bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2022–06–12
twenty-six papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Stress Granules determine the Development of Obesity-associated Pancreatic Cancer.
  2. Metabolic reprogramming: a bridge between aging and tumorigenesis.
  3. Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer.
  4. Melatonin modulates metabolic adaptation of pancreatic stellate cells subjected to hypoxia.
  5. Glycolysis addiction compensating for a defective pentose phosphate pathway confers gemcitabine sensitivity in SETD2-deficient pancreatic cancer.
  6. Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq.
  7. Inhibition of a Mitochondrial Potassium Channel in Combination with Gemcitabine and Abraxane Drastically Reduces Pancreatic Ductal Adenocarcinoma in an Immunocompetent Orthotopic Murine Model.
  8. Autophagy at the intersection of aging, senescence, and cancer.
  9. Targeting cellular senescence to combat cancer and aging.
  10. Emerging roles of mitotic autophagy.
  11. Comparison of FOLFIRINOX vs Gemcitabine Plus Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Ductal Adenocarcinoma.
  12. Cellular senescence and the tumor microenvironment.
  13. Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.
  14. ILC2s-Bipartisan politicians in cancer.
  15. Hypoxia controls plasma membrane targeting of polarity proteins by dynamic turnover of PI4P and PI(4,5)P2.
  16. Evaluating the glycolytic potential of mouse costimulated effector CD8+ T cells ex vivo.
  17. MALDI Mass Spectrometry Imaging for the Distinction of Adenocarcinomas of the Pancreas and Biliary Tree.
  18. An Update to Hallmarks of Cancer.
  19. Towards a molecular mechanism underlying mitochondrial protein import through the TOM and TIM23 complexes.
  20. Application and prospect of single-cell sequencing in cancer metastasis.
  21. Physiological functions and roles in cancer of the proliferation marker Ki-67.
  22. A Resource to Infer Molecular Paths Linking Cancer Mutations to Perturbation of Cell Metabolism.
  23. The Genetics of Autophagy in Multicellular Organisms.
  24. Systemic Therapy of Metastatic Pancreatic Adenocarcinoma: Current Status, Challenges, and Opportunities.
  25. Monounsaturated fatty acids: key regulators of cell viability and intracellular signalling in cancer.
  26. EviCor: Interactive Web Platform for Exploration of Molecular Features and Response to Anti-cancer Drugs.
  1. Cancer Discov. 2022 Jun 08. pii: candisc.1672.2021. [Epub ahead of print]
    Stress Granules determine the Development of Obesity-associated Pancreatic Cancer.
    Guillaume Fonteneau, Alexandra Redding, Hannah Hoag-Lee, Edward S Sim, Stefan Heinrich, Matthias M Gaida, Elda Grabocka.
      Obesity is a global epidemic and a major predisposing factor for cancer. Increasing evidence shows that obesity-associated stress is a key driver of cancer risk and progression. Previous work has identified the phase-separation organelles, stress granules (SGs), as mutant KRAS-dependent mediators of stress adaptation. However, the dependence of tumorigenesis on these organelles is unknown. Here, we establish a causal link between SGs and pancreatic ductal adenocarcinoma (PDAC). Importantly, we uncover that dependence on SGs is drastically heightened in obesity-associated PDAC. Furthermore, we identify a previously unknown regulator and component of SGs, namely the serine/arginine protein kinase 2 (SRPK2), as a specific determinant of SG formation in obesity-associated PDAC. We show that SRPK2-mediated SG formation in obesity-associated PDAC is driven by hyperactivation of the IGF1/PI3K/mTOR/S6K1 pathway, and that S6K1 inhibition selectively attenuates SGs and impairs obesity-associated PDAC development.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-1672
  2. Mol Oncol. 2022 Jun 05.
    Metabolic reprogramming: a bridge between aging and tumorigenesis.
    Stanislav Drapela, Didem Ilter, Ana P Gomes.
      Aging is the most robust risk factor for cancer development, with more than 60% of cancers occurring in those aged 60 and above. However, how aging and tumorigenesis are intertwined is poorly understood and a matter of significant debate. Metabolic changes are hallmarks of both aging and tumorigenesis. The deleterious consequences of aging include dysfunctional cellular processes, the build up of metabolic by-products and waste molecules in circulation and within tissues, and stiffer connective tissues that impede blood flow and oxygenation. Collectively, these age-driven changes lead to metabolic reprogramming in different cell types of a given tissue that significantly affects their cellular functions. Here, we put forward the idea that metabolic changes that happen during aging help create a favorable environment for tumorigenesis. We review parallels in metabolic changes that happen during aging and how these changes function both as adaptive mechanisms that enable the development of malignant phenotypes in a cell-autonomous manner and as mechanisms that suppress immune surveillance, collectively creating the perfect environment for cancers to thrive. Hence, anti-aging therapeutic strategies that target the metabolic reprogramming that occurs as we age might provide new opportunities to prevent cancer initiation and/or improve responses to standard-of-care anti-cancer therapies.
    Keywords:  Aging; cellular energetics; immune response; metabolic reprogramming; tumorigenesis
    DOI:  https://doi.org/10.1002/1878-0261.13261
  3. Cancer Cell. 2022 May 31. pii: S1535-6108(22)00217-3. [Epub ahead of print]
    Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer.
    Emma Kurz, Carolina Alcantara Hirsch, Tanner Dalton, Sorin Alberto Shadaloey, Alireza Khodadadi-Jamayran, George Miller, Sumedha Pareek, Hajar Rajaei, Chirayu Mohindroo, Seyda Baydogan, An Ngo-Huang, Nathan Parker, Matthew H G Katz, Maria Petzel, Emily Vucic, Florencia McAllister, Keri Schadler, Rafael Winograd, Dafna Bar-Sagi.
      Aerobic exercise is associated with decreased cancer incidence and cancer-associated mortality. However, little is known about the effects of exercise on pancreatic ductal adenocarcinoma (PDA), a disease for which current therapeutic options are limited. Herein, we show that aerobic exercise reduces PDA tumor growth, by modulating systemic and intra-tumoral immunity. Mechanistically, exercise promotes immune mobilization and accumulation of tumor-infiltrating IL15Rα+ CD8 T cells, which are responsible for the tumor-protective effects. In clinical samples, an exercise-dependent increase of intra-tumoral CD8 T cells is also observed. Underscoring the translational potential of the interleukin (IL)-15/IL-15Rα axis, IL-15 super-agonist (NIZ985) treatment attenuates tumor growth, prolongs survival, and enhances sensitivity to chemotherapy. Finally, exercise or NIZ985 both sensitize pancreatic tumors to αPD-1, with improved anti-tumor and survival benefits. Collectively, our findings highlight the therapeutic potential of an exercise-oncology axis and identify IL-15 activation as a promising treatment strategy for this deadly disease.
    Keywords:  IL-15; PD-1; T cell; checkpoint blockade; exercise; immunology; immunotherapy; pancreatic cancer; super-agonist
    DOI:  https://doi.org/10.1016/j.ccell.2022.05.006
  4. Biochem Pharmacol. 2022 Jun 04. pii: S0006-2952(22)00212-X. [Epub ahead of print] 115118
    Melatonin modulates metabolic adaptation of pancreatic stellate cells subjected to hypoxia.
    Matias Estaras, Remigio Martinez, Alfredo García, Cándido Ortiz-Placin, Juan L Iovanna, Patricia Santofimia-Castaño, Antonio Gonzalez.
      Pancreatic stellate cells (PSCs), the main cell type responsible for the development of fibrosis in pancreatic cancer, proliferate actively under hypoxia. Melatonin has received attention as a potential antifibrotic agent due to its anti-proliferative actions on PSCs. In this work, we investigated the activation of the PI3K/Akt/mTOR pathway and the metabolic adaptations that PSCs undergo under hypoxic conditions, as well as the probable modulation by melatonin. Incubation of cells under hypoxia induced an increase in cell proliferation, and in the expression of alpha-smooth muscle actin and of collagen type 1. In addition, an increase in the phosphorylation of Akt was observed, whereas a decrease in the phosphorylation of PTEN and GSK-3b was noted. The phosphorylation of mTOR and its substrate p70 S6K was decreased under hypoxia. Treatment of PSCs with melatonin under hypoxia diminished cell proliferation, the levels of alpha-smooth muscle actin and of collagen type 1, the phosphorylation of Akt and increased phosphorylation of mTOR. Mitochondrial activity decreased in PSCs under hypoxia. A glycolytic shift was observed. Melatonin further decreased mitochondrial activity. Under hypoxia, no increase in autophagic flux was noted. However, melatonin treatment induced autophagy activation. Nevertheless, inhibition of this process did not induce detectable changes in the viability of cells treated with melatonin. We conclude that PSCs undergo metabolic adaptation under hypoxia that might help them survive and that pharmacological concentrations of melatonin modulate cell responses to hypoxia. Our results contribute to the knowledge of the mechanisms by which melatonin could modulate fibrosis within the pancreas.
    Keywords:  fibrosis; glycolysis; hypoxia; melatonin; pancreatic stellate cells
    DOI:  https://doi.org/10.1016/j.bcp.2022.115118
  5. Biochem Biophys Res Commun. 2022 May 16. pii: S0006-291X(22)00745-8. [Epub ahead of print]615 9-16
    Glycolysis addiction compensating for a defective pentose phosphate pathway confers gemcitabine sensitivity in SETD2-deficient pancreatic cancer.
    Xuqing Shen, Yueyue Chen, Mingzhu Liu, Juanjuan Shi, Yingying Tang, Xiaotong Yang, Dapeng Xu, Hongfei Yao, Ping Lu, Yongwei Sun, Jing Xue, Ningning Niu.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy driven by genetic mutations and/or epigenetic dysregulation. Gemcitabine chemotherapy is the first-line regimen for pancreatic cancer but has limited efficacy. Our previous study revealed the role of SETD2-H3K36me3 loss in the initiation and metastasis of PDAC, but little is known about its role in tumor metabolism. Here, we found that SETD2-deficient PDAC enhanced glycolysis addiction via upregulation of glucose transporter 1 (GLUT1) to meet its large demand for glucose in progression. Moreover, SETD2 deficiency impaired nucleoside synthesis by directly downregulating the transcriptional level of transketolase (TKT) in the pentose phosphate pathway. The metabolic changes confer SETD2-deficient PDAC cells with increased sensitivity to gemcitabine under glycolysis restriction conditions. Collectively, our study provides mechanistic insights into how SETD2 deficiency reprograms glycolytic metabolism to compensate for insufficient nucleoside synthesis, suggesting that glycolysis restriction combined with gemcitabine might be a potential therapeutic strategy for PDAC patients with SETD2 deficiency.
    Keywords:  GLUT1; Metabolic reprogramming; PDAC; SETD2; TKT
    DOI:  https://doi.org/10.1016/j.bbrc.2022.05.047
  6. Cell. 2022 Jun 02. pii: S0092-8674(22)00597-9. [Epub ahead of print]
    Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq.
    Joseph M Replogle, Reuben A Saunders, Angela N Pogson, Jeffrey A Hussmann, Alexander Lenail, Alina Guna, Lauren Mascibroda, Eric J Wagner, Karen Adelman, Gila Lithwick-Yanai, Nika Iremadze, Florian Oberstrass, Doron Lipson, Jessica L Bonnar, Marco Jost, Thomas M Norman, Jonathan S Weissman.
      A central goal of genetics is to define the relationships between genotypes and phenotypes. High-content phenotypic screens such as Perturb-seq (CRISPR-based screens with single-cell RNA-sequencing readouts) enable massively parallel functional genomic mapping but, to date, have been used at limited scales. Here, we perform genome-scale Perturb-seq targeting all expressed genes with CRISPR interference (CRISPRi) across >2.5 million human cells. We use transcriptional phenotypes to predict the function of poorly characterized genes, uncovering new regulators of ribosome biogenesis (including CCDC86, ZNF236, and SPATA5L1), transcription (C7orf26), and mitochondrial respiration (TMEM242). In addition to assigning gene function, single-cell transcriptional phenotypes allow for in-depth dissection of complex cellular phenomena-from RNA processing to differentiation. We leverage this ability to systematically identify genetic drivers and consequences of aneuploidy and to discover an unanticipated layer of stress-specific regulation of the mitochondrial genome. Our information-rich genotype-phenotype map reveals a multidimensional portrait of gene and cellular function.
    Keywords:  CRISPR; Integrator complex; Perturb-seq; cell biology; chromosomal instability; genetic screens; genotype-phenotype map; mitochondrial genome stress response; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.cell.2022.05.013
  7. Cancers (Basel). 2022 May 25. pii: 2618. [Epub ahead of print]14(11):
    Inhibition of a Mitochondrial Potassium Channel in Combination with Gemcitabine and Abraxane Drastically Reduces Pancreatic Ductal Adenocarcinoma in an Immunocompetent Orthotopic Murine Model.
    Weiwei Li, Gregory C Wilson, Magdalena Bachmann, Jiang Wang, Andrea Mattarei, Cristina Paradisi, Michael J Edwards, Ildiko Szabo, Erich Gulbins, Syed A Ahmad, Sameer H Patel.
      Pancreas ductal adenocarcinoma (PDAC) is one the most aggressive cancers and associated with very high mortality, requiring the development of novel treatments. The mitochondrial voltage-gated potassium channel, Kv1.3 is emerging as an attractive oncologic target but its function in PDAC is unknown. Here, we evaluated the tissue expression of Kv1.3 in resected PDAC from 55 patients using immunohistochemistry (IHC) and show that all tumors expressed Kv1.3 with 60% of tumor specimens having high Kv1.3 expression. In Pan02 cells, the recently developed mitochondria-targeted Kv1.3 inhibitors PCARBTP and PAPTP strongly reduced cell survival in vitro. In an orthotopic pancreas tumor model (Pan02 cells injected into C57BL/6 mice) in immune-competent mice, injection of PAPTP or PCARBTP resulted in tumor reductions of 87% and 70%, respectively. When combined with clinically used Gemcitabine plus Abraxane (albumin-bound paclitaxel), reduction reached 95% and 80% without resultant organ toxicity. Drug-mediated tumor cell death occurred through the p38-MAPK pathway, loss of mitochondrial membrane potential, and oxidative stress. Resistant Pan02 clones to PCARBTP escaped cell death through upregulation of the antioxidant system. In contrast, tumor cells did not develop resistance to PAPTP. Our data show that Kv1.3 is highly expressed in resected human PDAC and the use of novel mitochondrial Kv1.3 inhibitors combined with cytotoxic chemotherapies might be a novel, effective treatment for PDAC.
    Keywords:  Kv1.3; mitochondria; pancreas adenocarcinoma; potassium channel
    DOI:  https://doi.org/10.3390/cancers14112618
  8. Mol Oncol. 2022 Jun 10.
    Autophagy at the intersection of aging, senescence, and cancer.
    Liam D Cassidy, Masashi Narita.
      Autophagy is an evolutionarily conserved cellular process in which macromolecules undergo lysosomal degradation. It fulfils essential roles in quality controlling cellular constituents and in energy homeostasis. Basal autophagy is also widely accepted to provide a protective role in aging and aging-related disorders, and its decline with age might precipitate the onset of a variety of diseases. In this review, we discuss the role of basal autophagy in maintaining homeostasis, in part through the maintenance of stem cell populations and the prevention of cellular senescence. We also consider how stress-induced senescence, for example during oncogene activation and in premalignant disease, might rely on autophagy, and the possibility that the age-associated decline in autophagy might promote tumor development through a variety of mechanisms. Ultimately, evidence suggests that autophagy is required for malignant cancer progression in a number of settings. Thus, autophagy appears to be tumor-suppressive during the early stages of tumorigenesis and tumor-promoting at later stages.
    Keywords:  Autophagy; aging; cancer; senescence
    DOI:  https://doi.org/10.1002/1878-0261.13269
  9. Mol Oncol. 2022 Jun 08.
    Targeting cellular senescence to combat cancer and aging.
    Chen Wang, Xue Hao, Rugang Zhang.
      Senescence is a complex cellular process that is implicated in various physiological and pathological processes. It is characterized by a stable state of cell growth arrest and by a secretome of diverse pro-inflammatory factors, chemokines and growth factors. In this review, we summarize the context-dependent role of cellular senescence in aging and in age-related diseases, such as cancer. We discuss current approaches to targeting senescence to develop therapeutic strategies to combat cancer and to promote healthy aging, and we outline our vision for future research directions for senescence-based interventions in these fields.
    Keywords:  aging; cancer; senescence; senolytics; senomorphics
    DOI:  https://doi.org/10.1002/1878-0261.13266
  10. J Cell Sci. 2022 Jun 01. pii: jcs255802. [Epub ahead of print]135(11):
    Emerging roles of mitotic autophagy.
    Eugenia Almacellas, Caroline Mauvezin.
      Lysosomes exert pleiotropic functions to maintain cellular homeostasis and degrade autophagy cargo. Despite the great advances that have boosted our understanding of autophagy and lysosomes in both physiology and pathology, their function in mitosis is still controversial. During mitosis, most organelles are reshaped or repurposed to allow the correct distribution of chromosomes. Mitotic entry is accompanied by a reduction in sites of autophagy initiation, supporting the idea of an inhibition of autophagy to protect the genetic material against harmful degradation. However, there is accumulating evidence revealing the requirement of selective autophagy and functional lysosomes for a faithful chromosome segregation. Degradation is the most-studied lysosomal activity, but recently described alternative functions that operate in mitosis highlight the lysosomes as guardians of mitotic progression. Because the involvement of autophagy in mitosis remains controversial, it is important to consider the specific contribution of signalling cascades, the functions of autophagic proteins and the multiple roles of lysosomes, as three entangled, but independent, factors controlling genomic stability. In this Review, we discuss the latest advances in this area and highlight the therapeutic potential of targeting autophagy for drug development.
    Keywords:  Autophagy; Cancer; Chromosomal instability; Chromosome segregation; Lysosomes; Mitosis
    DOI:  https://doi.org/10.1242/jcs.255802
  11. JAMA Netw Open. 2022 Jun 01. 5(6): e2216199
    Comparison of FOLFIRINOX vs Gemcitabine Plus Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Ductal Adenocarcinoma.
    Avital Klein-Brill, Shlomit Amar-Farkash, Gabriella Lawrence, Eric A Collisson, Dvir Aran.
       Importance: FOLFIRINOX (leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin) and gemcitabine plus nab-paclitaxel are the 2 common first-line therapies for metastatic adenocarcinoma of the pancreas (mPC), but they have not been directly compared in a clinical trial, and comparative clinical data analyses on their effectiveness are limited.
    Objective: To compare the FOLFIRINOX and gemcitabine plus nab-paclitaxel treatments of mPC in clinical data and evaluate whether there are differences in overall survival and posttreatment complications between them.
    Design, Setting, and Participants: This retrospective, nonrandomized comparative effectiveness study used data from the AIM Specialty Health-Anthem Cancer Care Quality Program and from administrative claims of commercially insured patients, spanning 388 outpatient centers and clinics for medical oncology located in 44 states across the US. Effectiveness and safety of the treatments were analyzed by matching or adjusting for age, Charlson Comorbidity Index, ECOG performance status (PS) score, Social Deprivation Index (SDI), liver and lymph node metastasis, prior radiotherapy or surgical procedures, and year of treatment. Patients with mPC treated between January 1, 2016, and December 31, 2019, and followed up until June 30, 2020, were included in the analysis.
    Interventions: Initiation of treatment with FOLFIRINOX or gemcitabine plus nab-paclitaxel.
    Main Outcomes and Measures: Outcomes were overall survival and posttreatment costs and hospitalization. Median survival time was calculated using Kaplan-Meier estimates adjusted with inverse probability of treatment weighting and 1:1 matching.
    Results: Among the 1102 patients included in the analysis (618 men [56.1%]; median age, 60.0 [IQR, 55.5-63.7] years), those treated with FOLFIRINOX were younger (median age, 59.1 [IQR, 53.9-63.3] vs 61.2 [IQR, 57.2-64.3] years; P < .001), with better PS scores (226 [39.9%] with PS of 0 in the FOLFIRINOX group vs 176 [32.8%] in the gemcitabine plus nab-paclitaxel group; P = .02), fewer comorbidities (median Charlson Comorbidity Index, 0.0 [IQR, 0.0-1.0] vs 1.0 [IQR, 0.0-1.0]), and lower SDI (median, 36.0 [IQR, 16.2-61.0] vs 42.0 [IQR, 23.8-66.2]). After adjustments, the median overall survival was 9.27 (IQR, 8.74-9.76) and 6.87 (IQR, 6.41-7.66) months for patients treated with FOLFIRINOX and gemcitabine plus nab-paclitaxel, respectively (P < .001). This survival benefit was observed among all subgroups, including different ECOG PS scores, ages, SDIs, and metastatic sites. FOLFIRINOX-treated patients also had 17.3% fewer posttreatment hospitalizations (P = .03) and 20% lower posttreatment costs (P < .001).
    Conclusions and Relevance: In this comparative effectiveness cohort study, FOLFIRINOX was associated with improved survival of approximately 2 months compared with gemcitabine plus nab-paclitaxel and was also associated with fewer posttreatment complications. A randomized clinical trial comparing these first-line treatments is warranted to test the survival and posttreatment hospitalization (or complications) benefit of FOLFIRINOX compared with gemcitabine plus nab-paclitaxel.
    DOI:  https://doi.org/10.1001/jamanetworkopen.2022.16199
  12. Mol Oncol. 2022 Jun 08.
    Cellular senescence and the tumor microenvironment.
    Masaki Takasugi, Yuya Yoshida, Naoko Ohtani.
      The senescence-associated secretory phenotype (SASP), where senescent cells produce a variety of secreted proteins including inflammatory cytokines, chemokines, matrix remodeling factors, growth factors, and so on, plays pivotal but varying roles in the tumor microenvironment. The effects of SASP on the surrounding microenvironment depend on the cell type and process of cellular senescence induction, which is often associated with innate immunity. Via SASP-mediated paracrine effects, senescent cells can remodel the surrounding tissues by modulating the character of adjacent cells, such as stromal, immune cells, as well as cancer cells. The SASP is associated with both tumor-suppressive and tumor-promoting effects, as observed in senescence surveillance effects (tumor-suppressive) and suppression of anti-tumor immunity in most senescent cancer-associated fibroblasts (CAFs) and senescent T cells (tumor-promoting). In this review, we discuss the features and roles of senescent cells in tumor microenvironment with emphasis on their context-dependency that determines whether they promote or suppress cancer development. Potential usage of recently developed drugs that suppress the SASP (senomorphics) or selectively kill senescence cells (senolytics) in cancer therapy are also discussed.
    Keywords:  SASP(senescence-associated secretory phenotype); cellular senescence; tumor microenvironment; anti-tumor immunity; senolysis; senomorphics
    DOI:  https://doi.org/10.1002/1878-0261.13268
  13. Nat Cancer. 2022 Jun 09.
    Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.
    Ali Vaziri-Gohar, Joel Cassel, Farheen S Mohammed, Mehrdad Zarei, Jonathan J Hue, Omid Hajihassani, Hallie J Graor, Yellamelli V V Srikanth, Saadia A Karim, Ata Abbas, Erin Prendergast, Vanessa Chen, Erryk S Katayama, Katerina Dukleska, Imran Khokhar, Anthony Andren, Li Zhang, Chunying Wu, Bernadette Erokwu, Chris A Flask, Mahsa Zarei, Rui Wang, Luke D Rothermel, Andrea M P Romani, Jessica Bowers, Robert Getts, Curtis Tatsuoka, Jennifer P Morton, Ilya Bederman, Henri Brunengraber, Costas A Lyssiotis, Joseph M Salvino, Jonathan R Brody, Jordan M Winter.
      Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.
    DOI:  https://doi.org/10.1038/s43018-022-00393-y
  14. Sci Immunol. 2022 Jun 03. 7(72): eabq2791
    ILC2s-Bipartisan politicians in cancer.
    Abderezak Zebboudj, Masataka Amisaki, Vinod P Balachandran.
      Group 2 innate lymphoid cells (ILC2s) are lymphocytes that both promote and suppress antitumor immunity. Jou and colleagues now report in colorectal tumorigenesis that the cytokine interleukin-25 activates ILC2s to induce myeloid cells that suppress antitumor immunity.
    DOI:  https://doi.org/10.1126/sciimmunol.abq2791
  15. Elife. 2022 Jun 09. pii: e79582. [Epub ahead of print]11
    Hypoxia controls plasma membrane targeting of polarity proteins by dynamic turnover of PI4P and PI(4,5)P2.
    Juan Lu, Wei Dong, Gerald R Hammond, Yang Hong.
      Phosphatidylinositol 4-phosphate (PI4P) and phosphatidylinositol 4,5-biphosphate (PIP2) are key phosphoinositides that determine the identity of the plasma membrane (PM) and regulate numerous key biological events there. To date, mechanisms regulating the homeostasis and dynamic turnover of PM PI4P and PIP2 in response to various physiological conditions and stresses remain to be fully elucidated. Here we report that hypoxia in Drosophila induces acute and reversible depletion of PM PI4P and PIP2 that severely disrupts the electrostatic PM targeting of multiple polybasic polarity proteins. Genetically encoded ATP sensors confirmed that hypoxia induces acute and reversible reduction of cellular ATP levels which showed a strong real-time correlation with the levels of PM PI4P and PIP2 in cultured cells. By combining genetic manipulations with quantitative imaging assays we showed that PI4KIIIα, as well as Rbo/EFR3 and TTC7 that are essential for targeting PI4KIIIα to PM, are required for maintaining the homeostasis and dynamic turnover of PM PI4P and PIP2 under normoxia and hypoxia. Our results revealed that in cells challenged by energetic stresses triggered by hypoxia, ATP inhibition and possibly ischemia, dramatic turnover of PM PI4P and PIP2 could have profound impact on many cellular processes including electrostatic PM targeting of numerous polybasic proteins.
    Keywords:  D. melanogaster; cell biology; developmental biology
    DOI:  https://doi.org/10.7554/eLife.79582
  16. STAR Protoc. 2022 Jun 17. 3(2): 101441
    Evaluating the glycolytic potential of mouse costimulated effector CD8+ T cells ex vivo.
    Federica Agliano, Antoine Ménoret, Anthony T Vella.
      Studying the metabolic fitness of T cells is fundamental to understand how immune responses are regulated. Here, we describe a step-by-step protocol optimized to efficiently generate and isolate effector antigen-specific CD8+ T cells ex vivo using costimulation. We also detail steps to evaluate their metabolic activity using Seahorse technology. This protocol can be used to measure the glycolytic potential of effector murine T cells in response to different manipulations, such as infections, adjuvant studies, gene editing, or metabolite supplementation. For complete details on the use and execution of this protocol, please refer to Agliano et al. (2022).
    Keywords:  Cell Biology; Cell isolation; Cell-based Assays; Flow Cytometry/Mass Cytometry; Immunology; Metabolism
    DOI:  https://doi.org/10.1016/j.xpro.2022.101441
  17. Molecules. 2022 May 27. pii: 3464. [Epub ahead of print]27(11):
    MALDI Mass Spectrometry Imaging for the Distinction of Adenocarcinomas of the Pancreas and Biliary Tree.
    Christine Bollwein, Juliana Pereira Lopes Gonҫalves, Kirsten Utpatel, Wilko Weichert, Kristina Schwamborn.
      Pancreatic ductal adenocarcinoma and cholangiocarcinoma constitute two aggressive tumor types that originate from the epithelial lining of the excretory ducts of the pancreatobiliary tract. Given their close histomorphological resemblance, a correct diagnosis can be challenging and almost impossible without clinical information. In this study, we investigated whether mass spectrometric peptide features could be employed to distinguish pancreatic ductal adenocarcinoma from cholangiocarcinoma. Three tissue microarrays of formalin-fixed and paraffin-embedded material (FFPE) comprising 41 cases of pancreatic ductal adenocarcinoma and 41 cases of cholangiocarcinoma were analyzed by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). The derived peptide features and respective intensities were used to build different supervised classification algorithms: gradient boosting (GB), support vector machine (SVM), and k-nearest neighbors (KNN). On a pixel-by-pixel level, a classification accuracy of up to 95% could be achieved. The tentative identification of discriminative tryptic peptide signatures revealed proteins that are involved in the epigenetic regulation of the genome and tumor microenvironment. Despite their histomorphological similarities, mass spectrometry imaging represents an efficient and reliable approach for the distinction of PDAC from CC, offering a promising complementary or alternative approach to the existing tools used in diagnostics such as immunohistochemistry.
    Keywords:  MALDI-MSI; cholangiocarcinoma; machine learning; pancreatic ductal adenocarcinoma; peptides; proteomics; supervised classification; tandem mass spectrometry
    DOI:  https://doi.org/10.3390/molecules27113464
  18. Cureus. 2022 May;14(5): e24803
    An Update to Hallmarks of Cancer.
    Swapna Ravi, Antonio M Alencar, Jemma Arakelyan, Weihao Xu, Roberta Stauber, Cheng-Chi I Wang, Ruzanna Papyan, Narine Ghazaryan, Rosalina M Pereira.
      In the last decade, there has been remarkable progress in research toward understanding and refining the hallmarks of cancer. In this review, we propose a new hallmark - "pro-survival autophagy." The importance of pro-survival autophagy is well established in tumorigenesis, as it is related to multiple steps in cancer progression and vital for some cancers. Autophagy is a potential anti-cancer therapeutic target. For this reason, autophagy is a good candidate as a new hallmark of cancer. We describe two enabling characteristics that play a major role in enabling cells to acquire the hallmarks of cancer - "tumor-promoting microenvironment and macroenvironment" and "cancer epigenetics, genome instability and mutation." We also discuss the recent updates, therapeutic and prognostic implications of the eight hallmarks of cancer described by Hanahan et al. in 2011. Understanding these hallmarks and enabling characteristics is key not only to developing new ways to treat cancer efficiently but also to exploring options to overcome cancer resistance to treatment.
    Keywords:  autophagy; cancer; genome instability; hallmark; macroenvironment; microenvironment; tumor
    DOI:  https://doi.org/10.7759/cureus.24803
  19. Elife. 2022 Jun 08. pii: e75426. [Epub ahead of print]11
    Towards a molecular mechanism underlying mitochondrial protein import through the TOM and TIM23 complexes.
    Holly C Ford, William J Allen, Gonçalo C Pereira, Xia Liu, Mark Simon Dillingham, Ian Collinson.
      Nearly all mitochondrial proteins need to be targeted for import from the cytosol. For the majority, the first port of call is the translocase of the outer membrane (TOM complex), followed by a procession of alternative molecular machines, conducting transport to their final destination. The pre-sequence translocase of the inner-membrane (TIM23-complex) imports proteins with cleavable pre-sequences. Progress in understanding these transport mechanisms has been hampered by the poor sensitivity and time-resolution of import assays. However, with the development of an assay based on split NanoLuc luciferase, we can now explore this process in greater detail. Here, we apply this new methodology to understand how ∆ψ and ATP hydrolysis, the two main driving forces for import into the matrix, contribute to the transport of pre-sequence-containing precursors (PCPs) with varying properties. Notably, we found that two major rate-limiting steps define PCP import time: passage of PCP across the outer membrane and initiation of inner membrane transport by the pre-sequence - the rates of which are influenced by PCP properties such as size and net charge. The apparent distinction between transport through the two membranes (passage through TOM is substantially complete before PCP-TIM engagement) is in contrast with the current view that import occurs through TOM and TIM in a single continuous step. Our results also indicate that PCPs spend very little time in the TIM23 channel - presumably rapid success or failure of import is critical for maintaining mitochondrial fitness.
    Keywords:  S. cerevisiae; biochemistry; chemical biology
    DOI:  https://doi.org/10.7554/eLife.75426
  20. Future Oncol. 2022 Jun 10.
    Application and prospect of single-cell sequencing in cancer metastasis.
    Yue Zheng, Xiaofeng Yang.
      Cancer metastasis is a complicated process driven by internal genetic variations and developed through interactions with the external environment. This process usually causes therapeutic resistance and results in a low survival rate. In recent years, single-cell sequencing has become a popular method for revealing the tumor evolutionary genetic lineage, intra-tumoral heterogeneity and tumor microenvironment of the metastasis process. So as to find more therapeutic targets for clinical application, the spatial transcriptomics method has become a new rising field of cancer studies, which promotes the combination between clinical medicine and molecular biology. In future prospects, more accurate and personalized treatment models will come into reality.
    Keywords:  cancer metastasis; circulating tumor cell; epithelial-mesenchymal transformation; intra-tumoral heterogeneity; single-cell sequencing; spatial transcriptomics; tumor microenvironment
    DOI:  https://doi.org/10.2217/fon-2022-0156
  21. J Cell Sci. 2022 Jun 01. pii: jcs258932. [Epub ahead of print]135(11):
    Physiological functions and roles in cancer of the proliferation marker Ki-67.
    Nuria Andrés-Sánchez, Daniel Fisher, Liliana Krasinska.
      What do we know about Ki-67, apart from its usefulness as a cell proliferation biomarker in histopathology? Discovered in 1983, the protein and its regulation of expression and localisation throughout the cell cycle have been well characterised. However, its function and molecular mechanisms have received little attention and few answers. Although Ki-67 has long been thought to be required for cell proliferation, recent genetic studies have conclusively demonstrated that this is not the case, as loss of Ki-67 has little or no impact on cell proliferation. In contrast, Ki-67 is important for localising nucleolar material to the mitotic chromosome periphery and for structuring perinucleolar heterochromatin, and emerging data indicate that it also has critical roles in cancer development. However, its mechanisms of action have not yet been fully identified. Here, we review recent findings and propose the hypothesis that Ki-67 is involved in structuring cellular sub-compartments that assemble by liquid-liquid phase separation. At the heterochromatin boundary, this may control access of chromatin regulators, with knock-on effects on gene expression programmes. These changes allow adaptation of the cell to its environment, which, for cancer cells, is a hostile one. We discuss unresolved questions and possible avenues for future exploration.
    Keywords:  Cancer; Cell proliferation; Heterochromatin; Ki-67
    DOI:  https://doi.org/10.1242/jcs.258932
  22. Front Mol Biosci. 2022 ;9 893256
    A Resource to Infer Molecular Paths Linking Cancer Mutations to Perturbation of Cell Metabolism.
    Marta Iannuccelli, Prisca Lo Surdo, Luana Licata, Luisa Castagnoli, Gianni Cesareni, Livia Perfetto.
      Some inherited or somatically-acquired gene variants are observed significantly more frequently in the genome of cancer cells. Although many of these cannot be confidently classified as driver mutations, they may contribute to shaping a cell environment that favours cancer onset and development. Understanding how these gene variants causally affect cancer phenotypes may help developing strategies for reverting the disease phenotype. Here we focus on variants of genes whose products have the potential to modulate metabolism to support uncontrolled cell growth. Over recent months our team of expert curators has undertaken an effort to annotate in the database SIGNOR 1) metabolic pathways that are deregulated in cancer and 2) interactions connecting oncogenes and tumour suppressors to metabolic enzymes. In addition, we refined a recently developed graph analysis tool that permits users to infer causal paths leading from any human gene to modulation of metabolic pathways. The tool grounds on a human signed and directed network that connects ∼8400 biological entities such as proteins and protein complexes via causal relationships. The network, which is based on more than 30,000 published causal links, can be downloaded from the SIGNOR website. In addition, as SIGNOR stores information on drugs or other chemicals targeting the activity of many of the genes in the network, the identification of likely functional paths offers a rational framework for exploring new therapeutic strategies that revert the disease phenotype.
    Keywords:  SIGNOR; cancer; causal interaction; metabolic pathway; network; rate limiting enzyme
    DOI:  https://doi.org/10.3389/fmolb.2022.893256
  23. Annu Rev Genet. 2022 Jun 09.
    The Genetics of Autophagy in Multicellular Organisms.
    Hong Zhang.
      Autophagy, a lysosome-mediated degradation process evolutionarily conserved from yeast to mammals, is essential for maintaining cellular homeostasis and combating diverse cellular stresses. Autophagy involves de novo synthesis of a double-membrane autophagosome, sequestration of selected cellular contents, and subsequent delivery of sequestrated contents to the vacuole (in yeasts and plants) or to lysosomes (in animal cells) for degradation and recycling. Genetic studies in unicellular and multicellular model organisms have systematically revealed the molecular machinery, regulation, and function of autophagy in physiological settings. I review genetic studies in model organisms-from yeast to worm to fly-that enable us to not only identify autophagy genes, including ATG genes and the metazoan-specific EPG genes, but also uncover variants of autophagy in developmental contexts, novel regulatory mechanisms, and signaling events involved in mediating systemic autophagy response. Genetic analysis also helps us understand the liquid-liquid phase separation and transition that control autophagic degradation of protein aggregates. The emerging role of autophagy in zebrafish tissue regeneration is also discussed. Expected final online publication date for the Annual Review of Genetics, Volume 56 is November 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-genet-022422-095608
  24. Cancers (Basel). 2022 May 24. pii: 2588. [Epub ahead of print]14(11):
    Systemic Therapy of Metastatic Pancreatic Adenocarcinoma: Current Status, Challenges, and Opportunities.
    Sakti Chakrabarti, Mandana Kamgar, Amit Mahipal.
      Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by nonspecific presenting symptoms, lack of a screening test, rapidly progressive clinical course, and presentation with an advanced-stage disease in the majority of patients. PDAC is essentially a systemic disease irrespective of the initial stage, as most patients with non-metastatic PDAC undergoing curative-intent treatment eventually experience metastatic relapse. Currently, cytotoxic chemotherapy remains the cornerstone of treatment in patients with advanced disease. However, the current standard treatment with multiagent chemotherapy has modest efficacy and results in median overall survival (OS) of less than a year and a 5-year OS of about 10%. The pathobiology of PDAC poses many challenges, including a unique tumor microenvironment interfering with drug delivery, intratumoral heterogeneity, and a strongly immunosuppressive microenvironment that supports cancer growth. Recent research is exploring a wide range of novel therapeutic targets, including genomic alterations, tumor microenvironment, and tumor metabolism. The rapid evolution of tumor genome sequencing technologies paves the way for personalized, targeted therapies. The present review summarizes the current chemotherapeutic treatment paradigm of advanced PDAC and discusses the evolving novel targets that are being investigated in a myriad of clinical trials.
    Keywords:  maintenance therapy; next-generation sequencing; pancreatic ductal adenocarcinoma (PDAC); targeted therapy
    DOI:  https://doi.org/10.3390/cancers14112588
  25. Mol Cancer Res. 2022 Jun 08. pii: molcanres.1069.2021. [Epub ahead of print]
    Monounsaturated fatty acids: key regulators of cell viability and intracellular signalling in cancer.
    Julia S Scott, Zeyad D Nassar, Johannes V Swinnen, Lisa M Butler.
      Cancer cells feature increased macromolecular biosynthesis to support the formation of new organelles and membranes for cell division. In particular, lipids are key macromolecules that comprise cellular membrane components, substrates for energy generation and mediators of inter- and intracellular signalling. The emergence of more sensitive and accurate technology for profiling the "lipidome" of cancer cells has led to unprecedented leaps in understanding the complexity of cancer metabolism, but also highlighted promising therapeutic vulnerabilities. Notably, fatty acids, as lipid building blocks, are critical players in all stages of cancer development and progression and the importance of fatty acid desaturation and its impact on cancer cell biology has been well established. Recent years have seen the reports of new mechanistic insights into the role of monounsaturated fatty acids (MUFAs) in cancer, as regulators of cell death and lipid-related cellular signalling. This commentary aims to highlight these diverse roles of MUFAs in cancer cells which may yield new directions for therapeutic interventions involving these important fatty acids.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-21-1069
  26. J Mol Biol. 2022 Jun 15. pii: S0022-2836(22)00102-4. [Epub ahead of print]434(11): 167528
    EviCor: Interactive Web Platform for Exploration of Molecular Features and Response to Anti-cancer Drugs.
    Iurii Petrov, Andrey Alexeyenko.
      Experimental biologists are often left alone with the task to download, process, and analyze big datasets in order to perform correlation or other simpler analyses. To address these issues, we introduce EviCor, a handy toolbox for exploration of data from large public resources such as The Cancer Genome Atlas and The Cancer Cell Line Encyclopedia, complemented with follow-up information on same samples, which couples omics datasets with drug response profiles (https://www.evicor.org/). The data was processed for easy retrieval from the server-side database and includes pre-computed drug-feature correlation tables. Using information from multiple independent sources, the task-oriented web interface presents relations between phenotype, single-molecule, and pathway variables with graphical, statistical, and network analysis tools. Building custom multivariate models is enabled via user-friendly web interface and programmatic access via RESTinterface. Project code is available at https://github.com/aveviort/HyperSet.
    Keywords:  cancer; correlation; drugs; multivariate model; network enrichment analysis; visualization
    DOI:  https://doi.org/10.1016/j.jmb.2022.167528
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