bims-cagime 2023-11-12 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2023‒11‒12
29 papers selected by
Kıvanç Görgülü, Technical University of Munich

p62 bodies: cytosolic zoning by phase separation.
MAF amplification licenses ERα through epigenetic remodelling to drive breast cancer metastasis.
Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma.
Targeting ribosome biogenesis reinforces ERK-dependent senescence in pancreatic cancer.
Autophagy-mediated control of ribosome homeostasis in oncogene-induced senescence.
CRISPR screening identifies mechanisms of resistance to KRASG12C and SHP2 inhibitor combinations in non-small cell lung cancer.
Mitohormesis.
Reductive stress in cancer: coming out of the shadows.
Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice.
ATG9B is a tissue-specific homotrimeric lipid scramblase that can compensate for ATG9A.
Metastatic outgrowth via the two-way interplay of autophagy and metabolism.
Metabolic dependencies of metastasis-initiating cells in female breast cancer.
Iron, Copper, and Selenium: Cancer's Thing for Redox Bling.
SREBF1/SREBP-1 concurrently regulates lipid synthesis and lipophagy to maintain lipid homeostasis and tumor growth.
TEAD Inhibition Overcomes YAP1/TAZ-driven Primary and Acquired Resistance to KRASG12C Inhibitors.
Effects of KRAS genetic interactions on outcomes in cancers of the lung, pancreas, and colorectum.
Integration of transcriptomes of senescent cell models with multi-tissue patient samples reveals reduced COL6A3 as an inducer of senescence.
IL-6/JAK2-dependent G6PD phosphorylation promotes nucleotide synthesis and supports tumor growth.
Molecular Crowding: Physiologic Sensing and Control.
Spatial immune composition of tumor microenvironment in patients with pancreatic cancer.
TOLLIP acts as a cargo adaptor to promote lysosomal degradation of aberrant ER membrane proteins.
ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy.
Proteostasis governs differential temperature sensitivity across embryonic cell types.
Glucose-dependent insulinotropic polypeptide regulates body weight and food intake via GABAergic neurons in mice.
Cachexia index as a prognostic predictor after resection of pancreatic ductal adenocarcinoma.
Synthetic autophagy receptor.
Pancreatic index: A prognostic factor of upfront surgery for body or tail pancreatic ductal adenocarcinoma with vascular involvement-A retrospective study.
The Reactome Pathway Knowledgebase 2024.
Vitamin B6 competition in the tumor microenvironment hampers antitumor functions of NK cells.

J Biochem. 2023 Nov 08. pii: mvad089. [Epub ahead of print]

p62 bodies: cytosolic zoning by phase separation.

Reo Kurusu, Hideaki Morishita, Masaaki Komatsu.

  Cellular zoning or partitioning is critical in preventing macromolecules from random diffusion and in orchestrating the spatiotemporal dynamics of biochemical reactions. Along with membranous organelles, membrane-less organelles contribute to the precise regulation of biochemical reactions inside cells. In response to environmental cues, membrane-less organelles rapidly form through liquid-liquid phase separation, sequester certain proteins and RNAs, mediate specific reactions, and dissociate. Among membrane-less organelles, ubiquitin-positive condensates, namely, p62 bodies, maintain cellular homeostasis through selective autophagy of themselves to contribute to intracellular quality control. p62 bodies also activate the anti-oxidative stress response regulated by the KEAP1-NRF2 system. In this review, we present an overview of recent advancements in cellular and molecular biology related to p62 bodies, highlighting their dynamic nature and functions.

Keywords:  Autophagy; KEAP1-NRF2 system; intracellular quality control; liquid-liquid phase separation; p62 body

DOI:  https://doi.org/10.1093/jb/mvad089
Nat Cell Biol. 2023 Nov 09.

MAF amplification licenses ERα through epigenetic remodelling to drive breast cancer metastasis.

Alicia Llorente, María Teresa Blasco, Irene Espuny, Marc Guiu, Cecilia Ballaré, Enrique Blanco, Adrià Caballé, Anna Bellmunt, Fernando Salvador, Andrea Morales, Marc Nuñez, Guillem Loren, Francesca Imbastari, Marta Fidalgo, Cristina Figueras-Puig, Patrizia Gibler, Mariona Graupera, Freddy Monteiro, Antoni Riera, Ingunn Holen, Alexandra Avgustinova, Luciano Di Croce, Roger R Gomis.

MAF amplification increases the risk of breast cancer (BCa) metastasis through mechanisms that are still poorly understood yet have important clinical implications. Oestrogen-receptor-positive (ER+) BCa requires oestrogen for both growth and metastasis, albeit by ill-known mechanisms. Here we integrate proteomics, transcriptomics, epigenomics, chromatin accessibility and functional assays from human and syngeneic mouse BCa models to show that MAF directly interacts with oestrogen receptor alpha (ERα), thereby promoting a unique chromatin landscape that favours metastatic spread. We identify metastasis-promoting genes that are de novo licensed following oestrogen exposure in a MAF-dependent manner. The histone demethylase KDM1A is key to the epigenomic remodelling that facilitates the expression of the pro-metastatic MAF/oestrogen-driven gene expression program, and loss of KDM1A activity prevents this metastasis. We have thus determined that the molecular basis underlying MAF/oestrogen-mediated metastasis requires genetic, epigenetic and hormone signals from the systemic environment, which influence the ability of BCa cells to metastasize.

DOI: https://doi.org/10.1038/s41556-023-01281-y
Cancer Discov. 2023 Nov 07.

Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma.

Zhuxuan Li, Xueqian Zhuang, Chun-Hao Pan, Yan Yan, Rohit Thummalapalli, Jill Hallin, Stefan R 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.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0289
Cell Cycle. 2023 Nov 09. 1-22

Targeting ribosome biogenesis reinforces ERK-dependent senescence in pancreatic cancer.

M C Rowell, X Deschênes-Simard, S Lopes-Paciencia, B Le Calvé, P Kalegari, L Mignacca, A Fernandez-Ruiz, J Guillon, F Lessard, V Bourdeau, S Igelmann, A M Duman, Y Stanom, F Kottakis, V Deshpande, V Krizhanovsky, N Bardeesy, G Ferbeyre.

  Pancreatic adenocarcinomas (PDAC) often possess mutations in K-Ras that stimulate the ERK pathway. Aberrantly high ERK activation triggers oncogene-induced senescence, which halts tumor progression. Here we report that low-grade pancreatic intraepithelial neoplasia displays very high levels of phospho-ERK consistent with a senescence response. However, advanced lesions that have circumvented the senescence barrier exhibit lower phospho-ERK levels. Restoring ERK hyperactivation in PDAC using activated RAF leads to ERK-dependent growth arrest with senescence biomarkers. ERK-dependent senescence in PDAC was characterized by a nucleolar stress response including a selective depletion of nucleolar phosphoproteins and intranucleolar foci containing RNA polymerase I designated as senescence-associated nucleolar foci (SANF). Accordingly, combining ribosome biogenesis inhibitors with ERK hyperactivation reinforced the senescence response in PDAC cells. Notably, comparable mechanisms were observed upon treatment with the platinum-based chemotherapy regimen FOLFIRINOX, currently a first-line treatment option for PDAC. We thus suggest that drugs targeting ribosome biogenesis can improve the senescence anticancer response in pancreatic cancer.

Keywords:  MAP kinase; folfirinox; nucleolus; pancreatic cancer; ribosome biogenesis; therapy-induced senescence

DOI:  https://doi.org/10.1080/15384101.2023.2278945
Cell Rep. 2023 Nov 05. pii: S2211-1247(23)01393-1. [Epub ahead of print]42(11): 113381

Autophagy-mediated control of ribosome homeostasis in oncogene-induced senescence.

Aida Rodríguez López, Maria H Jørgensen, Jesper F Havelund, Frederic S Arendrup, Srinivasa Prasad Kolapalli, Thorbjørn M Nielsen, Eva Pais, Carsten Jörn Beese, Ahmad Abdul-Al, Anna Constance Vind, Jiri Bartek, Simon Bekker-Jensen, Marta Montes, Panagiotis Galanos, Nils Faergeman, Lotta Happonen, Lisa B Frankel.

  Oncogene-induced senescence (OIS) is a persistent anti-proliferative response that acts as a barrier against malignant transformation. During OIS, cells undergo dynamic remodeling, which involves alterations in protein and organelle homeostasis through autophagy. Here, we show that ribosomes are selectively targeted for degradation by autophagy during OIS. By characterizing senescence-dependent alterations in the ribosomal interactome, we find that the deubiquitinase USP10 dissociates from the ribosome during the transition to OIS. This release of USP10 leads to an enhanced ribosome ubiquitination, particularly of small subunit proteins, including lysine 275 on RPS2. Both reinforcement of the USP10-ribosome interaction and mutation of RPS2 K275 abrogate ribosomal delivery to lysosomes without affecting bulk autophagy. We show that the selective recruitment of ubiquitinated ribosomes to autophagosomes is mediated by the p62 receptor. While ribophagy is not required for the establishment of senescence per se, it contributes to senescence-related metabolome alterations and facilitates the senescence-associated secretory phenotype.

Keywords:  CP: Cell biology; CP: Molecular biology; USP10; autophagy; oncogene-induced senescence; ribosomes; selective autophagy; ubiquitin

DOI:  https://doi.org/10.1016/j.celrep.2023.113381
Cancer Res. 2023 Nov 07.

CRISPR screening identifies mechanisms of resistance to KRASG12C and SHP2 inhibitor combinations in non-small cell lung cancer.

Anirudh Prahallad, Andreas Weiss, Hans Voshol, Grainne Kerr, Kathleen Sprouffske, Tina Yuan, David Ruddy, Morgane Meistertzheim, Malika Kazic-Legueux, Tina Kottarathil, Michelle Piquet, Yichen Cao, Laetitia Martinuzzi-Duboc, Alexandra Buhles, Flavia Alder, Salvatore Mannino, Luca Tordella, Laurent Sansregret, Sauveur-Michel Maira, Diana Graus Porta, Carmine Fedele, Saskia M Brachmann.

Although KRASG12C inhibitors show clinical activity in patients with KRAS G12C mutated non-small cell lung cancer (NSCLC) and other solid tumor malignancies, response is limited by multiple mechanisms of resistance. The KRASG12C inhibitor JDQ443 shows enhanced preclinical antitumor activity combined with the SHP2 inhibitor TNO155, and the combination is currently under clinical evaluation. To identify rational combination strategies that could help overcome or prevent some types of resistance, we evaluated the duration of tumor responses to JDQ443 ± TNO155, alone or combined with the PI3Kα inhibitor alpelisib and/or the CDK4/6 inhibitor ribociclib, in xenograft models derived from a KRASG12C-mutant NSCLC line and investigated the genetic mechanisms associated with loss of response to combined KRASG12C/SHP2 inhibition. Tumor regression by single-agent JDQ443 at clinically relevant doses lasted on average 2 weeks and was increasingly extended by the double, triple or quadruple combinations. Growth resumption was accompanied by progressively increased KRAS G12C amplification. Functional genome-wide CRISPR screening in KRASG12C-dependent NSCLC lines with distinct mutational profiles to identify adaptive mechanisms of resistance revealed sensitizing and rescuing genetic interactions with KRASG12C/SHP2 co-inhibition; FGFR1 loss was the strongest sensitizer, and PTEN loss the strongest rescuer. Consistently, the antiproliferative activity of KRASG12C/SHP2 inhibition was strongly enhanced by PI3K inhibitors. Overall, KRAS G12C amplification and alterations of the MAPK/PI3K pathway were predominant mechanisms of resistance to combined KRASG12C/SHP2 inhibitors in preclinical settings. The biological nodes identified by CRISPR screening might provide additional starting points for effective combination treatments.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-1127
Cell Metab. 2023 Nov 07. pii: S1550-4131(23)00380-7. [Epub ahead of print]35(11): 1872-1886

Mitohormesis.

Yu-Wei Cheng, Jie Liu, Toren Finkel.

Perturbation of mitochondrial function can trigger a host of cellular responses that seek to restore cellular metabolism, cytosolic proteostasis, and redox homeostasis. In some cases, these responses persist even after the stress is relieved, leaving the cell or tissue in a less vulnerable state. This process-termed mitohormesis-is increasingly viewed as an important aspect of normal physiology and a critical modulator of various disease processes. Here, we review aspects of mitochondrial stress signaling that, among other things, can rewire the cell's metabolism, activate the integrated stress response, and alter cytosolic quality-control pathways. We also discuss how these pathways are implicated in various disease states from pathogen challenge to chemotherapeutic resistance and how their therapeutic manipulation can lead to new strategies for a host of chronic conditions including aging itself.

DOI: https://doi.org/10.1016/j.cmet.2023.10.011
Trends Cancer. 2023 Nov 02. pii: S2405-8033(23)00213-3. [Epub ahead of print]

Reductive stress in cancer: coming out of the shadows.

Maolin Ge, Thales Papagiannakopoulos, Liron Bar-Peled.

  Redox imbalance is defined by disruption in oxidative and reductive pathways and has a central role in cancer initiation, development, and treatment. Although redox imbalance has traditionally been characterized by high levels of oxidative stress, emerging evidence suggests that an overly reductive environment is just as detrimental to cancer proliferation. Reductive stress is defined by heightened levels of antioxidants, including glutathione and elevated NADH, compared with oxidized NAD, which disrupts central biochemical pathways required for proliferation. With the advent of new technologies that measure and manipulate reductive stress, the sensors and drivers of this overlooked metabolic stress are beginning to be revealed. In certain genetically defined cancers, targeting reductive stress pathways may be an effective strategy. Redox-based pathways are gaining recognition as essential 'regulatory hubs,' and a broader understanding of reductive stress signaling promises not only to reveal new insights into metabolic homeostasis but also potentially to transform therapeutic options in cancer.

Keywords:  KEAP1/NRF2; cancer metabolism; redox homeostasis; reductive stress

DOI:  https://doi.org/10.1016/j.trecan.2023.10.002
Cell Metab. 2023 Nov 07. pii: S1550-4131(23)00374-1. [Epub ahead of print]35(11): 1976-1995.e6

Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice.

Cara L Green, Michaela E Trautman, Krittisak Chaiyakul, Raghav Jain, Yasmine H Alam, Reji Babygirija, Heidi H Pak, Michelle M Sonsalla, Mariah F Calubag, Chung-Yang Yeh, Anneliese Bleicher, Grace Novak, Teresa T Liu, Sarah Newman, Will A Ricke, Kristina A Matkowskyj, Irene M Ong, Cholsoon Jang, Judith Simcox, Dudley W Lamming.

  Low-protein diets promote health and longevity in diverse species. Restriction of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine recapitulates many of these benefits in young C57BL/6J mice. Restriction of dietary isoleucine (IleR) is sufficient to promote metabolic health and is required for many benefits of a low-protein diet in C57BL/6J males. Here, we test the hypothesis that IleR will promote healthy aging in genetically heterogeneous adult UM-HET3 mice. We find that IleR improves metabolic health in young and old HET3 mice, promoting leanness and glycemic control in both sexes, and reprograms hepatic metabolism in a sex-specific manner. IleR reduces frailty and extends the lifespan of male and female mice, but to a greater degree in males. Our results demonstrate that IleR increases healthspan and longevity in genetically diverse mice and suggests that IleR, or pharmaceuticals that mimic this effect, may have potential as a geroprotective intervention.

Keywords:  aging; branched-chain amino acids; frailty; isoleucine; lifespan; metabolic health; mice; nutritional interventions; protein restriction

DOI:  https://doi.org/10.1016/j.cmet.2023.10.005
Autophagy. 2023 Nov 08.

ATG9B is a tissue-specific homotrimeric lipid scramblase that can compensate for ATG9A.

George N Chiduza, Acely Garza-Garcia, Eugenia Almacellas, Stefano De Tito, Valerie E Pye, Alexander R van Vliet, Peter Cherepanov, Sharon A Tooze.

  Macroautophagy/autophagy is a fundamental aspect of eukaryotic biology, and the autophagy-related protein ATG9A is part of the core machinery facilitating this process. In addition to ATG9A vertebrates encode ATG9B, a poorly characterized paralog expressed in a subset of tissues. Herein, we characterize the structure of human ATG9B revealing the conserved homotrimeric quaternary structure and explore the conformational dynamics of the protein. Consistent with the experimental structure and computational chemistry, we establish that ATG9B is a functional lipid scramblase. We show that ATG9B can compensate for the absence of ATG9A in starvation-induced autophagy displaying similar subcellular trafficking and steady-state localization. Finally, we demonstrate that ATG9B can form a heteromeric complex with ATG2A. By establishing the molecular structure and function of ATG9B, our results inform the exploration of niche roles for autophagy machinery in more complex eukaryotes and reveal insights relevant across species.

Keywords:  ATG9A; Cryo-EM; autophagy; membrane protein dynamics; phagophore; scramblase; single-particle analysis

DOI:  https://doi.org/10.1080/15548627.2023.2275905
Biochim Biophys Acta Mol Basis Dis. 2023 Jul 28. pii: S0925-4439(23)00190-4. [Epub ahead of print] 166824

Metastatic outgrowth via the two-way interplay of autophagy and metabolism.

Amir Barzegar Behrooz, Marco Cordani, Massimo Donadelli, Saeid Ghavami.

  Metastasis represents one of the most dangerous issue of cancer progression, characterized by intricate interactions between invading tumor cells, various proteins, and other cells on the way towards target sites. Tumor cells, while undergoing metastasis, engage in dynamic dialogues with stromal cells and undertake epithelial-mesenchymal transition (EMT) phenoconversion. To ensure survival, tumor cells employ several strategies such as restructuring their metabolic needs to adapt to the alterations of the microenvironmental resources via different mechanisms including macroautophagy (autophagy) and to circumvent anoikis-a form of cell death induced upon detachment from the extracellular matrix (ECM). This review focuses on the puzzling connections of autophagy and energetic metabolism within the context of cancer metastasis.

Keywords:  Autophagy; Cancer metastasis; Epithelial-mesenchymal transition; Extracellular vesicles; Metabolism; Tumor microenvironment; Wnt/β-catenin

DOI:  https://doi.org/10.1016/j.bbadis.2023.166824
Nat Commun. 2023 Nov 04. 14(1): 7076

Metabolic dependencies of metastasis-initiating cells in female breast cancer.

C Megan Young, Laurent Beziaud, Pierre Dessen, Angela Madurga Alonso, Albert Santamaria-Martínez, Joerg Huelsken.

Understanding the mechanisms that enable cancer cells to metastasize is essential in preventing cancer progression. Here we examine the metabolic adaptations of metastasis-initiating cells (MICs) in female breast cancer and how those shape their metastatic phenotype. We find that endogenous MICs depend on the oxidative tricarboxylic acid cycle and fatty acid usage. Sorting tumor cells based upon solely mitochondrial membrane potential or lipid storage is sufficient at identifying MICs. We further identify that mitochondrially-generated citrate is exported to the cytoplasm to yield acetyl-CoA, and this is crucial to maintaining heightened levels of H3K27ac in MICs. Blocking acetyl-CoA generating pathways or H3K27ac-specific epigenetic writers and readers reduces expression of epithelial-to-mesenchymal related genes, MIC frequency, and metastatic potential. Exogenous supplementation of a short chain carboxylic acid, acetate, increases MIC frequency and metastasis. In patient cohorts, we observe that higher expression of oxidative phosphorylation related genes is associated with reduced distant relapse-free survival. These data demonstrate that MICs specifically and precisely alter their metabolism to efficiently colonize distant organs.

DOI: https://doi.org/10.1038/s41467-023-42748-8
Cold Spring Harb Perspect Med. 2023 Nov 06. pii: a041545. [Epub ahead of print]

Iron, Copper, and Selenium: Cancer's Thing for Redox Bling.

Erdem M Terzi, Richard Possemato.

Cells require micronutrients for numerous basic functions. Among these, iron, copper, and selenium are particularly critical for redox metabolism, and their importance is heightened during oncogene-driven perturbations in cancer. In this review, which particularly focuses on iron, we describe how these micronutrients are carefully chaperoned about the body and made available to tissues, a process that is designed to limit the toxicity of free iron and copper or by-products of selenium metabolism. We delineate perturbations in iron metabolism and iron-dependent proteins that are observed in cancer, and describe the current approaches being used to target iron metabolism and iron-dependent processes.

DOI: https://doi.org/10.1101/cshperspect.a041545
Autophagy. 2023 Nov 05. 1-3

SREBF1/SREBP-1 concurrently regulates lipid synthesis and lipophagy to maintain lipid homeostasis and tumor growth.

Feng Geng, Deliang Guo.

  Cholesterol is an essential structural component of the cell membrane, whereas excess cholesterol can be toxic and thus is stored in intracellular lipid droplets (LDs). Malignant tumor cells grow rapidly and require abundant cholesterol to build new membranes. How they maintain cholesterol homeostasis is largely unknown. We recently revealed that SREBF1/SREBP-1 (sterol regulatory element binding transcription factor 1), a key lipogenic transcription factor, plays a critical role in maintaining cholesterol homeostasis in tumor cells. We found that in addition to activation of de novo lipid synthesis and cholesterol uptake, SREBF1 also upregulates macroautophagy/autophagy to hydrolyze LDs, and increases the expression of NPC2, a lysosome cholesterol transporter, actively mobilizing LD-stored cholesterol and fatty acids to promote tumor growth. Our study demonstrates that SREBF1 controls the balance of lipid synthesis, uptake, storage and liberation to maintain lipid homeostasis for rapid tumor growth, while suggesting it as a very promising molecular target for cancer treatment.

Keywords:  Autophagy; cancer; cholesterol; glioblastoma; lipid droplets; lipophagy

DOI:  https://doi.org/10.1080/15548627.2023.2275501
Cancer Res. 2023 Nov 07.

TEAD Inhibition Overcomes YAP1/TAZ-driven Primary and Acquired Resistance to KRASG12C Inhibitors.

A Cole Edwards, Clint A Stalnecker, Alexis Jean Morales, Khalilah E Taylor, Jennifer E Klomp, Jeffrey A Klomp, Andrew M Waters, Niranjan Sudhakar, Jill Hallin, Tracy T Tang, Peter Olson, Leonard Post, James G Christensen, Adrienne D Cox, Channing J Der.

Primary/intrinsic and treatment-induced acquired resistance limit the initial response rate to and long-term efficacy of direct inhibitors of the KRASG12C mutant in cancer. To identify potential mechanisms of resistance, we applied a CRISPR/Cas9 loss-of-function screen and observed loss of multiple components of the Hippo tumor suppressor pathway, which acts to suppress YAP1/TAZ-regulated gene transcription. YAP1/TAZ activation impaired the anti-proliferative and pro-apoptotic effects of KRASG12C inhibitor (G12Ci) treatment in KRASG12C-mutant cancer cell lines. Conversely, genetic suppression of YAP1/WWTR1 (TAZ) enhanced G12Ci sensitivity. YAP1/TAZ activity overcame KRAS dependency through two distinct TEAD transcription factor-dependent mechanisms that phenocopy KRAS effector signaling. First, TEAD stimulated ERK-independent transcription of genes normally regulated by ERK (BIRC5, CDC20, ECT2, FOSL1 and MYC) to promote progression through the cell cycle. Second, TEAD caused activation of PI3K-AKT-mTOR signaling to overcome apoptosis. G12Ci treatment-induced acquired resistance was also caused by YAP1/TAZ-TEAD activation. Accordingly, concurrent treatment with pharmacologic inhibitors of TEAD synergistically enhanced KRASG12C inhibitor anti-tumor activity in vitro and prolonged tumor suppression in vivo. In summary, these observations reveal YAP1/TAZ-TEAD signaling as a crucial driver of primary and acquired resistance to KRAS inhibition and support the use of TEAD inhibitors to enhance the anti-tumor efficacy of KRAS-targeted therapies.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2994
Cancer Epidemiol Biomarkers Prev. 2023 Nov 09.

Effects of KRAS genetic interactions on outcomes in cancers of the lung, pancreas, and colorectum.

Isabella N Grabski, John V Heymach, Kenneth L Kehl, Scott Kopetz, Ken S Lau, Gregory J Riely, Deborah Schrag, Rona Yaeger, Rafael A Irizarry, Kevin M Haigis.

BACKGROUND: KRAS is among the most commonly mutated oncogenes in cancer, and previous studies have shown associations with survival in many cancer contexts. Evidence from both clinical observations and mouse experiments further suggests that these associations are allele- and tissue-specific. These findings motivate using clinical data to understand gene interactions and clinical covariates within different alleles and tissues.METHODS: We analyze genomic and clinical data from the AACR Project GENIE Biopharma Collaborative for samples from lung, colorectal, and pancreatic cancers. For each of these cancer types, we report epidemiological associations for different KRAS alleles, apply principal component analysis to discover groups of genes co-mutated with KRAS, and identify distinct clusters of patient profiles with implications for survival.
RESULTS: KRAS mutations were associated with inferior survival in lung, colon, and pancreas, although the specific mutations implicated varied by disease. Tissue- and allele-specific associations with smoking, sex, age, and race were found. Tissue-specific genetic interactions with KRAS were identified by principal components analysis, which were clustered to produce five, four, and two patient profiles in lung, colon, and pancreas. Membership in these profiles was associated with survival in all three cancer types.
CONCLUSION: KRAS mutations have tissue- and allele-specific associations with inferior survival, clinical covariates, and genetic interactions.
IMPACT: Our results provide greater insight into the tissue- and allele-specific associations with KRAS mutations and identify clusters of patients that are associated with survival and clinical attributes from combinations of genetic interactions with KRAS mutations.

DOI: https://doi.org/10.1158/1055-9965.EPI-23-0262
Cell Rep. 2023 Nov 07. pii: S2211-1247(23)01383-9. [Epub ahead of print]42(11): 113371

Integration of transcriptomes of senescent cell models with multi-tissue patient samples reveals reduced COL6A3 as an inducer of senescence.

Radoslav Savić, Jialiang Yang, Simon Koplev, Mahru C An, Priyanka L Patel, Robert N O'Brien, Brittany N Dubose, Tetyana Dodatko, Eduard Rogatsky, Katyayani Sukhavasi, Raili Ermel, Arno Ruusalepp, Sander M Houten, Jason C Kovacic, Andrew F Stewart, Christopher B Yohn, Eric E Schadt, Remi-Martin Laberge, Johan L M Björkegren, Zhidong Tu, Carmen Argmann.

  Senescent cells are a major contributor to age-dependent cardiovascular tissue dysfunction, but knowledge of their in vivo cell markers and tissue context is lacking. To reveal tissue-relevant senescence biology, we integrate the transcriptomes of 10 experimental senescence cell models with a 224 multi-tissue gene co-expression network based on RNA-seq data of seven tissues biopsies from ∼600 coronary artery disease (CAD) patients. We identify 56 senescence-associated modules, many enriched in CAD GWAS genes and correlated with cardiometabolic traits-which supports universality of senescence gene programs across tissues and in CAD. Cross-tissue network analyses reveal 86 candidate senescence-associated secretory phenotype (SASP) factors, including COL6A3. Experimental knockdown of COL6A3 induces transcriptional changes that overlap the majority of the experimental senescence models, with cell-cycle arrest linked to modulation of DREAM complex-targeted genes. We provide a transcriptomic resource for cellular senescence and identify candidate biomarkers, SASP factors, and potential drivers of senescence in human tissues.

Keywords:  COL6A3; CP: Cell biology; cellular senescence; collagen; disease; human; integration; network; transcriptomic

DOI:  https://doi.org/10.1016/j.celrep.2023.113371
Mol Metab. 2023 Nov 08. pii: S2212-8778(23)00170-9. [Epub ahead of print] 101836

IL-6/JAK2-dependent G6PD phosphorylation promotes nucleotide synthesis and supports tumor growth.

Xuemei Qiu, Hongping Ye, Xiaofei Li, Dan Li, Lu Jiang, Rui Liu, Zhe Zhao, Dan He.

  Tumor cells hijack inflammatory mechanisms to promote their own growth. IL-6 is one of the major cytokines, and is frequently upregulated in tumors. The pentose phosphate pathway (PPP) generates the indispensable building blocks to produce various nucleotides. However, whether and how PPP is timely tuned in response to IL-6 to support tumor growth remains largely unknown. Here we show that the metabolic flux of PPP and enzymatic activity of glucose-6-phosphate dehydrogenase (G6PD) is rapidly induced under IL-6 treatment, without obvious changes in G6PD expression level. Mechanistically, Janus kinase 2 (JAK2) phosphorylates G6PD Y437 under IL-6 treatment, which accentuates G6PD enzymatic activity by promoting G6PD binding with its substrate G6P. Further, JAK2-dependent G6PD Y437 phosphorylation is required for IL-6-induced nucleotide biosynthesis and tumor cell proliferation, and is associated with the progression of oral squamous cell carcinoma. Our findings report a new mechanism implicated in the crosstalk between tumor cells and inflammatory microenvironment, by which JAK2-dependent activation of G6PD governs nucleotide synthesis to support tumor cell proliferation, thereby highlighting its value as a potential anti-tumor target.

Keywords:  G6PD; JAK2; nucleotide metabolism; pentose phosphate pathway; tumorigenesis

DOI:  https://doi.org/10.1016/j.molmet.2023.101836
Annu Rev Physiol. 2023 Nov 06.

Molecular Crowding: Physiologic Sensing and Control.

Arohan R Subramanya, Cary R Boyd-Shiwarski.

The cytoplasm is densely packed with molecules that contribute to its nonideal behavior. Cytosolic crowding influences chemical reaction rates, intracellular water mobility, and macromolecular complex formation. Overcrowding is potentially catastrophic; to counteract this problem, cells have evolved acute and chronic homeostatic mechanisms that optimize cellular crowdedness. Here, we provide a physiology-focused overview of molecular crowding, highlighting contemporary advances in our understanding of its sensing and control. Long hypothesized as a form of crowding-induced microcompartmentation, phase separation allows cells to detect and respond to intracellular crowding through the action of biomolecular condensates, as indicated by recent studies. Growing evidence indicates that crowding is closely tied to cell size and fluid volume, homeostatic responses to physical compression and desiccation, tissue architecture, circadian rhythm, aging, transepithelial transport, and total body electrolyte and water balance. Thus, molecular crowding is a fundamental physiologic parameter that impacts diverse functions extending from molecule to organism. Expected final online publication date for the Annual Review of Physiology, Volume 86 is February 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-physiol-042222-025920
Cancer Immunol Immunother. 2023 Nov 08.

Spatial immune composition of tumor microenvironment in patients with pancreatic cancer.

Eline S Zwart, Thomas van Ee, Alsya J Affandi, Lenka N C Boyd, Ernesto Rodriguez, Joke M M den Haan, Arantza Farina, Nicole C T van Grieken, Laura L Meijer, Yvette van Kooyk, Reina E Mebius, Geert Kazemier.

  This study examined the composition of the immune microenvironment at different sites within resected pancreas specimens from patients with pancreatic ductal adenocarcinoma (PDAC). Therefore, single-cell suspensions were made from fresh tumor and non-tumorous tissue. Fourteen patients were included from whom twelve PDAC and five non-tumorous samples were obtained. These samples were analyzed with a nineteen marker panel on the Aurora spectral flow cytometer. Furthermore, slides from formalin-fixed paraffine PDACs of eight additional patients were stained with eight markers and analyzed by multispectral imaging. These corresponded to central tumor, periphery of the tumor, i.e., invasive front and resected lymph node and were divided into tumor and adjacent tissue. In the single-cell suspension, a decreased ratio between lymphoid and myeloid cells and between M1 and M2 macrophages was observed in the tumor tissue compared to non-tumorous tissue. Furthermore, an increase in CD169 + macrophages in patients undergoing neoadjuvant therapy was found. Using immunofluorescence, more macrophages compared to T cells were observed, as well as a lower ratio of CD8 to M2 macrophage, a higher ratio of CD4-CD8 T cells and a higher ratio of immune-suppressive cells to pro-inflammatory cells in the PDAC area compared to the adjacent non-tumorous tissue. Finally, there were more immune-suppressive cells in the central tumor area compared to the invasive front. In conclusion, we show a gradient in the immune-suppressive environment in PDAC from most suppressive in the central tumor to least suppressive in distant non-tumorous tissue.

Keywords:  Immunology; Neoadjuvant therapy; Pancreatic cancer; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00262-023-03573-6
EMBO J. 2023 Nov 06. e114272

TOLLIP acts as a cargo adaptor to promote lysosomal degradation of aberrant ER membrane proteins.

Yuki Hayashi, Sho Takatori, Waleed Y Warsame, Taisuke Tomita, Takao Fujisawa, Hidenori Ichijo.

  Endoplasmic reticulum (ER) proteostasis is maintained by various catabolic pathways. Lysosomes clear entire ER portions by ER-phagy, while proteasomes selectively clear misfolded or surplus aberrant proteins by ER-associated degradation (ERAD). Recently, lysosomes have also been implicated in the selective clearance of aberrant ER proteins, but the molecular basis remains unclear. Here, we show that the phosphatidylinositol-3-phosphate (PI3P)-binding protein TOLLIP promotes selective lysosomal degradation of aberrant membrane proteins, including an artificial substrate and motoneuron disease-causing mutants of VAPB and Seipin. These cargos are recognized by TOLLIP through its misfolding-sensing intrinsically disordered region (IDR) and ubiquitin-binding CUE domain. In contrast to ER-phagy receptors, which clear both native and aberrant proteins by ER-phagy, TOLLIP selectively clears aberrant cargos by coupling them with the PI3P-dependent lysosomal trafficking without promoting bulk ER turnover. Moreover, TOLLIP depletion augments ER stress after ERAD inhibition, indicating that TOLLIP and ERAD cooperatively safeguard ER proteostasis. Our study identifies TOLLIP as a unique type of cargo-specific adaptor dedicated to the clearance of aberrant ER cargos and provides insights into molecular mechanisms underlying lysosome-mediated quality control of membrane proteins.

Keywords:  ER-phagy; TOLLIP; cargo adaptor; intrinsically disordered region; lysosome

DOI:  https://doi.org/10.15252/embj.2023114272
Genes Dev. 2023 Nov 06.

ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy.

Mingchao Wang, Xiaojuan Ran, Wendy Leung, Ajinkya Kawale, Sneha Saxena, Jian Ouyang, Parasvi S Patel, Yuting Dong, Tao Yin, Jian Shu, Robert T Manguso, Li Lan, Xiao-Fan Wang, Michael S Lawrence, Lee Zou.

  The mismatch repair (MMR) deficiency of cancer cells drives mutagenesis and offers a useful biomarker for immunotherapy. However, many MMR-deficient (MMR-d) tumors do not respond to immunotherapy, highlighting the need for alternative approaches to target MMR-d cancer cells. Here, we show that inhibition of the ATR kinase preferentially kills MMR-d cancer cells. Mechanistically, ATR inhibitor (ATRi) imposes synthetic lethality on MMR-d cells by inducing DNA damage in a replication- and MUS81 nuclease-dependent manner. The DNA damage induced by ATRi is colocalized with both MSH2 and PCNA, suggesting that it arises from DNA structures recognized by MMR proteins during replication. In syngeneic mouse models, ATRi effectively reduces the growth of MMR-d tumors. Interestingly, the antitumor effects of ATRi are partially due to CD8+ T cells. In MMR-d cells, ATRi stimulates the accumulation of nascent DNA fragments in the cytoplasm, activating the cGAS-mediated interferon response. The combination of ATRi and anti-PD-1 antibody reduces the growth of MMR-d tumors more efficiently than ATRi or anti-PD-1 alone, showing the ability of ATRi to augment the immunotherapy of MMR-d tumors. Thus, ATRi selectively targets MMR-d tumor cells by inducing synthetic lethality and enhancing antitumor immunity, providing a promising strategy to complement and augment MMR deficiency-guided immunotherapy.

Keywords:  ATR; MMR; MSI; immunotherapy; synthetic lethality

DOI:  https://doi.org/10.1101/gad.351084.123
Cell. 2023 Nov 09. pii: S0092-8674(23)01129-7. [Epub ahead of print]186(23): 5015-5027.e12

Proteostasis governs differential temperature sensitivity across embryonic cell types.

Michael W Dorrity, Lauren M Saunders, Madeleine Duran, Sanjay R Srivatsan, Eliza Barkan, Dana L Jackson, Sydney M Sattler, Brent Ewing, Christine Queitsch, Jay Shendure, David W Raible, David Kimelman, Cole Trapnell.

  Embryonic development is remarkably robust, but temperature stress can degrade its ability to generate animals with invariant anatomy. Phenotypes associated with environmental stress suggest that some cell types are more sensitive to stress than others, but the basis of this sensitivity is unknown. Here, we characterize hundreds of individual zebrafish embryos under temperature stress using whole-animal single-cell RNA sequencing (RNA-seq) to identify cell types and molecular programs driving phenotypic variability. We find that temperature perturbs the normal proportions and gene expression programs of numerous cell types and also introduces asynchrony in developmental timing. The notochord is particularly sensitive to temperature, which we map to a specialized cell type: sheath cells. These cells accumulate misfolded protein at elevated temperature, leading to a cascading structural failure of the notochord and anatomic defects. Our study demonstrates that whole-animal single-cell RNA-seq can identify mechanisms for developmental robustness and pinpoint cell types that constitute key failure points.

Keywords:  developmental robustness; single-cell RNA-seq; variability; zebrafish

DOI:  https://doi.org/10.1016/j.cell.2023.10.013
Nat Metab. 2023 Nov 09.

Glucose-dependent insulinotropic polypeptide regulates body weight and food intake via GABAergic neurons in mice.

Arkadiusz Liskiewicz, Ahmed Khalil, Daniela Liskiewicz, Aaron Novikoff, Gerald Grandl, Gandhari Maity-Kumar, Robert M Gutgesell, Mostafa Bakhti, Aimée Bastidas-Ponce, Oliver Czarnecki, Konstantinos Makris, Heiko Lickert, Annette Feuchtinger, Monica Tost, Callum Coupland, Lisa Ständer, Seun Akindehin, Sneha Prakash, Faiyaz Abrar, Russell L Castelino, Yantao He, Patrick J Knerr, Bin Yang, Wouter F J Hogendorf, Shiqi Zhang, Susanna M Hofmann, Brian Finan, Richard D DiMarchi, Matthias H Tschöp, Jonathan D Douros, Timo D Müller.

The development of single-molecule co-agonists for the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) is considered a breakthrough in the treatment of obesity and type 2 diabetes. But although GIPR-GLP-1R co-agonism decreases body weight with superior efficacy relative to GLP-1R agonism alone in preclinical1-3 and clinical studies4,5, the role of GIP in regulating energy metabolism remains enigmatic. Increasing evidence suggests that long-acting GIPR agonists act in the brain to decrease body weight through the inhibition of food intake3,6-8; however, the mechanisms and neuronal populations through which GIP affects metabolism remain to be identified. Here, we report that long-acting GIPR agonists and GIPR-GLP-1R co-agonists decrease body weight and food intake via inhibitory GABAergic neurons. We show that acyl-GIP decreases body weight and food intake in male diet-induced obese wild-type mice, but not in mice with deletion of Gipr in Vgat(also known as Slc32a1)-expressing GABAergic neurons (Vgat-Gipr knockout). Whereas the GIPR-GLP-1R co-agonist MAR709 leads, in male diet-induced obese wild-type mice, to greater weight loss and further inhibition of food intake relative to a pharmacokinetically matched acyl-GLP-1 control, this superiority over GLP-1 vanishes in Vgat-Gipr knockout mice. Our data demonstrate that long-acting GIPR agonists crucially depend on GIPR signaling in inhibitory GABAergic neurons to decrease body weight and food intake.

DOI: https://doi.org/10.1038/s42255-023-00931-7
Ann Gastroenterol Surg. 2023 Nov;7(6): 977-986

Cachexia index as a prognostic predictor after resection of pancreatic ductal adenocarcinoma.

Tomonari Shimagaki, Keishi Sugimachi, Yohei Mano, Emi Onishi, Tomohiro Iguchi, Yuichiro Nakashima, Masahiko Sugiyama, Manabu Yamamoto, Masaru Morita, Yasushi Toh.

  Aim: This study was performed to investigate the relationship between the preoperative cachexia index (CXI) and long-term outcomes in patients who have undergone radical resection of pancreatic ductal adenocarcinoma (PDAC).Methods: In total, 144 patients who underwent pancreatic resection for treatment of PDAC were retrospectively analyzed. The relationship between the CXI and the patients' long-term outcomes after PDAC resection was investigated. The CXI was calculated based on the preoperative skeletal muscle index, serum albumin level, and neutrophil-to-lymphocyte ratio. After propensity-score matching, we compared clinicopathological features and outcomes.
Results: The multivariate analysis showed that lymph node metastasis (hazard ratio [HR], 1.93; 95% confidence interval [CI], 1.16-3.23; P = 0.0118), R1 resection (HR, 57.20; 95% CI, 9.39-348.30; P < 0.0001), and a low CXI (HR, 2.10; 95% CI, 1.27-3.46; P = 0.0038) were independent and significant predictors of disease-free survival (DFS) after PDAC resection. Moreover, a low CXI (HR, 3.14; 95% CI, 1.71-5.75; P = 0.0002) was an independent and significant predictor of overall survival (OS) after PDAC resection. After propensity-score matching, the low CXI group had a significantly worse prognosis than the high CXI group for both DFS and OS.
Conclusion: The CXI can be a useful prognostic factor for DFS and OS after pancreatic resection for treatment of PDAC.

Keywords:  cachexia index; pancreatic ductal adenocarcinoma; pancreatic resection

DOI:  https://doi.org/10.1002/ags3.12686
Autophagy. 2023 Nov 07.

Synthetic autophagy receptor.

Ziwen Jiang, Yu-Hsuan Kuo, Michelle R Arkin.

  Macroautophagy/autophagy receptors target their substrates to phagophores for subsequent sequestration within autophagosomes. During phagophore membrane expansion in mammalian cells, autophagy receptors simultaneously interact with the ubiquitinated substrates and the LC3/GABARAP proteins on the expanding membrane. In this punctum, we summarize and discuss our recent research progress on synthetic autophagy receptors (AceTACs). The series of AceTACs were designed by engineering the essential interacting domains and motifs of SQSTM1/p62 (sequestosome 1), a major mammalian autophagy receptor. Particularly, we replaced the ubiquitin-associated domain of SQSTM1 with a target-specific antibody, redirecting the bifunctional interactions of wild-type SQSTM1 and directing the degradation target into the autophagy process. We successfully demonstrated the targeted degradation of aggregation-prone proteins using the AceTAC degraders. Moreover, we presented a model system with a guideline to induce targeted degradation of organelles through the autophagy machinery.

Keywords:  Antibody-fusion protein; autophagy receptor; targeted organelle degradation; targeted protein degradation

DOI:  https://doi.org/10.1080/15548627.2023.2278954
Cancer Med. 2023 Nov 07.

Pancreatic index: A prognostic factor of upfront surgery for body or tail pancreatic ductal adenocarcinoma with vascular involvement-A retrospective study.

Lihan Qian, Jingfeng Li, Yanjun Sun, Weimin Chai, Xiaxing Deng, Weishen Wang, Baiyong Shen.

  BACKGROUND: The pancreatic index (PI) is a useful preoperative imaging predictor for pancreatic ductal adenocarcinoma (PDAC). In this retrospective study, we determined the predictive effect of PI to distinguish patients of pancreatic body/tail cancer (PBTC) with vascular involvement who can benefit from upfront surgery.METHOD: All patients who received distal pancreatectomy for PDAC from 2016 to 2020 at the Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine were considered for the study. A total of 429 patients with PBTC were assessed in relation to the value of PI. Fifty-five patients were eventually included and divided into low PI group and 29 patients in the normal PI group.
RESULTS: The median overall survival (mOS) was significantly shorter in the low PI group (13.1 vs. 30.0 months, p = 0.002) in this study, and PI ≥ 0.78 (OR = 0.552, 95% CI: 0.301-0.904, p = 0.020) was an independent influencing factor confirmed by multivariate analysis. Subgroup analysis showed that PI was an independent prognostic factor for LA-PBTC (OR = 0.272, 95% CI: 0.077-0.969, p = 0.045). As for BR PBTC, PI (OR = 0.519, 95% CI: 0.285-0.947, p = 0.033) combined with carbohydrate antigen 125 (CA125) (OR = 2.806, 95% CI: 1.206-6.526, p = 0.017) and chemotherapy (OR = 0.327, 95% CI: 0.140-0.763, p = 0.010) were independent factors.
CONCLUSION: This study suggests that the PI can be used as a predictive factor to optimize the surgical indication for PBTC with vascular involvement. Preoperative patients with normal PI and CA125 can achieve a long-term prognosis comparable to that of resectable PBTC patients.

Keywords:  borderline resectable; locally advanced; pancreatic body/tail cancer; pancreatic ductal adenocarcinoma; pancreatic index

DOI:  https://doi.org/10.1002/cam4.6687
Nucleic Acids Res. 2023 Nov 06. pii: gkad1025. [Epub ahead of print]

The Reactome Pathway Knowledgebase 2024.

Marija Milacic, Deidre Beavers, Patrick Conley, Chuqiao Gong, Marc Gillespie, Johannes Griss, Robin Haw, Bijay Jassal, Lisa Matthews, Bruce May, Robert Petryszak, Eliot Ragueneau, Karen Rothfels, Cristoffer Sevilla, Veronica Shamovsky, Ralf Stephan, Krishna Tiwari, Thawfeek Varusai, Joel Weiser, Adam Wright, Guanming Wu, Lincoln Stein, Henning Hermjakob, Peter D'Eustachio.

The Reactome Knowledgebase (https://reactome.org), an Elixir and GCBR core biological data resource, provides manually curated molecular details of a broad range of normal and disease-related biological processes. Processes are annotated as an ordered network of molecular transformations in a single consistent data model. Reactome thus functions both as a digital archive of manually curated human biological processes and as a tool for discovering functional relationships in data such as gene expression profiles or somatic mutation catalogs from tumor cells. Here we review progress towards annotation of the entire human proteome, targeted annotation of disease-causing genetic variants of proteins and of small-molecule drugs in a pathway context, and towards supporting explicit annotation of cell- and tissue-specific pathways. Finally, we briefly discuss issues involved in making Reactome more fully interoperable with other related resources such as the Gene Ontology and maintaining the resulting community resource network.

DOI: https://doi.org/10.1093/nar/gkad1025
Cancer Discov. 2023 Nov 07.

Vitamin B6 competition in the tumor microenvironment hampers antitumor functions of NK cells.

Chunbo He, Dezhen Wang, Surendra K Shukla, Tuo Hu, Ravi Thakur, Xiao Fu, Ryan J King, Sai Sundeep Kollala, Kuldeep S Attri, Divya Murthy, Nina V Chaika, Yuki Fujii, Daisy Gonzalez, Camila G Pacheco, Yudong Qiu, Pankaj K Singh, Jason W Locasale, Kamiya Mehla.

Nutritional factors play crucial roles in immune responses. The tumor-caused nutritional deficiencies are known to affect anti-tumor immunity. Here, we demonstrate that pancreatic ductal adenocarcinoma (PDAC) cells can suppress NK cell cytotoxicity by restricting the accessibility of vitamin B6 (VB6). PDAC cells actively consume VB6 to support one-carbon metabolism, and thus tumor cell growth, causing VB6 deprivation in the tumor microenvironment. In comparison, NK cells require VB6 for intracellular glycogen breakdown, which serves as a critical energy source for NK cell activation. VB6 supplementation in combination with one-carbon metabolism blockage effectively diminishes tumor burden in vivo. Our results expand the understanding of the critical role of micronutrients in regulating cancer progression and anti-tumor immunity, and open new avenues for developing novel therapeutic strategies against PDAC.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0334