bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2023–10–15
27 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Apoptotic stress causes mtDNA release during senescence and drives the SASP.
  2. Lysosomes in senescence and aging.
  3. Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma.
  4. A small molecule with big impact: MRTX1133 targets the KRASG12D mutation in pancreatic cancer.
  5. Vault-phagy: a phase-separation-mediated selective autophagy of vault, a non-membranous organelle.
  6. Mutant SF3B1 promotes malignancy in PDAC.
  7. Kupffer cells prevent pancreatic ductal adenocarcinoma metastasis to the liver in mice.
  8. Membrane curvature drives the formation of integrin adhesions on soft ECM fibres.
  9. Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution.
  10. The interplay of nuclear pores and lipids.
  11. Receptor-interacting protein kinase 2 is an immunotherapy target in pancreatic cancer.
  12. A Phase 1 Expansion Cohort Study Evaluating the Safety and Efficacy of the CHK1 Inhibitor LY2880070 with Low-Dose Gemcitabine in Metastatic Pancreatic Adenocarcinoma Patients.
  13. Oncogenic context shapes the fitness landscape of tumor suppression.
  14. Targeting pancreatic cancer metabolic dependencies through glutamine antagonism.
  15. GADD45A is a mediator of mitochondrial loss, atrophy, and weakness in skeletal muscle.
  16. ERRα fosters running endurance by driving myofiber aerobic transformation and fuel efficiency.
  17. Synergistic effect of antagonists to KRas4B/PDE6 molecular complex in pancreatic cancer.
  18. The functional significance of mitochondrial respiratory chain supercomplexes.
  19. Structural basis of lipid head group entry to the Kennedy pathway by FLVCR1.
  20. Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma.
  21. Endothelial lipid droplets suppress eNOS to link high fat consumption to blood pressure elevation.
  22. Red and processed meat and pancreatic cancer risk: a meta-analysis.
  23. Integrating Shear Flow and Trypsin Treatment to Assess Cell Adhesion Strength.
  24. An end-to-end workflow for multiplexed image processing and analysis.
  25. Identifying genes associated with resistance to KRAS G12C inhibitors via machine learning methods.
  26. Arginine reprograms metabolism in liver cancer via RBM39.
  27. Phase separation underlies signaling activation of oncogenic NTRK fusions.
  1. Nature. 2023 Oct 11.
    Apoptotic stress causes mtDNA release during senescence and drives the SASP.
    Stella Victorelli, Hanna Salmonowicz, James Chapman, Helene Martini, Maria Grazia Vizioli, Joel S Riley, Catherine Cloix, Ella Hall-Younger, Jair Machado Espindola-Netto, Diana Jurk, Anthony B Lagnado, Lilian Sales Gomez, Joshua N Farr, Dominik Saul, Rebecca Reed, George Kelly, Madeline Eppard, Laura C Greaves, Zhixun Dou, Nicholas Pirius, Karolina Szczepanowska, Rebecca A Porritt, Huijie Huang, Timothy Y Huang, Derek A Mann, Claudio Akio Masuda, Sundeep Khosla, Haiming Dai, Scott H Kaufmann, Emmanouil Zacharioudakis, Evripidis Gavathiotis, Nathan K LeBrasseur, Xue Lei, Alva G Sainz, Viktor I Korolchuk, Peter D Adams, Gerald S Shadel, Stephen W G Tait, João F Passos.
      Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.
    DOI:  https://doi.org/10.1038/s41586-023-06621-4
  2. EMBO Rep. 2023 Oct 09. e57265
    Lysosomes in senescence and aging.
    Jay Xiaojun Tan, Toren Finkel.
      Dysfunction of lysosomes, the primary hydrolytic organelles in animal cells, is frequently associated with aging and age-related diseases. At the cellular level, lysosomal dysfunction is strongly linked to cellular senescence or the induction of cell death pathways. However, the precise mechanisms by which lysosomal dysfunction participates in these various cellular or organismal phenotypes have remained elusive. The ability of lysosomes to degrade diverse macromolecules including damaged proteins and organelles puts lysosomes at the center of multiple cellular stress responses. Lysosomal activity is tightly regulated by many coordinated cellular processes including pathways that function inside and outside of the organelle. Here, we collectively classify these coordinated pathways as the lysosomal processing and adaptation system (LYPAS). We review evidence that the LYPAS is upregulated by diverse cellular stresses, its adaptability regulates senescence and cell death decisions, and it can form the basis for therapeutic manipulation for a wide range of age-related diseases and potentially for aging itself.
    Keywords:  LYPAS; age-related disease; autophagy; lysosomal quality control; senescence
    DOI:  https://doi.org/10.15252/embr.202357265
  3. Nat Cancer. 2023 Oct 09.
    Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma.
    Maria Victoria Recouvreux, Shea F Grenier, Yijuan Zhang, Edgar Esparza, Guillem Lambies, Cheska Marie Galapate, Swetha Maganti, Karen Duong-Polk, Deepika Bhullar, Razia Naeem, David A Scott, Andrew M Lowy, Hervé Tiriac, Cosimo Commisso.
      In pancreatic ductal adenocarcinoma (PDAC), glutamine is a critical nutrient that drives a wide array of metabolic and biosynthetic processes that support tumor growth. Here, we elucidate how 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist that broadly inhibits glutamine metabolism, blocks PDAC tumor growth and metastasis. We find that DON significantly reduces asparagine production by inhibiting asparagine synthetase (ASNS), and that the effects of DON are rescued by asparagine. As a metabolic adaptation, PDAC cells upregulate ASNS expression in response to DON, and we show that ASNS levels are inversely correlated with DON efficacy. We also show that L-asparaginase (ASNase) synergizes with DON to affect the viability of PDAC cells, and that DON and ASNase combination therapy has a significant impact on metastasis. These results shed light on the mechanisms that drive the effects of glutamine mimicry and point to the utility of cotargeting adaptive responses to control PDAC progression.
    DOI:  https://doi.org/10.1038/s43018-023-00649-1
  4. Clin Cancer Res. 2023 Oct 13.
    A small molecule with big impact: MRTX1133 targets the KRASG12D mutation in pancreatic cancer.
    Daoyan Wei, Liang Wang, Xiangsheng Zuo, Anirban Maitra, Robert S Bresalier.
      KRAS mutations driver oncogenic alterations in numerous cancers, particularly in human pancreatic ductal adenocarcinoma (PDAC). About 93% of PDAC have KRAS mutations, with G12D (~42% of cases) and G12V (~32% of cases) being the most common. The recent approval of sotorasib (AMG510), a small-molecule, covalent, and selective KRASG12C inhibitor, for treating patients with non-small cell lung cancer represents a breakthrough in KRAS targeted therapy. However, there is a need to develop other much-needed KRAS mutant inhibitors for PDAC therapy. Notably, Mirati Therapeutics recently developed MRTX1133, a small-molecule, non-covalent, and selective KRASG12D inhibitor through extensive structure-based drug design. MRTX1133 has demonstrated potent in vitro and in vivo antitumor efficacy against KRASG12D-mutant cancer cells, especially in PDAC, leading to its recent initiation of a phase I/II clinical trial. Here, we provide a summary of the recent advancements related to the use of MRTX1133 for treating KRASG12D-mutant PDAC, focusing on its efficacy and underlying mechanistic actions. Additionally, we discuss potential challenges and future directions for MRTX1133 therapy for PDAC, including overcoming intrinsic and acquired drug resistance, developing effective combination therapies, and improving MRTX1133's oral bioavailability and target spectrum. The promising results obtained from preclinical studies suggest that MRTX1133 could revolutionize the treatment of PDAC, bring about a paradigm shift in its management.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-2098
  5. Autophagy. 2023 Oct 10. 1-2
    Vault-phagy: a phase-separation-mediated selective autophagy of vault, a non-membranous organelle.
    Reo Kurusu, Hideaki Morishita, Masaaki Komatsu.
      SQSTM1/p62 bodies are phase-separated condensates that play a fundamental role in intracellular quality control and stress responses. Despite extensive studies investigating the mechanism of formation and degradation of SQSTM1/p62 bodies, the constituents of SQSTM1/p62 bodies remain elusive. We recently developed a purification method for intracellular SQSTM1/p62 bodies using a cell sorter and identified their constituents by mass spectrometry. Combined with mass spectrometry of tissues from selective autophagy-deficient mice, we identified vault, a ubiquitous non-membranous organelle composed of proteins and non-coding RNA, as a novel substrate for selective autophagy. Vault directly binds to NBR1, an SQSTM1/p62 binding partner recruited to SQSTM1/p62 bodies, and is subsequently degraded by selective autophagy dependent on the phase separation of SQSTM1/p62. We named this process "vault-phagy" and found that defects in vault-phagy are related to nonalcoholic steatohepatitis (NASH)-derived hepatocellular carcinoma. Our method for purifying SQSTM1/p62 bodies will contribute to elucidating the mechanisms of several stress responses and diseases mediated by SQSTM1/p62 bodies.
    Keywords:  Fluorescence-activated particle sorting; Mallory-Denk bodies; NBR1; liquid-liquid phase separation; nonalcoholic steatohepatitis; selective autophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2266996
  6. Elife. 2023 Oct 12. pii: e80683. [Epub ahead of print]12
    Mutant SF3B1 promotes malignancy in PDAC.
    Patrik Simmler, Eleonora I Ioannidi, Tamara Mengis, Kim Fabiano Marquart, Simran Asawa, Kjong Van-Lehmann, André Khales, Tinu Thomas, Cornelia Schwerdel, Nicola Aceto, Gunnar Rätsch, Markus Stoffel, Gerald Schwank.
      The splicing factor SF3B1 is recurrently mutated in various tumors, including pancreatic ductal adenocarcinoma (PDAC). The impact of the hotspot mutation SF3B1K700E on the PDAC pathogenesis, however, remains elusive. Here, we demonstrate that Sf3b1K700E alone is insufficient to induce malignant transformation of the murine pancreas, but that it increases aggressiveness of PDAC if it co-occurs with mutated KRAS and p53. We further show that Sf3b1K700E already plays a role during early stages of pancreatic tumor progression and reduces the expression of TGF-β1-responsive epithelial-mesenchymal transition (EMT) genes. Moreover, we found that SF3B1K700E confers resistance to TGF-β1-induced cell death in pancreatic organoids and cell lines, partly mediated through aberrant splicing of Map3k7. Overall, our findings demonstrate that SF3B1K700E acts as an oncogenic driver in PDAC, and suggest that it promotes the progression of early stage tumors by impeding the cellular response to tumor suppressive effects of TGF-β.
    Keywords:  cancer biology; mouse
    DOI:  https://doi.org/10.7554/eLife.80683
  7. Nat Commun. 2023 10 10. 14(1): 6330
    Kupffer cells prevent pancreatic ductal adenocarcinoma metastasis to the liver in mice.
    Stacy K Thomas, Max M Wattenberg, Shaanti Choi-Bose, Mark Uhlik, Ben Harrison, Heather Coho, Christopher R Cassella, Meredith L Stone, Dhruv Patel, Kelly Markowitz, Devora Delman, Michael Chisamore, Jeremy Drees, Nandita Bose, Gregory L Beatty.
      Although macrophages contribute to cancer cell dissemination, immune evasion, and metastatic outgrowth, they have also been reported to coordinate tumor-specific immune responses. We therefore hypothesized that macrophage polarization could be modulated therapeutically to prevent metastasis. Here, we show that macrophages respond to β-glucan (odetiglucan) treatment by inhibiting liver metastasis. β-glucan activated liver-resident macrophages (Kupffer cells), suppressed cancer cell proliferation, and invoked productive T cell-mediated responses against liver metastasis in pancreatic cancer mouse models. Although excluded from metastatic lesions, Kupffer cells were critical for the anti-metastatic activity of β-glucan, which also required T cells. Furthermore, β-glucan drove T cell activation and macrophage re-polarization in liver metastases in mice and humans and sensitized metastatic lesions to anti-PD1 therapy. These findings demonstrate the significance of macrophage function in metastasis and identify Kupffer cells as a potential therapeutic target against pancreatic cancer metastasis to the liver.
    DOI:  https://doi.org/10.1038/s41467-023-41771-z
  8. Nat Cell Biol. 2023 Oct 12.
    Membrane curvature drives the formation of integrin adhesions on soft ECM fibres.
      
    DOI:  https://doi.org/10.1038/s41556-023-01257-y
  9. Cancer Cell. 2023 Oct 09. pii: S1535-6108(23)00319-7. [Epub ahead of print]41(10): 1788-1802.e10
    Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution.
    Hongyi Zhang, Xuexin Yu, Jianfeng Ye, Huiyu Li, Jing Hu, Yuhao Tan, Yan Fang, Esra Akbay, Fulong Yu, Chen Weng, Vijay G Sankaran, Robert M Bachoo, Elizabeth Maher, John Minna, Anli Zhang, Bo Li.
      Mitochondria (MT) participate in most metabolic activities of mammalian cells. A near-unidirectional mitochondrial transfer from T cells to cancer cells was recently observed to "metabolically empower" cancer cells while "depleting immune cells," providing new insights into tumor-T cell interaction and immune evasion. Here, we leverage single-cell RNA-seq technology and introduce MERCI, a statistical deconvolution method for tracing and quantifying mitochondrial trafficking between cancer and T cells. Through rigorous benchmarking and validation, MERCI accurately predicts the recipient cells and their relative mitochondrial compositions. Application of MERCI to human cancer samples identifies a reproducible MT transfer phenotype, with its signature genes involved in cytoskeleton remodeling, energy production, and TNF-α signaling pathways. Moreover, MT transfer is associated with increased cell cycle activity and poor clinical outcome across different cancer types. In summary, MERCI enables systematic investigation of an understudied aspect of tumor-T cell interactions that may lead to the development of therapeutic opportunities.
    Keywords:  Mitochondrial Transfer; Statistical Deconvolution; T cell dysfunction; Tumor-Immune Interaction; mtDNA sequencing.; single cell genomics
    DOI:  https://doi.org/10.1016/j.ccell.2023.09.003
  10. Curr Opin Cell Biol. 2023 Oct 04. pii: S0955-0674(23)00100-X. [Epub ahead of print]85 102251
    The interplay of nuclear pores and lipids.
    Edvinas Stankunas, Alwin Köhler.
      Nuclear pore complexes (NPCs) mediate the bidirectional transport of cargo across the nuclear envelope (NE). NPCs are also membrane remodeling machines with a capacity to curve and fuse the membranes of the NE. However, little is known about the interplay of NPCs and lipids at a mechanistic level. A full understanding of NPC structure and function needs to encompass how the NPC shapes membranes and is itself shaped by lipids. Here we attempt to connect recent findings in NPC research with the broader field of membrane biochemistry to illustrate how an interplay between NPCs and lipids may facilitate the conformational plasticity of NPCs and the generation of a unique pore membrane topology. We highlight the need to better understand the NPC's lipid environment and outline experimental avenues towards that goal.
    DOI:  https://doi.org/10.1016/j.ceb.2023.102251
  11. Cancer Discov. 2023 Oct 12.
    Receptor-interacting protein kinase 2 is an immunotherapy target in pancreatic cancer.
    Wenhua Sang, Yiduo Zhou, Haiyan Chen, Chengxuan Yu, Lisi Dai, Zhongkun Liu, Lang Chen, Yimin Fang, Panpan Ma, Xiangji Wu, Hao Kong, Wenting Liao, Hong Jiang, Junbin Qian, Da Wang, Yun-Hua Liu.
      Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancies due to its aggressive nature and the paucity of effective treatment options. Almost all registered drugs have proven ineffective in addressing the needs of PDAC patients. This is the result of a poor understanding of the unique tumor immune microenvironment (TME) in PDAC. To identify druggable regulators of immunosuppressive TME, we performed a kinome- and membranome-focused CRISPR screening using orthotopic PDAC models. Our data showed that RIPK2 is a crucial driver of immune evasion of cytotoxic T-cell killing and that genetic or pharmacological targeting of RIPK2 sensitizes PDAC to anti-PD-1 immunotherapy, leading to prolonged survival or complete regression. Mechanistic studies revealed that tumor-intrinsic RIPK2 ablation disrupts desmoplastic TME and restores MHC-I surface levels through eliminating NBR1-mediated autophagy-lysosomal degradation. Our results provide a rationale for a novel combination therapy consisting of RIPK2 inhibition and anti-PD-1 immunotherapy for PDAC.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0584
  12. Clin Cancer Res. 2023 Oct 11.
    A Phase 1 Expansion Cohort Study Evaluating the Safety and Efficacy of the CHK1 Inhibitor LY2880070 with Low-Dose Gemcitabine in Metastatic Pancreatic Adenocarcinoma Patients.
    Brandon M Huffman, Hanrong Feng, Kalindi Parmar, Junning Wang, Kevin S Kapner, Bose Kochupurakkal, David B Martignetti, Golbahar Sadatrezaei, Thomas A Abrams, Leah H Biller, Marios Giannakis, Kimmie Ng, Anuj K Patel, Kimberly J Perez, Harshabad Singh, Douglas A Rubinson, Benjamin L Schlechter, Elizabeth Andrews, Alison M Hannigan, Stanley Dunwell, Zoe Getchell, Srivatsan Raghavan, Brian M Wolpin, Caroline Fortier, Alan D D'Andrea, Andrew J Aguirre, Geoffrey I Shapiro, James M Cleary.
       BACKGROUND: Combining gemcitabine with CHK1 inhibition has shown promise in preclinical models of pancreatic ductal adenocarcinoma (PDAC). Here, we report the findings from a phase I expansion cohort study (NCT02632448) investigating low-dose gemcitabine combined with the CHK1 inhibitor LY2880070 in patients with previously treated advanced PDAC.
    METHODS: Patients with metastatic PDAC were treated with gemcitabine intravenously at 100 mg/m2 on days 1, 8, and 15, and LY2880070 50 mg orally twice daily on days 2-6, 9-13, and 16-20 of each 21-day cycle. Pre-treatment tumor biopsies were obtained from each patient for correlative studies and generation of organoid cultures for drug sensitivity testing and biomarker analyses. >Results: Eleven patients with PDAC were enrolled in the expansion cohort between August 27, 2020 and July 30, 2021. Four patients (36%) experienced drug-related grade 3 adverse events. No objective radiological responses were observed, and all patients discontinued the trial by 3.2 months. In contrast to the lack of efficacy observed in patients, organoid cultures derived from biopsies procured from two patients demonstrated strong sensitivity to the gemcitabine/LY2880070 combination and showed treatment-induced upregulation of replication stress and DNA damage biomarkers, including pKAP1, pRPA32, and γ-H2AX, as well as induction of replication fork instability.
    CONCLUSIONS: No evidence of clinical activity was observed for combined low dose gemcitabine and LY2880070 in this treatment refractory PDAC cohort. However, the gemcitabine/LY2880070 combination showed in vitro efficacy, suggesting that drug sensitivity for this combination in organoid cultures may not predict clinical benefit in patients.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-2005
  13. Nat Commun. 2023 Oct 12. 14(1): 6422
    Oncogenic context shapes the fitness landscape of tumor suppression.
    Lily M Blair, Joseph M Juan, Lafia Sebastian, Vy B Tran, Wensheng Nie, Gregory D Wall, Mehmet Gerceker, Ian K Lai, Edwin A Apilado, Gabriel Grenot, David Amar, Giorgia Foggetti, Mariana Do Carmo, Zeynep Ugur, Debbie Deng, Alex Chenchik, Maria Paz Zafra, Lukas E Dow, Katerina Politi, Jonathan J MacQuitty, Dmitri A Petrov, Monte M Winslow, Michael J Rosen, Ian P Winters.
      Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. We show that the fitness landscape is rugged-the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context-and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors.
    DOI:  https://doi.org/10.1038/s41467-023-42156-y
  14. Nat Cancer. 2023 Oct 09.
    Targeting pancreatic cancer metabolic dependencies through glutamine antagonism.
    Joel Encarnación-Rosado, Albert S W Sohn, Douglas E Biancur, Elaine Y Lin, Victoria Osorio-Vasquez, Tori Rodrick, Diana González-Baerga, Ende Zhao, Yumi Yokoyama, Diane M Simeone, Drew R Jones, Seth J Parker, Robert Wild, Alec C Kimmelman.
      Pancreatic ductal adenocarcinoma (PDAC) cells use glutamine (Gln) to support proliferation and redox balance. Early attempts to inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming and therapeutic resistance. Here, we demonstrated that treating PDAC cells with a Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), led to a metabolic crisis in vitro. In addition, we observed a profound decrease in tumor growth in several in vivo models using sirpiglenastat (DRP-104), a pro-drug version of DON that was designed to circumvent DON-associated toxicity. We found that extracellular signal-regulated kinase (ERK) signaling is increased as a compensatory mechanism. Combinatorial treatment with DRP-104 and trametinib led to a significant increase in survival in a syngeneic model of PDAC. These proof-of-concept studies suggested that broadly targeting Gln metabolism could provide a therapeutic avenue for PDAC. The combination with an ERK signaling pathway inhibitor could further improve the therapeutic outcome.
    DOI:  https://doi.org/10.1038/s43018-023-00647-3
  15. JCI Insight. 2023 Oct 10. pii: e171772. [Epub ahead of print]
    GADD45A is a mediator of mitochondrial loss, atrophy, and weakness in skeletal muscle.
    George R Marcotte, Matthew J Miller, Hawley E Kunz, Zachary C Ryan, Matthew D Strub, Patrick M Vanderboom, Carrie J Heppelmann, Sarah Chau, Zachary D Von Ruff, Sean P Kilroe, Andrew T McKeen, Jason M Dierdorff, Jennifer I Stern, Karl A Nath, Chad E Grueter, Vitor A Lira, Andrew R Judge, Blake B Rasmussen, K Sreekumaran Nair, Ian R Lanza, Scott M Ebert, Christopher M Adams.
      Aging and many illnesses and injuries impair skeletal muscle mass and function, but the molecular mechanisms are not well understood. To better understand the mechanisms, we generated and studied transgenic mice with skeletal muscle-specific expression of Growth Arrest and DNA Damage Inducible Alpha (GADD45A), a signaling protein whose expression in skeletal muscle rises during aging and a wide range of illnesses and injuries. We found that GADD45A induced several cellular changes that are characteristic of skeletal muscle atrophy, including a reduction in skeletal muscle mitochondria and oxidative capacity, selective atrophy of glycolytic muscle fibers, and paradoxical expression of oxidative myosin heavy chains despite mitochondrial loss. These cellular changes were at least partly mediated by MEKK4, a protein kinase that is directly activated by GADD45A. By inducing these changes, GADD45A decreased the mass of muscles that are enriched in glycolytic fibers, and it impaired strength, specific force, and endurance exercise capacity. Furthermore, as predicted by data from mouse models, we found that GADD45A expression in skeletal muscle was associated with muscle weakness in humans. Collectively, these findings identify GADD45A as a mediator of mitochondrial loss, atrophy, and weakness in mouse skeletal muscle and a potential target for muscle weakness in humans.
    Keywords:  Metabolism; Mitochondria; Muscle Biology; Skeletal muscle
    DOI:  https://doi.org/10.1172/jci.insight.171772
  16. Mol Metab. 2023 Oct 05. pii: S2212-8778(23)00148-5. [Epub ahead of print] 101814
    ERRα fosters running endurance by driving myofiber aerobic transformation and fuel efficiency.
    Hui Xia, Charlotte Scholtes, Catherine R Dufour, Christina Guluzian, Vincent Giguère.
       OBJECTIVE: Estrogen related receptor α (ERRα) occupies a central node in the transcriptional control of energy metabolism, including in skeletal muscle, but whether modulation of its activity can directly contribute to extend endurance to exercise remains to be investigated. The goal of this study was to characterize the benefit of mice engineered to express a physiologically relevant activated form of ERRα on skeletal muscle exercise metabolism and performance.
    METHODS: We recently shown that mutational inactivation of three regulated phosphosites in the amino terminal domain of the nuclear receptor ERRα impedes its degradation, leading to an accumulation of ERRα proteins and perturbation of metabolic homeostasis in ERRα3SA mutant mice. Herein, we used a multi-omics approach in combination with physical endurance tests to ascertain the consequences of expressing the constitutively active phospho-deficient ERRα3SA form on muscle exercise performance and energy metabolism.
    RESULTS: Genetic heightening of ERRα activity enhanced exercise capacity, fatigue-resistance, and endurance. This phenotype resulted from extensive reprogramming of ERRα global DNA occupancy and transcriptome in muscle leading to an increase in oxidative fibers, mitochondrial biogenesis, fatty acid oxidation, and lactate homeostasis.
    CONCLUSION: Our findings support the potential to enhance physical performance and exercise-induced health benefits by targeting molecular pathways regulating ERRα transcriptional activity.
    Keywords:  Diabetes; Endurance exercise; Fuel metabolism; Lactate; Mitochondrial oxidative metabolism; Muscle function; Muscle wasting; Myofibers; Nuclear receptor
    DOI:  https://doi.org/10.1016/j.molmet.2023.101814
  17. Life Sci Alliance. 2023 12;pii: e202302019. [Epub ahead of print]6(12):
    Synergistic effect of antagonists to KRas4B/PDE6 molecular complex in pancreatic cancer.
    Paola Briseño-Díaz, Michael Schnoor, Martiniano Bello-Ramirez, Jose Correa-Basurto, Arturo Rojo-Domínguez, Leticia Arregui, Libia Vega, Enrique Núñez-González, Luis Andres Palau-Hernández, Carlos Guadalupe Parra-Torres, Oscar Manuel García Córdova, Ernesto Zepeda-Castilla, Eduardo Torices-Escalante, Leticia Domínguez-Camacho, Beatriz Xoconostle-Cazares, Marco Antonio Meraz-Ríos, Sandra Delfín-Azuara, Dayan Andrea Carrión-Estrada, Nicolas Villegas-Sepúlveda, Rosaura Hernández-Rivas, Maria Del Rocio Thompson-Bonilla, Miguel Vargas.
      Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among all human cancers as it is highly resistant to chemotherapy. K-Ras mutations usually trigger the development and progression of PDAC. We hypothesized that compounds stabilizing the KRas4B/PDE6δ complex could serve as PDAC treatments. Using in silico approaches, we identified the small molecules C14 and P8 that reduced K-Ras activation in primary PDAC cells. Importantly, C14 and P8 significantly prevented tumor growth in patient-derived xenotransplants. Combined treatment with C14 and P8 strongly increased cytotoxicity in PDAC cell lines and primary cultures and showed strong synergistic antineoplastic effects in preclinical murine PDAC models that were superior to conventional therapeutics without causing side effects. Mechanistically, C14 and P8 reduced tumor growth by inhibiting AKT and ERK signaling downstream of K-RAS leading to apoptosis, specifically in PDAC cells. Thus, combined treatment with C14 and P8 may be a superior pharmaceutical strategy to improve the outcome of PDAC.
    DOI:  https://doi.org/10.26508/lsa.202302019
  18. EMBO Rep. 2023 Oct 12. e57092
    The functional significance of mitochondrial respiratory chain supercomplexes.
    Andreas Kohler, Antoni Barrientos, Flavia Fontanesi, Martin Ott.
      The mitochondrial respiratory chain (MRC) is a key energy transducer in eukaryotic cells. Four respiratory chain complexes cooperate in the transfer of electrons derived from various metabolic pathways to molecular oxygen, thereby establishing an electrochemical gradient over the inner mitochondrial membrane that powers ATP synthesis. This electron transport relies on mobile electron carries that functionally connect the complexes. While the individual complexes can operate independently, they are in situ organized into large assemblies termed respiratory supercomplexes. Recent structural and functional studies have provided some answers to the question of whether the supercomplex organization confers an advantage for cellular energy conversion. However, the jury is still out, regarding the universality of these claims. In this review, we discuss the current knowledge on the functional significance of MRC supercomplexes, highlight experimental limitations, and suggest potential new strategies to overcome these obstacles.
    Keywords:  Mitochondria; bioenergetics; electron transfer; respiratory chain; supercomplexes
    DOI:  https://doi.org/10.15252/embr.202357092
  19. bioRxiv. 2023 Sep 28. pii: 2023.09.28.560019. [Epub ahead of print]
    Structural basis of lipid head group entry to the Kennedy pathway by FLVCR1.
    Yeeun Son, Timothy C Kenny, Artem Khan, Kıvanç Birsoy, Richard K Hite.
      Phosphatidylcholine and phosphatidylethanolamine, the two most abundant phospholipids in mammalian cells, are synthesized de novo by the Kennedy pathway from choline and ethanolamine, respectively 1-6 . Despite the importance of these lipids, the mechanisms that enable the cellular uptake of choline and ethanolamine remain unknown. Here, we show that FLVCR1, whose mutation leads to the neurodegenerative syndrome PCARP 7-9 , transports extracellular choline and ethanolamine into cells for phosphorylation by downstream kinases to initiate the Kennedy pathway. Structures of FLVCR1 in the presence of choline and ethanolamine reveal that both metabolites bind to a common binding site comprised of aromatic and polar residues. Despite binding to a common site, the larger quaternary amine of choline interacts differently with FLVCR1 than does the primary amine of ethanolamine. Structure-guided mutagenesis identified residues that are critical for the transport of ethanolamine, while being dispensable for choline transport, enabling functional separation of the entry points into the two branches of the Kennedy pathway. Altogether, these studies reveal how FLCVR1 is a high-affinity metabolite transporter that serves as the common origin for phospholipid biosynthesis by two branches of the Kennedy pathway.
    DOI:  https://doi.org/10.1101/2023.09.28.560019
  20. bioRxiv. 2023 Oct 01. pii: 2023.09.29.560194. [Epub ahead of print]
    Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma.
    Zhuxuan Li, Xueqian Zhuang, Chun-Hao Pan, Yan Yan, Rohit Thummalapalli, Jill Hallin, Stefan Torborg, Anupriya Singhal, Jason C Chang, Eusebio Manchado, Lukas E Dow, Rona Yaeger, James G Christensen, Scott W Lowe, Charles M Rudin, Simon Joost, Tuomas Tammela.
      Lung adenocarcinoma (LUAD), commonly driven by KRAS mutations, is responsible for 7% of all cancer mortality. The first allele-specific KRAS inhibitors were recently approved in LUAD, but clinical benefit is limited by intrinsic and acquired resistance. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem cells by self-renewing and replacing alveolar type 1 (AT1) cells. Using genetically engineered mouse models, patient-derived xenografts, and patient samples we found inhibition of KRAS promotes transition to a quiescent AT1-like cancer cell state in LUAD tumors. Similarly, suppressing Kras induced AT1 differentiation of wild-type AT2 cells upon lung injury. The AT1-like LUAD cells exhibited high growth and differentiation potential upon treatment cessation, whereas ablation of the AT1-like cells robustly improved treatment response to KRAS inhibitors. Our results uncover an unexpected role for KRAS in promoting intra-tumoral heterogeneity and suggest targeting alveolar differentiation may augment KRAS-targeted therapies in LUAD.
    Significance: Treatment resistance limits response to KRAS inhibitors in LUAD patients. We find LUAD residual disease following KRAS targeting is composed of AT1-like cancer cells with the capacity to reignite tumorigenesis. Targeting the AT1-like cells augments responses to KRAS inhibition, elucidating a therapeutic strategy to overcome resistance to KRAS-targeted therapy.
    DOI:  https://doi.org/10.1101/2023.09.29.560194
  21. J Clin Invest. 2023 Oct 12. pii: e173160. [Epub ahead of print]
    Endothelial lipid droplets suppress eNOS to link high fat consumption to blood pressure elevation.
    Boa Kim, Wencao Zhao, Soon Yew Tang, Michael G Levin, Ayon Ibrahim, Yifan Yang, Emilia M Roberts, Ling Lai, Jian Li, Richard K Assoian, Garret A FitzGerald, Zoltan Arany.
      The metabolic syndrome, today affecting more than 20% of the US population, is a group of five conditions that often co-exist and that strongly predispose to cardiovascular disease. How these conditions are linked mechanistically remains unclear, especially two of these: obesity and elevated blood pressure. Here we show that high fat consumption in mice leads to the accumulation of lipid droplets in endothelial cells throughout the organism, and that lipid droplet accumulation in endothelium suppresses endothelial nitric oxide synthase (eNOS), reduces NO production, elevates blood pressure, and accelerates atherosclerosis. Mechanistically, the accumulation of lipid droplets destabilizes eNOS mRNA and activates an endothelial inflammatory signaling cascade that suppresses eNOS and NO production. Pharmacological prevention of lipid droplet formation reverses the suppression of NO production in cell culture and in vivo, and blunts blood pressure elevation in response to high fat diet. These results highlight lipid droplets as a critical and unappreciated component of endothelial cell biology, explain how lipids increase blood pressure acutely, and provide a mechanistic account for the epidemiological link between obesity and elevated blood pressure.
    Keywords:  Cardiology; Endothelial cells
    DOI:  https://doi.org/10.1172/JCI173160
  22. Front Nutr. 2023 ;10 1249407
    Red and processed meat and pancreatic cancer risk: a meta-analysis.
    Yudi Sun, Xinyi He, Yan Sun.
       Background: The relationship between red and processed meat consumption and pancreatic cancer risk is controversial and no study has looked specifically at the correlation for 6 years. We conducted a meta-analysis to summarize the evidence about the association between them.
    Methods: We systematically searched PubMed, Embase and Cochrane Library for studies of red or processed meat consumption and pancreatic cancer published from December 2016 to July 2022. We performed random-effects models to pool the relative risks from individual studies. Subgroup analyses were used to figure out heterogeneity. We also performed publication bias analysis.
    Results: Seven cohort studies and one case-control study that contained a total of 7,158 pancreatic cancer cases from 805,177 participants were eligible for inclusion. The combined RRs (95% CI) comparing highest and lowest categories were 1.07 (95% CI: 0.91-1.26; p = 0.064) for red meat and 1.04 (95% CI: 0.81-1.33; p = 0.006) for processed meat with statistically significant heterogeneity.
    Conclusion: This meta-analysis suggested that red and processed meat consumption has no relationship with pancreatic cancer risk.
    Keywords:  daily diet; meta-analysis; pancreatic cancer; processed meat; red meat
    DOI:  https://doi.org/10.3389/fnut.2023.1249407
  23. bioRxiv. 2023 Sep 28. pii: 2023.09.26.559598. [Epub ahead of print]
    Integrating Shear Flow and Trypsin Treatment to Assess Cell Adhesion Strength.
    Antra Patel, Bhavana Bhavanam, Trevor Keenan, Venkat Maruthamuthu.
      Cell adhesion is of fundamental importance in cell and tissue organization, and for designing cell-laden constructs for tissue engineering. Prior methods to assess cell adhesion strength for strongly adherent cells using hydrodynamic shear flow either involved the use of specialized flow devices to generate high shear stress or used simpler implementations like larger height parallel plate chambers that enable multi-hour cell culture but generate low shear stress and are hence more applicable for weakly adherent cells. Here, we propose a shear flow assay for adhesion strength assessment of strongly adherent cells that employs off-the-shelf parallel plate chambers for shear flow as well as simultaneous trypsin treatment to tune down the adhesion strength of cells. We implement the assay with a strongly adherent cell type and show that shear stress in the 0.07 to 7 Pa range is sufficient to dislodge the cells with simultaneous trypsin treatment. Imaging of cells over a square centimeter area allows cell morphological analysis of hundreds of cells. We show that the cell area of cells that are dislodged, on average, does not monotonically increase with shear stress at the higher end of shear stresses used and suggest that this can be explained by the likely higher resistance of high circularity cells to trypsin digestion. The adhesion strength assay proposed can be easily adapted by labs to assess the adhesion strength of both weakly and strongly adherent cell types and has the potential to be adapted for substrate stiffness-dependent adhesion strength assessment in mechanobiology studies.
    DOI:  https://doi.org/10.1101/2023.09.26.559598
  24. Nat Protoc. 2023 Oct 10.
    An end-to-end workflow for multiplexed image processing and analysis.
    Jonas Windhager, Vito Riccardo Tomaso Zanotelli, Daniel Schulz, Lasse Meyer, Michelle Daniel, Bernd Bodenmiller, Nils Eling.
      Multiplexed imaging enables the simultaneous spatial profiling of dozens of biological molecules in tissues at single-cell resolution. Extracting biologically relevant information, such as the spatial distribution of cell phenotypes from multiplexed tissue imaging data, involves a number of computational tasks, including image segmentation, feature extraction and spatially resolved single-cell analysis. Here, we present an end-to-end workflow for multiplexed tissue image processing and analysis that integrates previously developed computational tools to enable these tasks in a user-friendly and customizable fashion. For data quality assessment, we highlight the utility of napari-imc for interactively inspecting raw imaging data and the cytomapper R/Bioconductor package for image visualization in R. Raw data preprocessing, image segmentation and feature extraction are performed using the steinbock toolkit. We showcase two alternative approaches for segmenting cells on the basis of supervised pixel classification and pretrained deep learning models. The extracted single-cell data are then read, processed and analyzed in R. The protocol describes the use of community-established data containers, facilitating the application of R/Bioconductor packages for dimensionality reduction, single-cell visualization and phenotyping. We provide instructions for performing spatially resolved single-cell analysis, including community analysis, cellular neighborhood detection and cell-cell interaction testing using the imcRtools R/Bioconductor package. The workflow has been previously applied to imaging mass cytometry data, but can be easily adapted to other highly multiplexed imaging technologies. This protocol can be implemented by researchers with basic bioinformatics training, and the analysis of the provided dataset can be completed within 5-6 h. An extended version is available at https://bodenmillergroup.github.io/IMCDataAnalysis/ .
    DOI:  https://doi.org/10.1038/s41596-023-00881-0
  25. Biochim Biophys Acta Gen Subj. 2023 Oct 05. pii: S0304-4165(23)00182-4. [Epub ahead of print]1867(12): 130484
    Identifying genes associated with resistance to KRAS G12C inhibitors via machine learning methods.
    Xiandong Lin, QingLan Ma, Lei Chen, Wei Guo, Zhiyi Huang, Tao Huang, Yu-Dong Cai.
       BACKGROUND: Targeted therapy has revolutionized cancer treatment, greatly improving patient outcomes and quality of life. Lung cancer, specifically non-small cell lung cancer, is frequently driven by the G12C mutation at the KRAS locus. The development of KRAS inhibitors has been a breakthrough in the field of cancer research, given the crucial role of KRAS mutations in driving tumor growth and progression. However, over half of patients with cancer bypass inhibition show limited response to treatment. The mechanisms underlying tumor cell resistance to this treatment remain poorly understood.
    METHODS: To address above gap in knowledge, we conducted a study aimed to elucidate the differences between tumor cells that respond positively to KRAS (G12C) inhibitor therapy and those that do not. Specifically, we analyzed single-cell gene expression profiles from KRAS G12C-mutant tumor cell models (H358, H2122, and SW1573) treated with KRAS G12C (ARS-1620) inhibitor, which contained 4297 cells that continued to proliferate under treatment and 3315 cells that became quiescent. Each cell was represented by the expression levels on 8687 genes. We then designed an innovative machine learning based framework, incorporating seven feature ranking algorithms and four classification algorithms to identify essential genes and establish quantitative rules.
    RESULTS: Our analysis identified some top-ranked genes, including H2AFZ, CKS1B, TUBA1B, RRM2, and BIRC5, that are known to be associated with the progression of multiple cancers.
    CONCLUSION: Above genes were relevant to tumor cell resistance to targeted therapy. This study provides important insights into the molecular mechanisms underlying tumor cell resistance to KRAS inhibitor treatment.
    Keywords:  KRAS; Machine learning; Single-cell gene expression; Tumor cell; cancer
    DOI:  https://doi.org/10.1016/j.bbagen.2023.130484
  26. Cell. 2023 Sep 26. pii: S0092-8674(23)01032-2. [Epub ahead of print]
    Arginine reprograms metabolism in liver cancer via RBM39.
    Dirk Mossmann, Christoph Müller, Sujin Park, Brendan Ryback, Marco Colombi, Nathalie Ritter, Diana Weißenberger, Eva Dazert, Mairene Coto-Llerena, Sandro Nuciforo, Lauriane Blukacz, Caner Ercan, Veronica Jimenez, Salvatore Piscuoglio, Fatima Bosch, Luigi M Terracciano, Uwe Sauer, Markus H Heim, Michael N Hall.
      Metabolic reprogramming is a hallmark of cancer. However, mechanisms underlying metabolic reprogramming and how altered metabolism in turn enhances tumorigenicity are poorly understood. Here, we report that arginine levels are elevated in murine and patient hepatocellular carcinoma (HCC), despite reduced expression of arginine synthesis genes. Tumor cells accumulate high levels of arginine due to increased uptake and reduced arginine-to-polyamine conversion. Importantly, the high levels of arginine promote tumor formation via further metabolic reprogramming, including changes in glucose, amino acid, nucleotide, and fatty acid metabolism. Mechanistically, arginine binds RNA-binding motif protein 39 (RBM39) to control expression of metabolic genes. RBM39-mediated upregulation of asparagine synthesis leads to enhanced arginine uptake, creating a positive feedback loop to sustain high arginine levels and oncogenic metabolism. Thus, arginine is a second messenger-like molecule that reprograms metabolism to promote tumor growth.
    Keywords:  AGMAT; ARG1; ASNS; RBM39; arginine; hepatocellular carcinoma; indisulam; metabolism
    DOI:  https://doi.org/10.1016/j.cell.2023.09.011
  27. Proc Natl Acad Sci U S A. 2023 Oct 17. 120(42): e2219589120
    Phase separation underlies signaling activation of oncogenic NTRK fusions.
    Tianxin Zhu, Jingjing Xie, Hao He, Huan Li, Xianbin Tang, Shuyang Wang, Ziwen Li, Yawen Tian, Lingyu Li, Jidong Zhu, Guangya Zhu.
      NTRK (neurotrophic tyrosine receptor kinase) gene fusions that encode chimeric proteins exhibiting constitutive activity of tropomyosin receptor kinases (TRK), are oncogenic drivers in multiple cancer types. However, the underlying mechanisms in oncogenesis that involve various N-terminal fusion partners of NTRK fusions remain elusive. Here, we show that NTRK fusion proteins form liquid-like condensates driven by their N-terminal fusion partners. The kinase reactions are accelerated in these condensates where the complexes for downstream signaling activation are also concentrated. Our work demonstrates that the phase separation driven by NTRK fusions is not only critical for TRK activation, but the condensates formed through phase separation serve as organizational hubs for oncogenic signaling.
    Keywords:  NTRK; fusion oncoproteins; kinase activation; liquid–liquid phase separation
    DOI:  https://doi.org/10.1073/pnas.2219589120
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