muscle fiber type composition. Muscles primarily composed of type IIx and/or IIb muscle fibers (i.e., extensor digitorum longus; EDLm) develop sarcopenia at a faster rate than other muscles. In the diaphragm, muscle fiber cross-sectional area (CSA) is reduced in old age, predominantly in type IIx and/or IIb fibers. Autophagy is a multistep, catabolic process that targets dysfunctional cytoplasmatic structures including proteins and organelles for degradation and recycling. Autophagy is impaired in old age across several tissues, including motor neurons and skeletal muscle. Expression of core autophagy proteins can indicate changes in autophagy, e.g., LC3 reflects initiation/elongation steps and p62 clearance reflects degradation. We hypothesize that impaired autophagy is associated with the development of sarcopenia in type-identified muscle fibers of the EDLm. Indeed, at 24-months of age, the CSA of type I and IIa fibers was not reduced, whereas the CSA of type IIx and/or IIb fibers was ~25% smaller (p<0.01 in both cases), compared to 6-month-old mice. These findings are consistent with fiber type selective sarcopenia in the EDLm. Expression of LC3 and p62 in the EDLm of mice at 6- and 24- months of age was evaluated via immunofluorescence by quantification of the number of LC3 and p62 puncta per muscle fiber type. In type I and IIa fibers, the number of LC3 puncta increased by ~30% and of p62 increased three-fold in 24- compared to 6-month-old mice (p<0.01 in both cases). In type IIx and/or IIb fibers, the number of LC3 puncta decreased by ~60% and p62 puncta increased by ~50% in 24- compared to 6-month-old mice (p<0.01 in both cases). Accordingly, compared to 6 month-old mice, autophagic degradation is impaired across muscle fiber types in 24-month old mice, but likely to a greater extent in type I and IIa fibers of old mice given the increase in both LC3 and p62. Autophagic initiation is primarily reduced in type IIx and/or IIb fibers in the EDL as indicated by the reduced LC3 expression. Taken together these findings indicate that fiber type selective sarcopenia may reflect differences in autophagy across muscle fiber types.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.L7909
  31. EMBO J. 2022 May 13. e111424
    Autophagy power expands: fuse those cells!
    Rojyar Khezri, Tor Erik Rusten.
      The lysosomal degradation pathway of autophagy depends on a set of evolutionarily conserved autophagy-related molecules (ATGs) bestowed with the power to direct membrane trafficking and biology. In this issue of EMBO Journal, Kakanj P et al reveal a surprising role for the autophagy machinery in cell fusion (Kakanj et al, 2022). Autophagy is physiologically required for cell syncytium formation through dismantling the lateral plasma membrane during wound healing, and unchecked autophagy can drive cell fusion in epithelial tissues without compromising epithelial integrity.
    DOI:  https://doi.org/10.15252/embj.2022111424
  32. Cell. 2022 May 09. pii: S0092-8674(22)00472-X. [Epub ahead of print]
    Topical therapy for regression and melanoma prevention of congenital giant nevi.
    Yeon Sook Choi, Tal H Erlich, Max von Franque, Inbal Rachmin, Jessica L Flesher, Erik B Schiferle, Yi Zhang, Marcello Pereira da Silva, Alva Jiang, Allison S Dobry, Mack Su, Sharon Germana, Sebastian Lacher, Orly Freund, Ezra Feder, Jose L Cortez, Suyeon Ryu, Tamar Babila Propp, Yedidyah Leo Samuels, Labib R Zakka, Marjan Azin, Christin E Burd, Norman E Sharpless, X Shirley Liu, Clifford Meyer, William Gerald Austen, Branko Bojovic, Curtis L Cetrulo, Martin C Mihm, Dave S Hoon, Shadmehr Demehri, Elena B Hawryluk, David E Fisher.
      Giant congenital melanocytic nevi are NRAS-driven proliferations that may cover up to 80% of the body surface. Their most dangerous consequence is progression to melanoma. This risk often triggers preemptive extensive surgical excisions in childhood, producing severe lifelong challenges. We have presented preclinical models, including multiple genetically engineered mice and xenografted human lesions, which enabled testing locally applied pharmacologic agents to avoid surgery. The murine models permitted the identification of proliferative versus senescent nevus phases and treatments targeting both. These nevi recapitulated the histologic and molecular features of human giant congenital nevi, including the risk of melanoma transformation. Cutaneously delivered MEK, PI3K, and c-KIT inhibitors or proinflammatory squaric acid dibutylester (SADBE) achieved major regressions. SADBE triggered innate immunity that ablated detectable nevocytes, fully prevented melanoma, and regressed human giant nevus xenografts. These findings reveal nevus mechanistic vulnerabilities and suggest opportunities for topical interventions that may alter the therapeutic options for children with congenital giant nevi.
    Keywords:  Nras; congenital melanocytic nevus; hapten; melanoma; mole; prevention; topical
    DOI:  https://doi.org/10.1016/j.cell.2022.04.025
  33. Trends Biotechnol. 2022 May 07. pii: S0167-7799(22)00101-9. [Epub ahead of print]
    A hitchhiker's guide to cancer models.
    Karim I Budhwani, Zeelu H Patel, Rachael E Guenter, Areesha A Charania.
      Cancer is a complex and uniquely personal disease. More than 1.7 million people in the United States are diagnosed with cancer every year. As the burden of cancer grows, so does the need for new, more effective therapeutics and for predictive tools to identify optimal, personalized treatment options for every patient. Cancer models that recapitulate various aspects of the disease are fundamental to making advances along the continuum of cancer treatment from benchside discoveries to bedside delivery. In this review, we use a thought experiment as a vehicle to arrive at four broad categories of cancer models and explore the strengths, weaknesses, opportunities, and threats for each category in advancing our understanding of the disease and improving treatment strategies.
    Keywords:  SWOT analysis; clinical translation; disease modeling; ex vivo; in silico; in vitro; in vivo; personalized medicine; precision medicine; therapeutic discovery
    DOI:  https://doi.org/10.1016/j.tibtech.2022.04.003
  34. Sci Adv. 2022 May 13. 8(19): eabn7232
    Molecular architecture of the human caveolin-1 complex.
    Jason C Porta, Bing Han, Alican Gulsevin, Jeong Min Chung, Yelena Peskova, Sarah Connolly, Hassane S Mchaourab, Jens Meiler, Erkan Karakas, Anne K Kenworthy, Melanie D Ohi.
      Membrane-sculpting proteins shape the morphology of cell membranes and facilitate remodeling in response to physiological and environmental cues. Complexes of the monotopic membrane protein caveolin function as essential curvature-generating components of caveolae, flask-shaped invaginations that sense and respond to plasma membrane tension. However, the structural basis for caveolin's membrane remodeling activity is currently unknown. Here, we show that, using cryo-electron microscopy, the human caveolin-1 complex is composed of 11 protomers organized into a tightly packed disc with a flat membrane-embedded surface. The structural insights suggest a previously unrecognized mechanism for how membrane-sculpting proteins interact with membranes and reveal how key regions of caveolin-1, including its scaffolding, oligomerization, and intramembrane domains, contribute to its function.
    DOI:  https://doi.org/10.1126/sciadv.abn7232
  35. J Pathol. 2022 May 09.
    Cancer-associated fibroblasts in pancreatic cancer: new subtypes, new markers, new targets.
    Shinelle Menezes, Mohamed Hazem Okail, Siti Munira Abd Jalil, Hemant M Kocher, Angus J M Cameron.
      Cancer-associated fibroblasts (CAFs) have conflicting roles in the suppression and promotion of cancer. Current research focuses on targeting undesirable properties of CAFs while attempting to maintain tumour suppressive roles. CAFs have been widely associated with primary or secondary therapeutic resistance, and strategies to modify CAF function have therefore largely focussed on their combination with existing therapies. Despite significant progress in pre-clinical studies, clinical translation of CAF targeted therapies has achieved limited success. Here we will review our emerging understanding of heterogeneous CAF populations in tumour biology and use examples from pancreatic ductal adenocarcinoma (PDAC) to explore why successful clinical targeting of pro-tumourigenic CAF functions remains elusive. Single-cell technologies have allowed the identification of CAF subtypes with differential impact on prognosis and response to therapy, but currently without clear consensus. Identification and pharmacological targeting of CAF subtypes associated with immunotherapy response offers new hope to expand clinical options for pancreatic cancer. Various CAF subtype markers may represent biomarkers for patient stratification, to obtain enhanced response with existing and emerging combinatorial therapeutic strategies. Thus, CAF sub-typing is the next frontier in understanding and exploiting the tumour micro-environment (TME) for therapeutic benefit. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/path.5926
  36. Clin Nutr. 2022 Apr 21. pii: S0261-5614(22)00139-X. [Epub ahead of print]41(6): 1316-1319
    Calorie restriction in cancer patients undergoing chemotherapy: Facts, phantasy or misunderstanding.
    Federico Bozzetti.
      BACKGROUND & AIMS: Experimental studies in cancer cell lines and tumour-bearing animals support the concept that a short-period fasting could potentiate the effect of antineoplastic chemotherapy due to a particular metabolic adaptation normal cells whereas cancer cells would remain particularly sensitive to the toxic effects of the therapy. The potential of such approach is actually emphasized by the media but data in humans are very scant and many oncologists fear that peri-chemotherapy fasting might worsen the patient nutritional status. The aim of this review is to focus on the benefits versus the adverse effects of the peri-chemotherapy fasting and to clarify if discrepancy of opinions regarding this approach relies on data from clinical trials or simply on misunderstandings or prejudices.METHODS: We reviewed all the available literature regarding the peri-chemotherapy fasting in cancer patients with a special focus on compliance, adverse event prevalence and tumour response.
    RESULTS: Seven papers were available for the analysis. All studies included seemingly well-nourished patients and most of them had a breast or a gynaecologic cancer. Almost all concluded for the feasibility of the peri-chemotherapy fasting, with a good patient compliance. Weight loss was always reported but it was generally mild even if sometimes required a nutritional intervention between the cycles of chemotherapy. One RCT reported a better radiological response of the breast cancer at the neoadjuvant chemotherapy.
    CONCLUSION: Peri-chemotherapy fasting appears a safe procedure in well-nourished patients receiving a short-term chemotherapy. However claims of oncologic benefit are premature and rumors about its efficacy are presently unjustified.
    Keywords:  Calorie restriction; Differential stress resistance; Fasting mimicking diet; Peri-chemotherapy fasting; Peri-chemotherapy nutritional support; Tumour growth during calorie restriction
    DOI:  https://doi.org/10.1016/j.clnu.2022.04.020
  37. Science. 2022 May 12. eabo0510
    Mapping the developing human immune system across organs.
    Chenqu Suo, Emma Dann, Issac Goh, Laura Jardine, Vitalii Kleshchevnikov, Jong-Eun Park, Rachel A Botting, Emily Stephenson, Justin Engelbert, Zewen Kelvin Tuong, Krzysztof Polanski, Nadav Yayon, Chuan Xu, Ondrej Suchanek, Rasa Elmentaite, Cecilia Domínguez Conde, Peng He, Sophie Pritchard, Mohi Miah, Corina Moldovan, Alexander S Steemers, Pavel Mazin, Martin Prete, Dave Horsfall, John C Marioni, Menna R Clatworthy, Muzlifah Haniffa, Sarah A Teichmann.
      Single-cell genomics studies have decoded the immune-cell composition of several human prenatal organs but were limited in understanding the developing immune system as a distributed network across tissues. We profiled nine prenatal tissues combining single-cell RNA sequencing, antigen-receptor sequencing, and spatial transcriptomics to reconstruct the developing human immune system. This revealed the late acquisition of immune effector functions by myeloid and lymphoid cell subsets and the maturation of monocytes and T cells prior to peripheral tissue seeding. Moreover, we uncovered system-wide blood and immune cell development beyond primary hematopoietic organs, characterized human prenatal B1 cells, and shed light on the origin of unconventional T cells. Our atlas provides both valuable data resources and biological insights that will facilitate cell engineering, regenerative medicine, and disease understanding.
    DOI:  https://doi.org/10.1126/science.abo0510
  38. Cancers (Basel). 2022 Apr 23. pii: 2107. [Epub ahead of print]14(9):
    Molecular Mechanisms and Current Treatment Options for Cancer Cachexia.
    Syed Sayeed Ahmad, Khurshid Ahmad, Sibhghatulla Shaikh, Hye Jin You, Eun-Young Lee, Shahid Ali, Eun Ju Lee, Inho Choi.
      Cancer cachexia is a condition marked by functional, metabolic, and immunological dysfunctions associated with skeletal muscle (SM) atrophy, adipose tissue loss, fat reduction, systemic inflammation, and anorexia. Generally, the condition is caused by a variety of mediators produced by cancer cells and cells in tumor microenvironments. Myostatin and activin signaling, IGF-1/PI3K/AKT signaling, and JAK-STAT signaling are known to play roles in cachexia, and thus, these pathways are considered potential therapeutic targets. This review discusses the current state of knowledge of the molecular mechanisms underlying cachexia and the available therapeutic options and was undertaken to increase understanding of the various factors/pathways/mediators involved and to identify potential treatment options.
    Keywords:  cancer cachexia; inhibitors; myostatin; natural compounds; skeletal muscle
    DOI:  https://doi.org/10.3390/cancers14092107
  39. Cells. 2022 Apr 27. pii: 1472. [Epub ahead of print]11(9):
    Obesity-Associated Cancers: Evidence from Studies in Mouse Models.
    Ho Lee.
      Obesity, one of the major problems in modern human society, is correlated with various diseases, including type 2 diabetes mellitus (T2DM). In particular, epidemiological and experimental evidence indicates that obesity is closely linked to at least 13 different types of cancer. The mechanisms that potentially explain the link between obesity and cancer include hyperactivation of the IGF pathway, metabolic dysregulation, dysfunctional angiogenesis, chronic inflammation, and interaction between pro-inflammatory cytokines, endocrine hormones, and adipokines. However, how the largely uniform morbidity of obesity leads to different types of cancer still needs to be investigated. To study the link between obesity and cancer, researchers have commonly used preclinical animal models, particularly mouse models. These models include monogenic models of obesity (e.g., ob/ob and db/db mice) and genetically modified mouse models of human cancers (e.g., Kras-driven pancreatic cancer, Apc-mutated colorectal cancer, and Her2/neu-overexpressing breast cancer). The experimental results obtained using these mouse models revealed strong evidence of a link between obesity and cancer and suggested their underlying mechanisms.
    Keywords:  mouse cancer model; obesity; obesity-associated cancer
    DOI:  https://doi.org/10.3390/cells11091472
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