bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024–02–18
twenty-one papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Targeting LGR4-Wnt activates ferroptosis and reverses drug resistance in colorectal cancer.
  2. A gut-liver axis in intestinal stem cell fitness.
  3. Corticosteroids impair epithelial regeneration in immune-mediated intestinal damage.
  4. Interferon gamma induces higher neutrophil extracellular traps leading to tumor-killing activity in microsatellite stable colorectal cancer.
  5. Stromal niche signals that orchestrate intestinal regeneration.
  6. Tumorigenicity and prediction of clinical prognosis of patient-derived gastric cancer organoids.
  7. Preclinical efficacy of carfilzomib in BRAF-mutant colorectal cancer models.
  8. Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer.
  9. Effect of air-liquid interface on cultured human intestinal epithelial cells.
  10. Glycerol-3-phosphate acyltransferase 3-mediated lipid droplets accumulation confers chemoresistance of colorectal cancer.
  11. Beyond genetics: driving cancer with the tumour microenvironment behind the wheel.
  12. Epithelial metabolism as a rheostat for intestinal inflammation and malignancy.
  13. Tumor acidosis-induced DNA damage response and tetraploidy enhance sensitivity to ATM and ATR inhibitors.
  14. Immunotherapy for colorectal cancer: insight from inherited genetics.
  15. Tissue-location-specific transcription programs drive tumor dependencies in colon cancer.
  16. Immune cell-intrinsic Ah receptor facilitates the expression of antimicrobial REG3G in the small intestine.
  17. Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer.
  18. Mechanisms Driving Fasting-Induced Protection from Genotoxic Injury in the Small Intestine.
  19. ER stress and the unfolded protein response in gastrointestinal stem cells and carcinogenesis.
  20. KAT8-catalyzed lactylation promotes eEF1A2-mediated protein synthesis and colorectal carcinogenesis.
  21. The dopamine transporter antagonist vanoxerine inhibits G9a and suppresses cancer stem cell functions in colon tumors.
  1. Nat Cancer. 2024 Feb 14.
    Targeting LGR4-Wnt activates ferroptosis and reverses drug resistance in colorectal cancer.
      
    DOI:  https://doi.org/10.1038/s43018-023-00714-9
  2. Nat Rev Gastroenterol Hepatol. 2024 Feb 14.
    A gut-liver axis in intestinal stem cell fitness.
    Katrina Ray.
      
    DOI:  https://doi.org/10.1038/s41575-024-00910-7
  3. J Clin Invest. 2024 Feb 13. pii: e155880. [Epub ahead of print]
    Corticosteroids impair epithelial regeneration in immune-mediated intestinal damage.
    Viktor Arnhold, Winston Y Chang, Suze A Jansen, Govindarajan Thangavelu, Marco Calafiore, Paola Vinci, Ya-Yuan Fu, Takahiro Ito, Shuichiro Takashima, Anastasiya Egorova, Jason Kuttiyara, Adam Perlstein, Marliek van Hoesel, Chen Liu, Bruce R Blazar, Caroline A Lindemans, Alan M Hanash.
      Corticosteroid treatment (CST) failure is associated with poor outcomes for patients with gastrointestinal graft-versus-host disease (GI GVHD). CST is intended to target the immune system, but the glucocorticoid receptor is widely expressed, including within the intestines, where its effects are poorly understood. Here, we report that corticosteroids directly target intestinal epithelium, potentially worsening immune-mediated GI damage. Corticosteroids administered to mice in vivo and intestinal organoid cultures ex vivo reduced epithelial proliferation. Following irradiation, immediate CST mitigated GI damage, but delayed treatment attenuated regeneration and exacerbated damage. In a murine steroid-refractory GVHD model, CST impaired epithelial regeneration, worsened crypt loss, and reduced intestinal stem cell (ISC) frequencies. CST also exacerbated immune-mediated damage in organoid cultures with "steroid-refractory" GR-deficient T cells or Interferon-γ. These findings correlated with corticosteroid-dependent changes in apoptosis-related gene expression and STAT3-related epithelial proliferation. Conversely, Interleukin-22 administration enhanced STAT3 activity and overcame corticosteroid-mediated attenuation of regeneration, reducing crypt loss and promoting ISC expansion in steroid-treated mice with GVHD. Therefore, CST has the potential to exacerbate GI damage if it fails to control the damage-inducing immune response, but this risk may be countered by strategies augmenting epithelial regeneration, thus providing rationale for clinical approaches combining such tissue-targeted therapies with immunosuppression.
    Keywords:  Bone marrow transplantation; Immunology; Mouse models; Mouse stem cells; Transplantation
    DOI:  https://doi.org/10.1172/JCI155880
  4. Mol Cancer Ther. 2024 Feb 13.
    Interferon gamma induces higher neutrophil extracellular traps leading to tumor-killing activity in microsatellite stable colorectal cancer.
    Hao-Wei Teng, Tean-Ya Wang, Chun-Chi Lin, Zhen-Jie Tong, Hsiao-Wei Cheng, Hsiang-Tsui Wang.
      Many colorectal cancer (CRC) patients do not respond to immune checkpoint blockade (ICB) therapy, highlighting the urgent need to understand tumor resistance mechanisms. Recently, the link between the IFNγ signaling pathway integrity and ICB resistance in the CRC tumor microenvironment has been revealed. The immunosuppressive microenvironment poses a significant challenge to antitumor immunity in CRC development. Tumor-associated neutrophils (TANs) found in tumor tissues exhibit an immunosuppressive phenotype and are associated with CRC patient prognosis. Neutrophil extracellular traps (NETs), DNA meshes containing cytotoxic enzymes released into the extracellular space, may be promising therapeutic targets in cancer. This study showed increased NETs in tumor tissues and peripheral neutrophils of high levels of microsatellite instability (MSI-H) CRC patients compared to microsatellite stable (MSS) CRC patients. IFNγ response genes were enriched in MSI-H CRC patients compared to MSS CRC patients. Co-culturing neutrophils with MSI-H CRC cell lines induced more NET formation and higher cellular apoptosis than MSS CRC cell lines. IFNγ treatment induced more NET formation and apoptosis in MSS CRC cell lines. Using subcutaneous or orthotopic CT-26 (MSS)-tumor-bearing mice models, IFNγ reduced tumor size and enhanced PD-1 antibody-induced tumor-killing activity, accompanied by upregulated NETs and cellular apoptosis. These findings suggest IFNγ could be a therapeutic strategy for MSS CRC.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-23-0744
  5. Cell Mol Gastroenterol Hepatol. 2024 Feb 09. pii: S2352-345X(24)00031-6. [Epub ahead of print]
    Stromal niche signals that orchestrate intestinal regeneration.
    Helen E Abud, Shanika L Amarasinghe, Diana Micati, Thierry Jardé.
      Stromal cell populations have a central role in providing signals that support the maintenance, differentiation and function of the intestinal epithelium. The behaviour and fate of epithelial cells is directed by the spatial organisation of stromal cells that either sustain stem and progenitor cell identity or drive differentiation. A combination of single-cell analyses, mouse models and organoid co-culture assays have provided insight into the diversity of signals delivered by stromal cells. Signalling gradients are established and fine-tuned by the expression of both signalling agonists and antagonists along the crypt-villus axis. Upon epithelial injury, there are disruptions to both the abundance and organisation of stromal populations. There are also distinct changes in the signals originating from these cells that impact remodelling of the epithelium. How these signals coordinate to mediate epithelial repair or sustain tissue injury in inflammatory bowel diseases is beginning to emerge. Understanding of these processes may lead to opportunities to target stromal cell populations as a strategy to modify disease states.
    Keywords:  Intestine; niche; regeneration; stem cells; stromal cells; telocyte; trophocyte
    DOI:  https://doi.org/10.1016/j.jcmgh.2024.02.003
  6. Clin Transl Med. 2024 Feb;14(2): e1588
    Tumorigenicity and prediction of clinical prognosis of patient-derived gastric cancer organoids.
    Ting Wang, Wanlu Song, Qingyu Meng, Chuanqing Qu, Shaohua Guo, Yalong Wang, Ronghui Tan, Baoqing Jia, Ye-Guang Chen.
      
    DOI:  https://doi.org/10.1002/ctm2.1588
  7. Mol Oncol. 2024 Feb 13.
    Preclinical efficacy of carfilzomib in BRAF-mutant colorectal cancer models.
    Federica Maione, Daniele Oddo, Federica Galvagno, Chiara Falcomatà, Marta Pandini, Marco Macagno, Valeria Pessei, Ludovic Barault, Chiara Gigliotti, Alessia Mira, Giorgio Corti, Simona Lamba, Chiara Riganti, Barbara Castella, Massimo Massaia, Roland Rad, Dieter Saur, Alberto Bardelli, Federica Di Nicolantonio.
      Serine/threonine-protein kinase B-raf (BRAF) mutations are found in 8-15% of colorectal cancer patients and identify a subset of tumors with poor outcome in the metastatic setting. We have previously reported that BRAF-mutant human cells display a high rate of protein production, causing proteotoxic stress, and are selectively sensitive to the proteasome inhibitors bortezomib and carfilzomib. In this work, we tested whether carfilzomib could restrain the growth of BRAF-mutant colorectal tumors not only by targeting cancer cells directly, but also by promoting an immune-mediated antitumor response. In human and mouse colorectal cancer cells, carfilzomib triggered robust endoplasmic reticulum stress and autophagy, followed by the emission of immunogenic-damage-associated molecules. Intravenous administration of carfilzomib delayed the growth of BRAF-mutant murine tumors and mobilized the danger-signal proteins calreticulin and high mobility group box 1 (HMGB1). Analyses of drug-treated samples revealed increased intratumor recruitment of activated cytotoxic T cells and natural killers, concomitant with the downregulation of forkhead box protein P3 (Foxp3)+ T-cell surface glycoprotein CD4 (CD4)+ T cells, indicating that carfilzomib promotes reshaping of the immune microenvironment of BRAF-mutant murine colorectal tumors. These results will inform the design of clinical trials in BRAF-mutant colorectal cancer patients.
    Keywords:  BRAF mutant colorectal cancer; endoplasmic reticulum stress; immune microenvironment; immunogenic cell death; oncogene; proteasome inhibitors
    DOI:  https://doi.org/10.1002/1878-0261.13595
  8. Nat Genet. 2024 Feb 13.
    Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer.
    Sudhir B Malla, Ryan M Byrne, Maxime W Lafarge, Shania M Corry, Natalie C Fisher, Petros K Tsantoulis, Megan L Mills, Rachel A Ridgway, Tamsin R M Lannagan, Arafath K Najumudeen, Kathryn L Gilroy, Raheleh Amirkhah, Sarah L Maguire, Eoghan J Mulholland, Hayley L Belnoue-Davis, Elena Grassi, Marco Viviani, Emily Rogan, Keara L Redmond, Svetlana Sakhnevych, Aoife J McCooey, Courtney Bull, Emily Hoey, Nicoleta Sinevici, Holly Hall, Baharak Ahmaderaghi, Enric Domingo, Andrew Blake, Susan D Richman, Claudio Isella, Crispin Miller, Andrea Bertotti, Livio Trusolino, Maurice B Loughrey, Emma M Kerr, Sabine Tejpar, Timothy S Maughan, Mark Lawler, Andrew D Campbell, Simon J Leedham, Viktor H Koelzer, Owen J Sansom, Philip D Dunne.
      Molecular stratification using gene-level transcriptional data has identified subtypes with distinctive genotypic and phenotypic traits, as exemplified by the consensus molecular subtypes (CMS) in colorectal cancer (CRC). Here, rather than gene-level data, we make use of gene ontology and biological activation state information for initial molecular class discovery. In doing so, we defined three pathway-derived subtypes (PDS) in CRC: PDS1 tumors, which are canonical/LGR5+ stem-rich, highly proliferative and display good prognosis; PDS2 tumors, which are regenerative/ANXA1+ stem-rich, with elevated stromal and immune tumor microenvironmental lineages; and PDS3 tumors, which represent a previously overlooked slow-cycling subset of tumors within CMS2 with reduced stem populations and increased differentiated lineages, particularly enterocytes and enteroendocrine cells, yet display the worst prognosis in locally advanced disease. These PDS3 phenotypic traits are evident across numerous bulk and single-cell datasets, and demark a series of subtle biological states that are currently under-represented in pre-clinical models and are not identified using existing subtyping classifiers.
    DOI:  https://doi.org/10.1038/s41588-024-01654-5
  9. FASEB Bioadv. 2024 Feb;6(2): 41-52
    Effect of air-liquid interface on cultured human intestinal epithelial cells.
    Akanksha Sabapaty, Po-Yu Lin, James C Y Dunn.
      The intestinal epithelium is a dynamic barrier that allows the selective exchange of ions, hormones, proteins, and nutrients. To accomplish this, the intestinal epithelium adopts a highly columnar morphology which is partially lost in submerged culturing systems. To achieve this, small intestinal tissue samples were utilized to obtain human intestinal crypts to form enteroids. The Transwell system was subsequently employed to form a monolayer of cells that was cultured in either the submerged condition or the air-liquid Interface (ALI) condition. We found that the human intestinal monolayer under the ALI condition exhibited morphology more similar to the normal intestinal epithelium. F-actin localization and brush border formation were observed apically, and the integrity of the tight junctions was preserved in the ALI condition. Fewer apoptotic cells were observed in the ALI conditions as compared to the submerged conditions. The monolayer of cells expressed a higher level of secretory cell lineage genes in the ALI condition. The ALI condition positively contributes toward a more differentiated phenotype of epithelial cells. It serves as an amplifier that enhances the existing differentiation cue. The ALI system provides a more differentiated platform to study intestinal function compared to submerged conditions.
    Keywords:  air‐liquid interface; enteroids; intestinal epithelial cells; monolayer; submerged conditions
    DOI:  https://doi.org/10.1096/fba.2023-00132
  10. MedComm (2020). 2024 Feb;5(2): e486
    Glycerol-3-phosphate acyltransferase 3-mediated lipid droplets accumulation confers chemoresistance of colorectal cancer.
    Ying Wang, Caihua Xu, Xianfeng Yang, Xiaofei Liu, Zijian Guo, Xinyu Lin, Lihua Li, Zhaohui Huang.
      Colorectal cancer (CRC) is the third most common malignancy worldwide. It is well known that lipid metabolism reprogramming contributes to the tumor progression. However, the lipid metabolic alterations and potential remodeling mechanism underlying the chemoresistance of CRC remain largely unclear. In this study, we compared the gene expression profiles of chemoresistant versus control CRC cells from the GEO database and identified a key factor, Glycerol-3-phosphate acyltransferase 3 (GPAT3), that promotes lipid droplet (LD) production and confers chemoresistance of CRC. With applying of HPLC-MS and molecular dynamics simulation, we also demonstrated that the activity of lysophosphatidic acid synthesis by GPAT3 was dependent on its acetylation at K316 site. In particular, GPAT3-mediated LD accumulation inhibited immunogenic cell death of tumor, and thus facilitated CD8+ T-cell exhaustion and malignant progression in mouse xenografts and hepatic-metastasis tumors in CRC patients. High GPAT3 expression turned CRC cells into nonimmunogenic cells after (Oxaliplatin) Oxa treatment, which was supported by a decrease in cytotoxic IFN-γ release and CD8+ T-cell exhaustion. In conclusion, these findings revealed the role of GPAT3-associated LD accumulation, which conferred a malignant phenotype (chemoresistance) and regulated the tumor microenvironment of CRC. These results suggest that GPAT3 is a potential target to enhance CRC chemosensitivity and develop novel therapeutic interventions.
    DOI:  https://doi.org/10.1002/mco2.486
  11. Nat Rev Cancer. 2024 Feb 12.
    Beyond genetics: driving cancer with the tumour microenvironment behind the wheel.
    Shaopeng Yuan, Jorge Almagro, Elaine Fuchs.
      Cancer has long been viewed as a genetic disease of cumulative mutations. This notion is fuelled by studies showing that ageing tissues are often riddled with clones of complex oncogenic backgrounds coexisting in seeming harmony with their normal tissue counterparts. Equally puzzling, however, is how cancer cells harbouring high mutational burden contribute to normal, tumour-free mice when allowed to develop within the confines of healthy embryos. Conversely, recent evidence suggests that adult tissue cells expressing only one or a few oncogenes can, in some contexts, generate tumours exhibiting many of the features of a malignant, invasive cancer. These disparate observations are difficult to reconcile without invoking environmental cues triggering epigenetic changes that can either dampen or drive malignant transformation. In this Review, we focus on how certain oncogenes can launch a two-way dialogue of miscommunication between a stem cell and its environment that can rewire downstream events non-genetically and skew the morphogenetic course of the tissue. We review the cells and molecules of and the physical forces acting in the resulting tumour microenvironments that can profoundly affect the behaviours of transformed cells. Finally, we discuss possible explanations for the remarkable diversity in the relative importance of mutational burden versus tumour microenvironment and its clinical relevance.
    DOI:  https://doi.org/10.1038/s41568-023-00660-9
  12. Trends Cell Biol. 2024 Feb 09. pii: S0962-8924(24)00004-7. [Epub ahead of print]
    Epithelial metabolism as a rheostat for intestinal inflammation and malignancy.
    Julian Schwärzler, Lisa Mayr, Felix Grabherr, Herbert Tilg, Timon E Adolph.
      The gut epithelium protects the host from a potentially hostile environment while allowing nutrient uptake that is vital for the organism. To maintain this delicate task, the gut epithelium has evolved multilayered cellular functions ranging from mucus production to hormone release and orchestration of mucosal immunity. Here, we review the execution of intestinal epithelial metabolism in health and illustrate how perturbation of epithelial metabolism affects experimental gut inflammation and tumorigenesis. We also discuss the impact of environmental factors and host-microbe interactions on epithelial metabolism in the context of inflammatory bowel disease and colorectal cancer. Insights into epithelial metabolism hold promise to unravel mechanisms of organismal health that may be therapeutically exploited in humans in the future.
    Keywords:  colorectal cancer; gut inflammation; inflammatory bowel disease; intestinal epithelium; metabolism; tumorigenesis
    DOI:  https://doi.org/10.1016/j.tcb.2024.01.004
  13. EMBO Rep. 2024 Feb 16.
    Tumor acidosis-induced DNA damage response and tetraploidy enhance sensitivity to ATM and ATR inhibitors.
    Léo Aubert, Estelle Bastien, Ophélie Renoult, Céline Guilbaud, Kübra Özkan, Davide Brusa, Caroline Bouzin, Elena Richiardone, Corentin Richard, Romain Boidot, Daniel Léonard, Cyril Corbet, Olivier Feron.
      Tumor acidosis is associated with increased invasiveness and drug resistance. Here, we take an unbiased approach to identify vulnerabilities of acid-exposed cancer cells by combining pH-dependent flow cytometry cell sorting from 3D colorectal tumor spheroids and transcriptomic profiling. Besides metabolic rewiring, we identify an increase in tetraploid cell frequency and DNA damage response as consistent hallmarks of acid-exposed cancer cells, supported by the activation of ATM and ATR signaling pathways. We find that regardless of the cell replication error status, both ATM and ATR inhibitors exert preferential growth inhibitory effects on acid-exposed cancer cells. The efficacy of a combination of these drugs with 5-FU is further documented in 3D spheroids as well as in patient-derived colorectal tumor organoids. These data position tumor acidosis as a revelator of the therapeutic potential of DNA repair blockers and as an attractive clinical biomarker to predict the response to a combination with chemotherapy.
    Keywords:  3D Spheroids; ATM; DNA Damage Response; Organoids; Tumor Acidosis
    DOI:  https://doi.org/10.1038/s44319-024-00089-7
  14. Trends Cancer. 2024 Feb 14. pii: S2405-8033(24)00008-6. [Epub ahead of print]
    Immunotherapy for colorectal cancer: insight from inherited genetics.
    Nijole Pollock Tjader, Amanda Ewart Toland.
      Immunotherapy shows efficacy for multiple cancer types and potential for expanded use. However, current immune checkpoint inhibitors (ICIs) are ineffective against microsatellite-stable colorectal cancer (CRC), which is more commonly diagnosed. Immunotherapy strategies for non-responsive CRC, including new targets and new combination therapies, are being tested to address this need. Importantly, a subset of inherited germline genetic variants associated with CRC risk are predicted to regulate genes with immune functions, including genes related to existing ICIs, as well as new potential targets in the major histocompatibility complex (MHC) region and immunoregulatory cytokines. We review discoveries in the inherited genetics of CRC related to the immune system and draw connections with ongoing developments and emerging immunotherapy targets.
    Keywords:  GWAS; colorectal cancer; immune checkpoint inhibitor; immunotherapy; pharmacogenomics
    DOI:  https://doi.org/10.1016/j.trecan.2024.01.008
  15. Nat Commun. 2024 Feb 15. 15(1): 1384
    Tissue-location-specific transcription programs drive tumor dependencies in colon cancer.
    Lijing Yang, Lei Tu, Shilpa Bisht, Yiqing Mao, Daniel Petkovich, Sara-Jayne Thursby, Jinxiao Liang, Nibedita Patel, Ray-Whay Chiu Yen, Tina Largent, Cynthia Zahnow, Malcolm Brock, Kathy Gabrielson, Kevan J Salimian, Stephen B Baylin, Hariharan Easwaran.
      Cancers of the same tissue-type but in anatomically distinct locations exhibit different molecular dependencies for tumorigenesis. Proximal and distal colon cancers exemplify such characteristics, with BRAFV600E predominantly occurring in proximal colon cancers along with increased DNA methylation phenotype. Using mouse colon organoids, here we show that proximal and distal colon stem cells have distinct transcriptional programs that regulate stemness and differentiation. We identify that the homeobox transcription factor, CDX2, which is silenced by DNA methylation in proximal colon cancers, is a key mediator of the differential transcriptional programs. Cdx2-mediated proximal colon-specific transcriptional program concurrently is tumor suppressive, and Cdx2 loss sufficiently creates permissive state for BRAFV600E-driven transformation. Human proximal colon cancers with CDX2 downregulation showed similar transcriptional program as in mouse proximal organoids with Cdx2 loss. Developmental transcription factors, such as CDX2, are thus critical in maintaining tissue-location specific transcriptional programs that create tissue-type origin specific dependencies for tumor development.
    DOI:  https://doi.org/10.1038/s41467-024-45605-4
  16. FASEB J. 2024 Feb 29. 38(4): e23471
    Immune cell-intrinsic Ah receptor facilitates the expression of antimicrobial REG3G in the small intestine.
    Debopriya Chakraborty, Denise M Coslo, Iain A Murray, Anitha Vijay, Andrew D Patterson, Gary H Perdew.
      The intestinal epithelial layer is susceptible to damage by chemical, physiological and mechanical stress. While it is essential to maintain the integrity of epithelium, the biochemical pathways that contribute to the barrier function have not been completely investigated. Here we demonstrate an aryl hydrocarbon receptor (AHR)-dependent mechanism facilitating the production of the antimicrobial peptide AMP regenerating islet-derived protein 3 gamma (REG3G), which is essential for intestinal homeostasis. Genetic ablation of AHR in mice impairs pSTAT3-mediated REG3G expression and increases bacterial numbers of Segmented filamentous bacteria (SFB) and Akkermansia muciniphila in the small intestine. Studies with tissue-specific conditional knockout mice revealed that the presence of AHR in the epithelial cells of the small intestine is not required for the production of REG3G through the phosphorylated STAT3-mediated pathway. However, immune-cell-specific AHR activity is necessary for normal expression of REG3G in all regions of the small intestine. A diet rich in broccoli, capable of inducing AHR activity, increases REG3G production when compared to a semi-purified diet that is devoid of ligands that can potentially activate the AHR, thus highlighting the importance of AHR in antimicrobial function. Overall, these data suggest that homeostatic antimicrobial REG3G production is increased by an AHR pathway intrinsic to the immune cells in the small intestine.
    DOI:  https://doi.org/10.1096/fj.202302319R
  17. Nat Med. 2024 Feb 12.
    Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer.
    Kohei Shitara, Kei Muro, Jun Watanabe, Kentaro Yamazaki, Hisatsugu Ohori, Manabu Shiozawa, Atsuo Takashima, Mitsuru Yokota, Akitaka Makiyama, Naoya Akazawa, Hitoshi Ojima, Yasuhiro Yuasa, Keisuke Miwa, Hirofumi Yasui, Eiji Oki, Takeo Sato, Takeshi Naitoh, Yoshito Komatsu, Takeshi Kato, Ikuo Mori, Kazunori Yamanaka, Masamitsu Hihara, Junpei Soeda, Toshihiro Misumi, Kouji Yamamoto, Riu Yamashita, Kiwamu Akagi, Atsushi Ochiai, Hiroyuki Uetake, Katsuya Tsuchihara, Takayuki Yoshino.
      Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS, PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62-0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83-1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795 .
    DOI:  https://doi.org/10.1038/s41591-023-02791-w
  18. Am J Physiol Gastrointest Liver Physiol. 2024 Feb 13.
    Mechanisms Driving Fasting-Induced Protection from Genotoxic Injury in the Small Intestine.
    Kali Deans-Fielder, Timothy Wu, Thanh Nguyen, Sarah To, Yang-Zhe Huang, Steven J Bark, Jason C Mills, Noah F Shroyer.
      Genotoxic agents like doxorubicin (DXR) can cause damage to the intestines that can be ameliorated by fasting. How fasting is protective and the optimal timing of fasting and refeeding remain unclear. Here, our analysis of fasting/refeeding-induced global intestinal transcriptional changes revealed metabolic shifts and implicated the cellular energetic hub mTORC1 in protecting from DXR-induced DNA damage. Our analysis of specific transcripts and proteins in intestinal tissue and tissue extracts showed that fasting followed by refeeding at the time of DXR administration reduced damage and caused a spike in mTORC1 activity. However, continued fasting after DXR prevented the mTORC1 spike and damage reduction. Surprisingly, the mTORC1 inhibitor, rapamycin, did not block fasting/refeeding-induced reduction in DNA damage, suggesting that increased mTORC1 is dispensable for protection against the initial DNA damage response. In Ddit4-/- mice (DDIT4 functions to regulate mTORC1 activity), fasting reduced DNA damage and increased intestinal crypt viability versus ad libitum-fed Ddit4-/- mice. Fasted/refed Ddit4-/- mice maintained body weight, with increased crypt proliferation by 5 days post-DXR, while ad libitum-fed Ddit4-/- mice continued to lose weight and displayed limited crypt proliferation. Genes encoding epithelial stem cell and DNA repair proteins were elevated in DXR-injured fasted vs ad libitum Ddit4-/- intestines. Thus, fasting strongly reduced intestinal damage when normal dynamic regulation of mTORC1 was lost. Overall, the results confirm that fasting protects the intestines against DXR and suggests that fasting works by pleiotropic - including both mTORC1-dependent and independent - mechanisms across the temporally dynamic injury response.
    Keywords:  DNA damage inducible transcript 4; Regulated in DNA damage and development 1; mucositis; refeeding; short-term fast
    DOI:  https://doi.org/10.1152/ajpgi.00126.2023
  19. Cancer Lett. 2024 Feb 13. pii: S0304-3835(24)00071-5. [Epub ahead of print] 216678
    ER stress and the unfolded protein response in gastrointestinal stem cells and carcinogenesis.
    R J de Boer, J F van Lidth de Jeude, J Heijmans.
      Endoplasmic reticulum (ER) stress and the adaptive response that follows, termed the unfolded protein response (UPR), are crucial molecular mechanisms to maintain cellular integrity by safeguarding proper protein synthesis. Next to being important in protein homeostasis, the UPR is intricate in cell fate decisions such as proliferation, differentiation, and stemness. In the intestine, stem cells are critical in governing epithelial homeostasis and they are the cell of origin of gastrointestinal malignancies. In this review, we will discuss the role of ER stress and the UPR in the gastrointestinal tract, focusing on stem cells and carcinogenesis. Insights in mechanisms that connect ER stress and UPR with stemness and carcinogenesis may broaden our understanding in the development of cancer throughout the gastrointestinal tract and how we can exploit these mechanisms to target these malignancies.
    DOI:  https://doi.org/10.1016/j.canlet.2024.216678
  20. Proc Natl Acad Sci U S A. 2024 Feb 20. 121(8): e2314128121
    KAT8-catalyzed lactylation promotes eEF1A2-mediated protein synthesis and colorectal carcinogenesis.
    Bingteng Xie, Mengdi Zhang, Jie Li, Jianxin Cui, Pengju Zhang, Fangming Liu, Yuxi Wu, Weiwei Deng, Jihong Ma, Xinyu Li, Bingchen Pan, Baohui Zhang, Hongbing Zhang, Aiqin Luo, Yinzhe Xu, Mo Li, Yang Pu.
      Aberrant lysine lactylation (Kla) is associated with various diseases which are caused by excessive glycolysis metabolism. However, the regulatory molecules and downstream protein targets of Kla remain largely unclear. Here, we observed a global Kla abundance profile in colorectal cancer (CRC) that negatively correlates with prognosis. Among lactylated proteins detected in CRC, lactylation of eEF1A2K408 resulted in boosted translation elongation and enhanced protein synthesis which contributed to tumorigenesis. By screening eEF1A2 interacting proteins, we identified that KAT8, a lysine acetyltransferase that acted as a pan-Kla writer, was responsible for installing Kla on many protein substrates involving in diverse biological processes. Deletion of KAT8 inhibited CRC tumor growth, especially in a high-lactic tumor microenvironment. Therefore, the KAT8-eEF1A2 Kla axis is utilized to meet increased translational requirements for oncogenic adaptation. As a lactyltransferase, KAT8 may represent a potential therapeutic target for CRC.
    Keywords:  colorectal cancer; lactylation; lactyltransferase; protein synthesis
    DOI:  https://doi.org/10.1073/pnas.2314128121
  21. Nat Cancer. 2024 Feb 13.
    The dopamine transporter antagonist vanoxerine inhibits G9a and suppresses cancer stem cell functions in colon tumors.
    Christopher J Bergin, Aïcha Zouggar, Amanda Mendes da Silva, Tanguy Fenouil, Joshua R Haebe, Angelique N Masibag, Gautam Agrawal, Muhammad S Shah, Tamara Sandouka, Mario Tiberi, Rebecca C Auer, Michele Ardolino, Yannick D Benoit.
      Cancer stem cells (CSCs), functionally characterized by self-renewal and tumor-initiating activity, contribute to decreased tumor immunogenicity, while fostering tumor growth and metastasis. Targeting G9a histone methyltransferase (HMTase) effectively blocks CSC functions in colorectal tumors by altering pluripotent-like molecular networks; however, existing molecules directly targeting G9a HMTase activity failed to reach clinical stages due to safety concerns. Using a stem cell-based phenotypic drug-screening pipeline, we identified the dopamine transporter (DAT) antagonist vanoxerine, a compound with previously demonstrated clinical safety, as a cancer-specific downregulator of G9a expression. Here we show that gene silencing and chemical antagonism of DAT impede colorectal CSC functions by repressing G9a expression. Antagonizing DAT also enhanced tumor lymphocytic infiltration by activating endogenous transposable elements and type-I interferon response. Our study unveils the direct implication of the DAT-G9a axis in the maintenance of CSC populations and an approach to improve antitumor immune response in colon tumors.
    DOI:  https://doi.org/10.1038/s43018-024-00727-y
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