bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024‒08‒11
twenty papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. KAT2A and KAT2B prevent double-stranded RNA accumulation and interferon signaling to maintain intestinal stem cell renewal.
  2. Interaction between microRNA-195 and HuR regulates Paneth cell function in the intestinal epithelium by altering SOX9 translation.
  3. Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy.
  4. Glutamine withdrawal leads to the preferential activation of lipid metabolism in metastatic colorectal cancer.
  5. Benefit of adjuvant chemotherapy on recurrence free survival per consensus molecular subtype in stage III colon cancer.
  6. Fatty acid metabolism-related enzymes in colorectal cancer metastasis: from biological function to molecular mechanism.
  7. Epigenetic and oncogenic inhibitors cooperatively drive differentiation and kill KRAS-mutant colorectal cancers.
  8. From neoadjuvant to organ-sparing immunotherapy for colorectal cancer.
  9. The MondoA-dependent TXNIP/GDF15 axis predicts oxaliplatin response in colorectal adenocarcinomas.
  10. CRISPR-Cas9 Mediated AGO2 Knockout inhibits tumorigenesis in human colorectal cancer cells.
  11. Regulation of cancer cell lipid metabolism and oxidative phosphorylation by microenvironmental acidosis.
  12. The genomic landscape of 2,023 colorectal cancers.
  13. A spatial expression atlas of the adult human proximal small intestine.
  14. Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance.
  15. Enteroendocrine cells regulate intestinal homeostasis and epithelial function.
  16. The origin of novel traits in cancer.
  17. A New Genetic Signature of Lactate Metabolism-Associated Genes Predicting Clinically Distinctive Features and Tumor Microenvironment in Colorectal Cancer.
  18. Metabolic and transcriptomic reprogramming during contact inhibition-induced quiescence is mediated by YAP-dependent and YAP-independent mechanisms.
  19. FASN promotes anoikis resistance in colorectal liver metastases through the ERK1/2 pathway.
  20. Protocol for establishing spontaneous metastasis in mice using a subcutaneous tumor model.
  1. Sci Adv. 2024 Aug 09. 10(32): eadl1584
    KAT2A and KAT2B prevent double-stranded RNA accumulation and interferon signaling to maintain intestinal stem cell renewal.
    Mai-Uyen Nguyen, Jahangir Iqbal, Sarah Potgieter, Winston Huang, Julie Pfeffer, Sean Woo, Caifeng Zhao, Matthew Lawlor, Richard Yang, Rahma Rizly, Angela Halstead, Sharon Dent, José B Sáenz, Haiyan Zheng, Zuo-Fei Yuan, Simone Sidoli, Christopher E Ellison, Michael P Verzi.
      Histone acetyltransferases KAT2A and KAT2B are paralogs highly expressed in the intestinal epithelium, but their functions are not well understood. In this study, double knockout of murine Kat2 genes in the intestinal epithelium was lethal, resulting in robust activation of interferon signaling and interferon-associated phenotypes including the loss of intestinal stem cells. Use of pharmacological agents and sterile organoid cultures indicated a cell-intrinsic double-stranded RNA trigger for interferon signaling. Acetyl-proteomics and sequencing of immunoprecipitated double-stranded RNA were used to interrogate the mechanism behind this response, which identified mitochondria-encoded double-stranded RNA as the source of intrinsic interferon signaling. Kat2a and Kat2b therefore play an essential role in regulating mitochondrial functions and maintaining intestinal health.
    DOI:  https://doi.org/10.1126/sciadv.adl1584
  2. Am J Physiol Cell Physiol. 2024 Aug 05.
    Interaction between microRNA-195 and HuR regulates Paneth cell function in the intestinal epithelium by altering SOX9 translation.
    Min S Kwon, Hee K Chung, Lan Xiao, Ting-Xi Yu, Shweta Sharma, Cassandra M Cairns, Ting Chen, Songah Chae, Douglas J Turner, Jian-Ying Wang.
      Paneth cells at the bottom of small intestinal crypts secrete antimicrobial peptides, enzymes, and growth factors and contribute to pathogen clearance and maintenance of the stem cell niche. Loss of Paneth cells and their dysfunction occur commonly in various pathologies, but the mechanism underlying the control of Paneth cell function remains largely unknown. Here we identified microRNA-195 (miR-195) as a repressor of Paneth cell development and activity by altering SOX9 translation via interaction with RNA-binding protein HuR. Tissue-specific transgenic expression of miR-195 (miR195-Tg) in the intestinal epithelium decreased the levels of mucosal SOX9 and reduced the numbers of lysozyme-positive (Paneth) cells in mice. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restored Paneth cell development ex vivo. miR-195 did not bind to Sox9 mRNA but it directly interacted with HuR and prevented HuR binding to Sox9 mRNA, thus inhibiting SOX9 translation. Intestinal mucosa from mice that harbored both Sox9 transgene and ablation of the HuR locus exhibited lower levels of SOX9 protein and Paneth cell numbers than those observed in miR-195-Tg mice. Inhibition of miR-195 activity by its specific antagomir improved Paneth cell function in HuR-deficient intestinal organoids. These results indicate that interaction of miR-195 with HuR regulates Paneth cell function by altering SOX9 translation in the small intestinal epithelium.
    Keywords:  gut mucosal defense; intestinal epithelium homeostasis; noncoding RNAs; posttranscriptional regulation
    DOI:  https://doi.org/10.1152/ajpcell.00325.2024
  3. Front Immunol. 2024 ;15 1353787
    Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy.
    Andrea Nicolini, Paola Ferrari.
      Metabolic reprogramming is a k`ey hallmark of tumors, developed in response to hypoxia and nutrient deficiency during tumor progression. In both cancer and immune cells, there is a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, also known as the Warburg effect, which then leads to lactate acidification, increased lipid synthesis, and glutaminolysis. This reprogramming facilitates tumor immune evasion and, within the tumor microenvironment (TME), cancer and immune cells collaborate to create a suppressive tumor immune microenvironment (TIME). The growing interest in the metabolic reprogramming of the TME, particularly its significance in colorectal cancer (CRC)-one of the most prevalent cancers-has prompted us to explore this topic. CRC exhibits abnormal glycolysis, glutaminolysis, and increased lipid synthesis. Acidosis in CRC cells hampers the activity of anti-tumor immune cells and inhibits the phagocytosis of tumor-associated macrophages (TAMs), while nutrient deficiency promotes the development of regulatory T cells (Tregs) and M2-like macrophages. In CRC cells, activation of G-protein coupled receptor 81 (GPR81) signaling leads to overexpression of programmed death-ligand 1 (PD-L1) and reduces the antigen presentation capability of dendritic cells. Moreover, the genetic and epigenetic cell phenotype, along with the microbiota, significantly influence CRC metabolic reprogramming. Activating RAS mutations and overexpression of epidermal growth factor receptor (EGFR) occur in approximately 50% and 80% of patients, respectively, stimulating glycolysis and increasing levels of hypoxia-inducible factor 1 alpha (HIF-1α) and MYC proteins. Certain bacteria produce short-chain fatty acids (SCFAs), which activate CD8+ cells and genes involved in antigen processing and presentation, while other mechanisms support pro-tumor activities. The use of immune checkpoint inhibitors (ICIs) in selected CRC patients has shown promise, and the combination of these with drugs that inhibit aerobic glycolysis is currently being intensively researched to enhance the efficacy of immunotherapy.
    Keywords:  colorectal cancer; immunotherapy; metabolic reprogramming; tumor immune escape; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1353787
  4. Transl Oncol. 2024 Aug 06. pii: S1936-5233(24)00205-5. [Epub ahead of print]48 102078
    Glutamine withdrawal leads to the preferential activation of lipid metabolism in metastatic colorectal cancer.
    Aliye Ezgi Güleç Taşkıran, Diren Arda Karaoğlu, Cemil Can Eylem, Çağdaş Ermiş, İsmail Güderer, Emirhan Nemutlu, Seçil Demirkol Canlı, Sreeparna Banerjee.
      INTRODUCTION: Glutamine is a non-essential amino acid that is critical for cell growth. However, the differential metabolism of l-glutamine in metastatic versus primary colorectal cancer (CRC) has not been evaluated adequately.MATERIALS AND METHODS: Differential expression of glutamine-related genes was determined in primary versus metastatic CRC. Univariate Cox regression and hierarchical clustering were used to generate a gene signature for prognostication. Untargeted metabolomics and 18O based fluxomics were used to identify differential metabolite levels and energy turnover in the paired primary (SW480) and metastatic (SW620) CRC cells. Western blot and qRT-PCR were used to validate differential gene expression. Subcellular localization of E-cadherin was determined by immunocytochemistry. Lipid droplets were visualized with Nile Red.
    RESULTS: The GO term "Glutamine metabolism" was significantly enriched in metastatic versus primary tumors. Supporting this, SW620 cells showed decreased membrane localization of E-cadherin and increased motility upon l-Glutamine withdrawal. A glutamine related signature associated with worse prognosis was identified and validated in multiple datasets. A fluxomics assay revealed a slower TCA cycle in SW480 and SW620 cells upon l-Glutamine withdrawal. SW620 cells, however, could maintain high ATP levels. Untargeted metabolomics indicated the preferential metabolism of fatty acids in SW620 but not SW480 cells. Lipids were mainly obtained from the environment rather than by de novo synthesis.
    CONCLUSIONS: Metastatic CRC cells can display aberrant glutamine metabolism. We show for the first time that upon l-glutamine withdrawal, SW620 (but not SW480) cells were metabolically plastic and could metabolize lipids for survival and cellular motility.
    Keywords:  Colorectal cancer; L-Glutamine; Lipid metabolism; Metabolic plasticity
    DOI:  https://doi.org/10.1016/j.tranon.2024.102078
  5. Int J Cancer. 2024 Aug 08.
    Benefit of adjuvant chemotherapy on recurrence free survival per consensus molecular subtype in stage III colon cancer.
    Simone van de Weerd, Arezo Torang, Inge van den Berg, Veerle Lammers, Saskia van den Bergh, Nelleke Brouwer, Iris D Nagtegaal, Miriam Koopman, Geraldine R Vink, Frederieke H van der Baan, Han van Krieken, Jan Koster, Jan N Ijzermans, Jeanine M L Roodhart, Jan Paul Medema.
      The consensus molecular subtype (CMS) classification divides colon tumors into four subtypes holding promise as a predictive biomarker. However, the effect of adjuvant chemotherapy on recurrence free survival (RFS) per CMS in stage III patients remains inadequately explored. With this intention, we selected stage III colon cancer (CC) patients from the MATCH cohort (n = 575) and RadboudUMC (n = 276) diagnosed between 2005 and 2018. Patients treated with and without adjuvant chemotherapy were matched based on tumor location, T- and N-stage (n = 522). Tumor material was available for 464 patients, with successful RNA extraction and CMS subtyping achieved in 390 patients (surgery alone group: 192, adjuvant chemotherapy group: 198). In the overall cohort, CMS4 was associated with poorest prognosis (HR 1.55; p = .03). Multivariate analysis revealed favorable RFS for the adjuvant chemotherapy group in CMS1, CMS2, and CMS4 tumors (HR 0.19; p = .01, HR 0.27; p < .01, HR 0.19; p < .01, respectively), while no significant difference between treatment groups was observed within CMS3 (HR 0.68; p = .51). CMS subtyping in this non-randomized cohort identified patients with poor prognosis and patients who may not benefit significantly from adjuvant chemotherapy.
    Keywords:  CMS; adjuvant chemotherapy; biomarker; colorectal cancer; stage III
    DOI:  https://doi.org/10.1002/ijc.35120
  6. Cell Death Discov. 2024 Aug 05. 10(1): 350
    Fatty acid metabolism-related enzymes in colorectal cancer metastasis: from biological function to molecular mechanism.
    Biao Li, Jing Mi, Qi Yuan.
      Colorectal cancer (CRC) is a highly aggressive and life-threatening malignancy that metastasizes in ~50% of patients, posing significant challenges to patient survival and treatment. Fatty acid (FA) metabolism regulates proliferation, immune escape, metastasis, angiogenesis, and drug resistance in CRC. FA metabolism consists of three pathways: de novo synthesis, uptake, and FA oxidation (FAO). FA metabolism-related enzymes promote CRC metastasis by regulating reactive oxygen species (ROS), matrix metalloproteinases (MMPs), angiogenesis and epithelial-mesenchymal transformation (EMT). Mechanistically, the PI3K/AKT/mTOR pathway, wnt/β-catenin pathway, and non-coding RNA signaling pathway are regulated by crosstalk of enzymes related to FA metabolism. Given the important role of FA metabolism in CRC metastasis, targeting FA metabolism-related enzymes and their signaling pathways is a potential strategy to treat CRC metastasis.
    DOI:  https://doi.org/10.1038/s41420-024-02126-9
  7. Cancer Discov. 2024 Aug 12.
    Epigenetic and oncogenic inhibitors cooperatively drive differentiation and kill KRAS-mutant colorectal cancers.
    Patrick Loi, Amy E Schade, Carrie L Rodriguez, Anjana Krishnan, Naiara Perurena, Van T M Nguyen, Yilin Xu, Marina Watanabe, Rachel A Davis, Alycia Gardner, Natalie F Pilla, Kaia Mattioli, Olesja Popow, Nuray Gunduz, Tamsin R M Lannagan, Samantha Fitzgerald, Ewa T Sicinska, Jia-Ren Lin, William Tan, Lauren K Brais, Kevin M Haigis, Marios Giannakis, Kimmie Ng, Sandro Santagata, Kristian Helin, Owen J Sansom, Karen Cichowski.
      Current treatments for KRAS-mutant colorectal cancers (CRCs) are often limited by cellular plasticity and rewiring responses. Here we describe a promising therapeutic strategy that simultaneously targets epigenetic and oncogenic signals. Specifically, we show that inhibitors of the histone methyltransferase, EZH2, synergize with various RAS pathway inhibitors and promote dramatic tumor regression in vivo. Together these agents cooperatively suppress WNT-driven transcription and drive CRCs into a more differentiated cell state by inducing the Groucho/TLE corepressor, TLE4, along with a network of WNT pathway inhibitors and intestinal differentiation proteins. However, these agents also induce the pro-apoptotic protein BMF, which subsequently kills these more differentiated cells. Accordingly, cell death can be prevented by activating β-catenin, blocking differentiation, or by ablating BMF expression. Collectively, these studies reveal a new therapeutic approach for treating KRAS-mutant CRCs and illustrate a critical convergence of EZH2 and RAS on oncogenic WNT signals, intestinal differentiation, and apoptosis.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0866
  8. Nat Med. 2024 Aug 08.
    From neoadjuvant to organ-sparing immunotherapy for colorectal cancer.
    Benoit Rousseau, Andrea Cercek, Luis A Diaz.
      
    DOI:  https://doi.org/10.1038/s41591-024-03182-5
  9. EMBO Mol Med. 2024 Aug 05.
    The MondoA-dependent TXNIP/GDF15 axis predicts oxaliplatin response in colorectal adenocarcinomas.
    Jinhai Deng, Teng Pan, Dan Wang, Yourae Hong, Zaoqu Liu, Xingang Zhou, Zhengwen An, Lifeng Li, Giovanna Alfano, Gang Li, Luigi Dolcetti, Rachel Evans, Jose M Vicencio, Petra Vlckova, Yue Chen, James Monypenny, Camila Araujo De Carvalho Gomes, Gregory Weitsman, Kenrick Ng, Caitlin McCarthy, Xiaoping Yang, Zedong Hu, Joanna C Porter, Christopher J Tape, Mingzhu Yin, Fengxiang Wei, Manuel Rodriguez-Justo, Jin Zhang, Sabine Tejpar, Richard Beatson, Tony Ng.
      Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognized to activate host immune responses to produce durable outcomes. Here, in colorectal adenocarcinoma (CRC) we identify oxaliplatin-induced Thioredoxin-Interacting Protein (TXNIP), a MondoA-dependent tumor suppressor gene, as a negative regulator of Growth/Differentiation Factor 15 (GDF15). GDF15 is a negative prognostic factor in CRC and promotes the differentiation of regulatory T cells (Tregs), which inhibit CD8 T-cell activation. Intriguingly, multiple models including patient-derived tumor organoids demonstrate that the loss of TXNIP and GDF15 responsiveness to oxaliplatin is associated with advanced disease or chemotherapeutic resistance, with transcriptomic or proteomic GDF15/TXNIP ratios showing potential as a prognostic biomarker. These findings illustrate a potentially common pathway where chemotherapy-induced epithelial oxidative stress drives local immune remodeling for patient benefit, with disruption of this pathway seen in refractory or advanced cases.
    Keywords:  Colorectal Cancer; Functional Biomarker; GDF15; Oxaliplatin; TXNIP
    DOI:  https://doi.org/10.1038/s44321-024-00105-2
  10. Cell Mol Biol (Noisy-le-grand). 2024 Jul 28. 70(7): 174-179
    CRISPR-Cas9 Mediated AGO2 Knockout inhibits tumorigenesis in human colorectal cancer cells.
    Yizhi Zhu, Gengfang Wang, Haoran Xu, Yuan Guo.
      AGO2 plays a vital role in small RNA-guided gene silencing, which has been implied in the tumorigenesis of different types of tumors. Fundamentally, increased expression of AGO2 protein is associated with cancer progression and metastasis. This study aims to investigate the molecular mechanism by which AGO2 promotes tumorigenesis in colorectal cancer (CRC). Databases were used to analyze the expression levels of AGO2 in CRC and confirmed by a quantitative reverse transcriptase-PCR (qRT-PCR) assay in CRC tissues and normal adjacent tissues collected from 25 CRC patients. CRISPR/Cas9-mediated genome editing was used to knockout the AGO2 in HCT116 cells as a model system for colorectal cancers. The cell proliferation, migration and invasion ability of HCT116 cells were detected by CCK-8 assay, Wound scratch assay and Transwell assay. Moreover, the quantities of miRNA binding with AGO2 were detected by RNA-Binding Protein Immunoprecipitation (RIP-Assay). We demonstrated that AGO2 was aberrantly high-expressed in 25 matched-tissue pairs of colorectal cancer and para-carcinoma tissue. The following functional experiments verified that knockout of AGO2 suppressed cell proliferation, migration and tumorigenesis to hamper the aggressiveness of CRC. Our study also suggests a possible link between AGO2 and miRNA in RISC. AGO2 was elevated in CRC and knockout of AGO2 suppressed proliferation and tumorigenicity of CRC cells. Moreover, RISC formation and the function of miRNAs are also subject to AGO2. AGO2 may be a meaningful target for CRC therapy.
    DOI:  https://doi.org/10.14715/cmb/2024.70.7.25
  11. Am J Physiol Cell Physiol. 2024 Aug 05.
    Regulation of cancer cell lipid metabolism and oxidative phosphorylation by microenvironmental acidosis.
    Michala G Rolver, Marc Severin, Stine F Pedersen.
      The expansion of cancer cell mass in solid tumors generates a harsh environment characterized by dynamically varying levels of acidosis, hypoxia and nutrient deprivation. Because acidosis inhibits glycolytic metabolism and hypoxia inhibits oxidative phosphorylation, cancer cells that survive and grow in these environments must rewire their metabolism and develop a high degree of metabolic plasticity to meet their energetic and biosynthetic demands. Cancer cells frequently upregulate pathways enabling the uptake and utilization of lipids and other nutrients derived from dead or recruited stromal cells, and in particular lipid uptake is strongly enhanced in acidic microenvironments. The resulting lipid accumulation and increased reliance on β-oxidation and mitochondrial metabolism increases susceptibility to oxidative stress, lipotoxicity and ferroptosis, in turn driving changes that may mitigate such risks. The spatially and temporally heterogeneous tumor microenvironment thus selects for invasive, metabolically flexible, and resilient cancer cells capable of exploiting their local conditions as well as of seeking out more favorable surroundings. This phenotype relies on the interplay between metabolism, acidosis and oncogenic mutations, driving metabolic signaling pathways such as peroxisome proliferator-activated receptors (PPARs). Understanding the particular vulnerabilities of such cells may uncover novel therapeutic liabilities of the most aggressive cancer cells.
    Keywords:  ferroptosis; lipid metabolism; mitochondria; oxidative phosphorylation; peroxisomes
    DOI:  https://doi.org/10.1152/ajpcell.00429.2024
  12. Nature. 2024 Aug 07.
    The genomic landscape of 2,023 colorectal cancers.
    Alex J Cornish, Andreas J Gruber, Ben Kinnersley, Daniel Chubb, Anna Frangou, Giulio Caravagna, Boris Noyvert, Eszter Lakatos, Henry M Wood, Steve Thorn, Richard Culliford, Claudia Arnedo-Pac, Jacob Househam, William Cross, Amit Sud, Philip Law, Maire Ni Leathlobhair, Aliah Hawari, Connor Woolley, Kitty Sherwood, Nathalie Feeley, Güler Gül, Juan Fernandez-Tajes, Luis Zapata, Ludmil B Alexandrov, Nirupa Murugaesu, Alona Sosinsky, Jonathan Mitchell, Nuria Lopez-Bigas, Philip Quirke, David N Church, Ian P M Tomlinson, Andrea Sottoriva, Trevor A Graham, David C Wedge, Richard S Houlston.
      Colorectal carcinoma (CRC) is a common cause of mortality1, but a comprehensive description of its genomic landscape is lacking2-9. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia colipks+ colibactin in rectal cancers10 and the importance of the SBS93 signature11-13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.
    DOI:  https://doi.org/10.1038/s41586-024-07747-9
  13. Nature. 2024 Aug 07.
    A spatial expression atlas of the adult human proximal small intestine.
    Yotam Harnik, Oran Yakubovsky, Rouven Hoefflin, Roy Novoselsky, Keren Bahar Halpern, Tal Barkai, Yael Korem Kohanim, Adi Egozi, Ofra Golani, Yoseph Addadi, Merav Kedmi, Tal Keidar Haran, Yishai Levin, Alon Savidor, Hadas Keren-Shaul, Chen Mayer, Niv Pencovich, Ron Pery, Dror S Shouval, Itay Tirosh, Ido Nachmany, Shalev Itzkovitz.
      The mouse small intestine shows profound variability in gene expression along the crypt-villus axis1,2. Whether similar spatial heterogeneity exists in the adult human gut remains unclear. Here we use spatial transcriptomics, spatial proteomics and single-molecule fluorescence in situ hybridization to reconstruct a comprehensive spatial expression atlas of the adult human proximal small intestine. We describe zonated expression and cell type representation for epithelial, mesenchymal and immune cell types. We find that migrating enterocytes switch from lipid droplet assembly and iron uptake at the villus bottom to chylomicron biosynthesis and iron release at the tip. Villus tip cells are pro-immunogenic, recruiting γδ T cells and macrophages to the tip, in contrast to their immunosuppressive roles in mouse. We also show that the human small intestine contains abundant serrated and branched villi that are enriched at the tops of circular folds. Our study presents a detailed resource for understanding the biology of the adult human small intestine.
    DOI:  https://doi.org/10.1038/s41586-024-07793-3
  14. Nat Cancer. 2024 Aug 05.
    Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance.
    Venu Thatikonda, Hengyu Lyu, Sabine Jurado, Kaja Kostyrko, Christopher A Bristow, Christoph Albrecht, Donat Alpar, Heribert Arnhof, Oliver Bergner, Karin Bosch, Ningping Feng, Sisi Gao, Daniel Gerlach, Michael Gmachl, Melanie Hinkel, Simone Lieb, Astrid Jeschko, Annette A Machado, Thomas Madensky, Ethan D Marszalek, Mikhila Mahendra, Gabriella Melo-Zainzinger, Jessica M Molkentine, Philipp A Jaeger, David H Peng, Robyn L Schenk, Alexey Sorokin, Sandra Strauss, Francesca Trapani, Scott Kopetz, Christopher P Vellano, Mark Petronczki, Norbert Kraut, Timothy P Heffernan, Joseph R Marszalek, Mark Pearson, Irene C Waizenegger, Marco H Hofmann.
      Combination approaches are needed to strengthen and extend the clinical response to KRASG12C inhibitors (KRASG12Ci). Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRASG12Ci seemed to be driven by upregulation of MRAS activity, which both SOS1i and SHP2i were found to potently inhibit. Knockdown of SHOC2, a MRAS complex partner, partially restored response to KRASG12Ci treatment. These results suggest KRASG12C plus SOS1i to be a promising strategy for treating both KRASG12Ci naive and relapsed KRASG12C-mutant tumors.
    DOI:  https://doi.org/10.1038/s43018-024-00800-6
  15. Mol Cell Endocrinol. 2024 Aug 05. pii: S0303-7207(24)00195-3. [Epub ahead of print]593 112339
    Enteroendocrine cells regulate intestinal homeostasis and epithelial function.
    Jennifer G Nwako, Heather A McCauley.
      Enteroendocrine cells (EECs) are well-known for their systemic hormonal effects, especially in the regulation of appetite and glycemia. Much less is known about how the products made by EECs regulate their local environment within the intestine. Here, we focus on paracrine interactions between EECs and other intestinal cells as they regulate three essential aspects of intestinal homeostasis and physiology: 1) intestinal stem cell function and proliferation; 2) nutrient absorption; and 3) mucosal barrier function. We also discuss the ability of EECs to express multiple hormones, describe in vitro and in vivo models to study EECs, and consider how EECs are altered in GI disease.
    Keywords:  Barrier function; Enteroendocrine cells; Gastrointestinal disease; Gut hormone; Intestinal homeostasis; Nutrient absorption
    DOI:  https://doi.org/10.1016/j.mce.2024.112339
  16. Trends Cancer. 2024 Aug 06. pii: S2405-8033(24)00145-6. [Epub ahead of print]
    The origin of novel traits in cancer.
    Steven A Frank, Itai Yanai.
      The traditional view of cancer emphasizes a genes-first process. Novel cancer traits arise by genetic mutations that spread to drive phenotypic change. However, recent data support a phenotypes-first process in which nonheritable cellular variability creates novel traits that later become heritably stabilized by genetic and epigenetic changes. Single-cell measurements reinforce the idea that phenotypes lead genotypes, showing how cancer evolution follows normal developmental plasticity and creates novel traits by recombining parts of different cellular developmental programs. In parallel, studies in evolutionary biology also support a phenotypes-first process driven by developmental plasticity and developmental recombination. These advances in cancer research and evolutionary biology mutually reinforce a revolution in our understanding of how cells and organisms evolve novel traits in response to environmental challenges.
    Keywords:  cancer progression; cellular plasticity; drug resistance; evolution
    DOI:  https://doi.org/10.1016/j.trecan.2024.07.005
  17. Cancer Control. 2024 Jan-Dec;31:31 10732748241272721
    A New Genetic Signature of Lactate Metabolism-Associated Genes Predicting Clinically Distinctive Features and Tumor Microenvironment in Colorectal Cancer.
    Kaiwen Wang, Yu Lou, Zhihui Tao.
      BACKGROUND: Colorectal cancer (CRC) is characterized by its high malignancy and challenging prognosis. A significant aspect of cancer is metabolic reprogramming, where lactate serves as a crucial metabolite that contributes to the development of cancer and the tumor microenvironment (TME). Current studies have indicated that lactate plays a significant role in the progression of CRC. However, the relationship between lactate and the tumor microenvironment remains understudied, underscoring the potential of lactate as a novel biomarker.METHODS: We sourced transcriptomic data for colorectal cancer (CRC) patients from The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC), and the Gene Expression Omnibus (GEO) portals, along with the corresponding clinical information. Utilizing univariate Cox regression in conjunction with LASSO regression analysis, we identified genes involved in lactate metabolism that are associated with CRC prognosis. Subsequently, we developed models based on multi-factor Cox regression. To evaluate the correlation between tumor mutational burden (TMB), tumor microenvironment (TME), and lactate scores with patient survival, we conducted gene set enrichment analysis (GSEA) and immunogenic signature analyses.
    RESULTS: 3 lactate metabolism-related genes (LMRGs) (SLC16A8, GATA1, and PYGL) were used to construct models that categorized patients into 2 subgroups based on their lactate scores. The function of the differential genes between the 2 subgroups was mainly enriched in cell cycle and mRNA division, and the prognosis of patients in the high score subgroup was poor. Furthermore, a significant positive correlation was observed between TMB and LMRGs scores in the high-scoring group (P = 0.003, r2 = 0.12). Lastly, LMRGs also reflected the characteristics of TME, with differences in immune cells and immune checkpoints between the 2 subgroups.
    CONCLUSIONS: LMRGs may serve as a promising biomarker for predicting prognostic survival in CRC patients and to assess the TME.
    Keywords:  CRC; lactate; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.1177/10732748241272721
  18. Nat Commun. 2024 Aug 08. 15(1): 6777
    Metabolic and transcriptomic reprogramming during contact inhibition-induced quiescence is mediated by YAP-dependent and YAP-independent mechanisms.
    Soeun Kang, Maciek R Antoniewicz, Nissim Hay.
      Metabolic rewiring during the proliferation-to-quiescence transition is poorly understood. Here, using a model of contact inhibition-induced quiescence, we conducted 13C-metabolic flux analysis in proliferating (P) and quiescent (Q) mouse embryonic fibroblasts (MEFs) to investigate this process. Q cells exhibit reduced glycolysis but increased TCA cycle flux and mitochondrial respiration. Reduced glycolytic flux in Q cells correlates with reduced glycolytic enzyme expression mediated by yes-associated protein (YAP) inhibition. The increased TCA cycle activity and respiration in Q cells is mediated by induced mitochondrial pyruvate carrier (MPC) expression, rendering them vulnerable to MPC inhibition. The malate-to-pyruvate flux, which generates NADPH, is markedly reduced by modulating malic enzyme 1 (ME1) dimerization in Q cells. Conversely, the malate dehydrogenase 1 (MDH1)-mediated oxaloacetate-to-malate flux is reversed and elevated in Q cells, driven by high mitochondrial-derived malate levels, reduced cytosolic oxaloacetate, elevated MDH1 levels, and a high cytoplasmic NAD+/NADH ratio. Transcriptomic analysis revealed large number of genes are induced in Q cells, many of which are associated with the extracellular matrix (ECM), while YAP-dependent and cell cycle-related genes are repressed. The results suggest that high TCA cycle flux and respiration in Q cells are required to generate ATP and amino acids to maintain de-novo ECM protein synthesis and secretion.
    DOI:  https://doi.org/10.1038/s41467-024-51117-y
  19. Biochem Biophys Res Commun. 2024 Aug 05. pii: S0006-291X(24)01030-1. [Epub ahead of print]736 150494
    FASN promotes anoikis resistance in colorectal liver metastases through the ERK1/2 pathway.
    Jiaru Wu, Fei Liu, Xudan Guo, Chunxue Cui.
      PURPOSE: Colorectal cancer (CRC) is recognized as the third most common form of malignancy, with the liver frequently serving as the main site for metastasis. Anoikis resistance (AR) is critical in colorectal cancer liver metastases (CRLM). Fatty acid synthase (FASN), essential in lipid synthesis, mediates AR in many cancers. The present research examines the function of FASN in ERK1/2-mediated AR in CRLM and evaluates its therapeutic potential.METHODS: We performed scratch and migration experiment to evaluate the migration capacity of the LoVo cells. Flow cytometry was employed to identify cell apoptosis. The levels of FASN, p-ERK1/2, and proteins related to apoptosis was analyzed by Western blot. The mRNA level of FASN was determined by q-PCR after FASN silencing. In addition, we used an intrasplenic liver metastasis model of nude to assess the effect of FASN on CRLM.
    RESULTS: In vitro experiments showed that after FASN silencing, the cell apoptosis rate was increased, migration capability was notably decreased, the expression of p-ERK1/2, the proteins related to anti-apoptotic were significantly decreased, and the proteins related to apoptosis were significantly increased. In vivo experiments showed that AR significantly increased the number of liver metastatic foci, whereas FASN silencing significantly inhibited CRLM.
    CONCLUSION: These results suggest that FASN silencing suppressed AR through the ERK 1/2 pathway, which in turn suppressed CRLM.
    Keywords:  Anoikis resistance; Colorectal liver metastases; ERK1/2 pathway; FASN
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150494
  20. STAR Protoc. 2024 Aug 02. pii: S2666-1667(24)00404-0. [Epub ahead of print]5(3): 103239
    Protocol for establishing spontaneous metastasis in mice using a subcutaneous tumor model.
    Shiqin Liu, Michelle Shen, Kewei Le, Alifiani B Hartono, Tanya Stoyanova.
      Recapitulating spontaneous metastasis in preclinical models is crucial for understanding mechanisms underlying cancer progression and testing effective therapeutic interventions. We present a protocol for establishing and characterizing the spontaneous metastasis model in mice. We describe steps for generating primary tumors, tumor resection, monitoring metastatic dissemination, and evaluating metastatic burden using histological and imaging techniques. This protocol provides a valuable tool for studying metastasis in vivo and testing therapeutic strategies aimed at preventing or targeting metastatic diseases. For complete details on the use and execution of this protocol, please refer to Liu et al.1.
    Keywords:  Cancer; Cell Biology; Model Organisms; Molecular Biology
    DOI:  https://doi.org/10.1016/j.xpro.2024.103239
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