bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2026–03–15
thirteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. WNT7B drives a program for pancreatic cancer subtype switching and progression.
  2. Fat bolsters tumours against ferroptosis.
  3. Riboflavin metabolism shapes FSP1-driven ferroptosis resistance.
  4. Labile iron pool dynamics do not drive ferroptosis in colorectal cancer cells.
  5. Vitamin B2 metabolism promotes FSP1 stability to prevent ferroptosis.
  6. Lipid Droplets as Cellular Sensors of Lipid Metabolic Reprogramming in Colon Cancer: Insights from Essential Amino Acid Supplementation Using Raman Spectroscopy and Imaging.
  7. DGAT1 Inhibition Induces Ferroptosis and Enhances Cancer Immunotherapy Efficacy.
  8. 14,15-epoxyeicosatrienoic acid drives intestinal adenoma growth and its value as an early biomarker for intestinal adenoma occurrence.
  9. Enterocytes rely on purine biosynthesis/salvage pathway to facilitate dietary fat absorption.
  10. Ageing promotes metastasis via activation of the integrated stress response.
  11. Selective inhibition of ALDH1A3 impedes breast cancer growth and metastasis by blocking ALDH1A3-driven transcriptional programs.
  12. Circadian reprogramming by timed sodium intake reveals transcriptional pathways of daily salt handling in the colon.
  13. Paneth cell SIRT1 deficiency increases intestinal stress resistance by modulating the gut microbiota.
  1. iScience. 2026 Mar 20. 29(3): 115050
    WNT7B drives a program for pancreatic cancer subtype switching and progression.
    Joep Sprangers, Jeroen M Bugter, Despina Xanthakis, Michiel Boekhout, Rutger N U Kok, Veerle E Geurts, Hans Clevers, Lodewijk A A Brosens, Frederike Dijk, Maria J Rodríguez Colman, Jelte Y van der Vaart, Madelon M Maurice.
      Hyperactivation of WNT signaling is a hallmark of cancer, often driven by increased expression of WNT ligands. In pancreatic ductal adenocarcinoma (PDAC), elevated WNT7B and WNT10A correlate with aggressive, basal-like disease and poor patient survival, but the mechanisms underlying this association remain unclear. Using patient-derived organoids, we show that WNT7B promotes proliferation and maintains basal-like transcriptional states by preventing differentiation toward a more classical PDAC signature. Clonal WNT7B reporter organoids reveal that WNT-high cells are heterogeneously distributed and stably coexist with WNT-low/negative lineages. Hybrid co-cultures demonstrate that WNT7B-expressing cells support the survival and growth of neighboring WNT-negative cells via short-range, contact-dependent signaling. These findings highlight the functional importance of heterogeneous WNT7B/10A expression in driving PDAC aggressiveness and suggest that targeted WNT inhibition may shift tumors toward a more differentiated, less aggressive state, offering potential therapeutic benefit.
    Keywords:  cancer; cell biology; functional aspects of cell biology
    DOI:  https://doi.org/10.1016/j.isci.2026.115050
  2. Nat Cell Biol. 2026 Mar 11.
    Fat bolsters tumours against ferroptosis.
    Eikan Mishima, Marcus Conrad.
      
    DOI:  https://doi.org/10.1038/s41556-026-01904-0
  3. Nat Cell Biol. 2026 Mar 13.
    Riboflavin metabolism shapes FSP1-driven ferroptosis resistance.
    Vera Skafar, Izadora de Souza, Biplab Ghosh, Ancely Ferreira Dos Santos, Florencio Porto Freitas, Zhiyi Chen, Shibo Sun, Merce Donate Castillo, Palina Nepachalovich, Lars Seufert, Sebastian Bothe, Juliane Tschuck, Apoorva Mathur, Ariane Nunes-Alves, Jannik Buhr, Camilo Aponte-Santamaría, Werner Schmitz, Matthias Mack, Martin Eilers, Ralf Bargou, Milena Chaufan, Mayher Kaur, Mario Palma, Jessalyn M Ubellacker, Ulrich Elling, Hellmut G Augustin, Kamyar Hadian, Svenja Meierjohann, Bettina Proneth, Marcus Conrad, Maria Fedorova, Hamed Alborzinia, José Pedro Friedmann Angeli.
      Membrane protection against oxidative insults is achieved by the concerted action of glutathione peroxidase 4 (GPX4) and endogenous lipophilic antioxidants such as ubiquinone and vitamin E. More recently, ferroptosis suppressor protein 1 (FSP1) was identified as a critical ferroptosis inhibitor, acting via the regeneration of membrane-embedded antioxidants. Yet, regulators of FSP1 are largely uncharacterized, and their identification is essential for understanding the mechanisms buffering phospholipid peroxidation and ferroptosis. Here we report a focused CRISPR-Cas9 screen to uncover factors influencing FSP1 function, identifying riboflavin (vitamin B2) as a modulator of ferroptosis sensitivity. We demonstrate that riboflavin supports FSP1 stability and the recycling of lipid-soluble antioxidants, thereby mitigating phospholipid peroxidation. Furthermore, we show that the riboflavin antimetabolite roseoflavin markedly impairs FSP1 function and sensitizes cancer cells to ferroptosis. Our findings provide a rational strategy to modulate the FSP1-antioxidant recycling pathway and underscore the therapeutic potential of targeting riboflavin metabolism, with implications for understanding the interaction of nutrients, as well as their contributions to a cell's antioxidant capacity.
    DOI:  https://doi.org/10.1038/s41556-025-01856-x
  4. J Biol Chem. 2026 Mar 10. pii: S0021-9258(26)00227-9. [Epub ahead of print] 111357
    Labile iron pool dynamics do not drive ferroptosis in colorectal cancer cells.
    Varun Ponnusamy, Deahzana R Randall, Zheng Hong Lee, Nupur K Das, Liang Zhao, Kathryn Buscher, Sumeet Solanki, Adam R Renslo, Peggy P Hsu, Yatrik M Shah.
      Colorectal cancer (CRC) is a leading cause of cancer-related mortality. CRC tumors exhibit aberrant iron accumulation, which supports tumor cell proliferation through multiple metabolic pathways. However, the elevated iron must be counterbalanced given its potential to generate damaging reactive oxygen species. Ferroptosis is a regulated, non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation. Selenoenzyme glutathione peroxidase 4 (GPX4) controls this process by reducing lipid peroxides and can be pharmacologically inhibited by agents such as RSL3 and JKE1674. A key source of redox-active iron is the labile iron pool (LIP), yet its role in regulating ferroptosis remains incompletely defined and whether ferroptosis is accompanied by dynamic changes in the LIP is unknown. To examine this, we treated CRC cells with exogenous iron and pharmacologic ferroptosis inducers. Iron supplementation significantly reduced cell viability, suggesting that expansion of the LIP potentiates ferroptotic cell death. However, by assessing expression of iron regulatory genes as well as employing two orthogonal approaches to measure labile iron, we found that the LIP did not measurably increase during ferroptosis induction with GPX4 or SLC7A11 inhibition. These findings suggest that the LIP does not expand upon pharmacologically initiated ferroptosis, despite the potentiating effect of exogenous iron supplementation.
    Keywords:  Cell Death; Colon Cancer; Iron; Lipid Peroxidation; Metabolic Regulation; Metal Homeostasis; Oxidative Stress
    DOI:  https://doi.org/10.1016/j.jbc.2026.111357
  5. Nat Struct Mol Biol. 2026 Mar 13.
    Vitamin B2 metabolism promotes FSP1 stability to prevent ferroptosis.
    Kirandeep K Deol, Cynthia A Harris, Sydney J Tomlinson, Colin J Delaney, Amr Al-Farhan, Alyssa J Mathiowetz, Cody E Doubravsky, Derek A Pratt, James A Olzmann.
      Ferroptosis, a regulated form of cell death driven by excessive lipid peroxidation, has emerged as a promising therapeutic target in cancer. Ferroptosis suppressor protein 1 (FSP1) is a critical regulator of ferroptosis resistance, yet the mechanisms controlling its expression and stability remain mostly unexplored. To uncover regulators of FSP1 abundance, we conducted CRISPR-Cas9 screens using a genome-edited, dual-fluorescent FSP1 reporter cell line, identifying both transcriptional and post-translational mechanisms that determine FSP1 levels. Notably, we identified riboflavin kinase and flavin adenine dinucleotide (FAD) synthase, enzymes that are essential for synthesizing FAD from vitamin B2, as key contributors to FSP1 stability. Biochemical and cellular analyses revealed that FAD binding is critical for both FSP1 activity and stability. FAD deficiency and mutations blocking FSP1-FAD binding triggered FSP1 degradation through a ubiquitin-proteasome pathway involving the E3 ligase RNF8. Unlike other vitamins that inhibit ferroptosis by scavenging radicals, vitamin B2 supports ferroptosis resistance through FAD cofactor binding, ensuring proper FSP1 stability and function. This study provides a rich resource detailing mechanisms that regulate FSP1 abundance and highlights a novel connection between vitamin B2 metabolism and ferroptosis resistance, with implications for therapeutic strategies targeting FSP1 in cancer.
    DOI:  https://doi.org/10.1038/s41594-026-01759-x
  6. Molecules. 2026 Feb 25. pii: 762. [Epub ahead of print]31(5):
    Lipid Droplets as Cellular Sensors of Lipid Metabolic Reprogramming in Colon Cancer: Insights from Essential Amino Acid Supplementation Using Raman Spectroscopy and Imaging.
    Monika Kopeć, Karolina Beton-Mysur, Beata Brożek-Płuska.
      Herein, we present a comprehensive single-cell investigation of the biochemical and metabolic responses of normal human colon fibroblasts (CCD-18Co) and colorectal adenocarcinoma cells (Caco-2) to supplementation with the amino acids leucine, threonine, and arginine, employing State-of-the-Art Raman spectroscopy and Raman imaging. This fully label-free and noninvasive methodology enabled high-spatial-resolution mapping of intracellular components, providing unprecedented insight into subcellular biochemical organization and metabolic remodeling associated with colorectal carcinogenesis. By synergistically integrating Raman spectroscopic data with advanced chemometric methods, we demonstrate robust, reproducible discrimination between normal and malignant colon cells, both in their native state and after amino acid treatment, based solely on their intrinsic vibrational fingerprints. Partial Least Squares Discriminant Analysis (PLS-DA) and one-way ANOVA revealed that perturbations in lipid metabolism and protein composition constitute key molecular determinants underlying the observed phenotypic divergence between control and amino acid-supplemented cells. Notably, detailed analysis of diagnostic Raman band intensity ratios (2845/3015, 2845/2930, 3015/2888, and 1444/1256) uncovered pronounced amino acid-driven alterations in metabolic pathways at the single-cell level. Raman imaging further enabled spatially resolved visualization of these biochemical shifts and changes in Raman band intensities, highlighting distinct lipid- and protein-rich subcellular domains that respond differentially to amino acid exposure in normal versus cancerous cells. Collectively, our findings establish Raman spectroscopy combined with chemometric analysis as a powerful and sensitive platform for decoding amino acid-induced metabolic reprogramming in colorectal cells. This approach deepens the mechanistic understanding of nutrient-cancer cell interactions and opens new avenues for the development of Raman-based strategies in cancer diagnostics and therapeutic response assessment.
    Keywords:  Raman spectroscopy; amino acids; colon cancer; lipid droplets
    DOI:  https://doi.org/10.3390/molecules31050762
  7. Cancer Res. 2026 Mar 11.
    DGAT1 Inhibition Induces Ferroptosis and Enhances Cancer Immunotherapy Efficacy.
    Dong Pan, Meng Jiao, Yanyan Zhu, Mengjie Hu, Fang Li, Jinming Yu, Chuan-Yuan Li.
      Ferroptosis, a form of regulated cell death driven by lipid peroxidation, has emerged as a promising mechanism in cancer therapy. However, the lack of clinically viable ferroptosis inducers has precluded its therapeutic evaluation in patients. Here, we demonstrated that inhibition of diacylglycerol O-acyltransferase 1 (DGAT1) induces a ferroptosis-like phenotype in cancer cells and enhances the efficacy of immune checkpoint blockade (ICB) therapy. In human cancer cohorts, low DGAT1 expression correlated with improved prognosis and elevated ferroptosis-associated gene signatures. In murine models, both genetic knockout and pharmacological inhibition of DGAT1 enhanced ICB therapy efficacy by promoting increased infiltration of cytotoxic T lymphocytes (CTLs). Mechanistically, DGAT1 inhibition reduced lipid droplet (LD) accumulation, triggering elevated lipid peroxidation, mitochondrial dysfunction, and reactive oxygen species (ROS) production. These events culminated in glutathione peroxidase 4 (GPX4) depletion and ferroptosis. Given the availability of clinical-stage DGAT1 inhibitors, these findings provide a strong rationale for repurposing these agents as ferroptosis inducers to improve responses to cancer immunotherapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0840
  8. Oncogenesis. 2026 Mar 11.
    14,15-epoxyeicosatrienoic acid drives intestinal adenoma growth and its value as an early biomarker for intestinal adenoma occurrence.
    Shihui He, Ruyu Zeng, Bobing Zheng, Lingbi Jiang, Jinghong Zhu, Jiangchao Li.
      Intestinal adenomas are premalignant lesions that develop into colorectal cancer (CRC), yet the metabolic pathways underlying their malignant transformation remain poorly characterized. Using targeted metabolomics via ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), we found that serum levels of the bioactive lipid metabolite 14,15-epoxyeicosatrienoic acid (14,15-EET) were dramatically elevated in ApcMin/+ adenoma model mice as early as pre-adenoma stages, compared to C57BL/6 controls. The results were also consistent in adenomas and CRC patients. ELISA data and bioinformatics analyses revealed both elevated serum 14,15-EET levels and upregulated cytochrome P450 2J2 (CYP2J2) expression in tumor. Functional studies showed that 14,15-EET accelerates adenoma growth in vivo, and promotes proliferation, migration, and invasion in vitro by activating AKT (Ser473)/ERK1/2 signaling and inducing epithelial-mesenchymal transition (EMT). Its early elevation in premalignant lesions, and relative molecules 14,15-EET/CYP2J2 represents a novel strategy for disrupting adenoma-carcinoma transition, and offering new biomarker for CRC prevention.
    DOI:  https://doi.org/10.1038/s41389-026-00604-6
  9. Nat Commun. 2026 Mar 13.
    Enterocytes rely on purine biosynthesis/salvage pathway to facilitate dietary fat absorption.
    Yu Wang, Li Chen, Yingze Ma, Mingqi Zhou, Aleksander Geske, Marcus Seldin, Jiangjiang Zhu, Alexander M Zak, Xinzhong Dong, Robert N Cole, Svetlana Lutsenko.
      Dietary fat absorption is among the most energy-demanding processes of nutrient uptake. Fatty acid activation, triglyceride synthesis, and the trafficking of chylomicrons through the secretory pathway - all require ATP. How enterocytes accommodate the surge in ATP consumption following fat uptake is unclear. We show that the purine biosynthesis/salvage pathway supplies necessary ATP and that Ankyrin Repeat Domain 9 (ANKRD9) couples ATP synthesis and lipoprotein trafficking. Ankrd9 regulates enzymes within the purine biosynthesis pathway to increase ATP synthesis and facilitate Golgi dynamics. Intracellular localization of ANKRD9 is lipid and ATP-dependent. Inactivation of Ankrd9 in mice reduces intestinal ATP despite intact mitochondrial and glycolytic function, alters Golgi morphology, delays ApoB/chylomicron trafficking, and causes lipid accumulation in enterocytes, along with a lean body phenotype. Taken together, the results reveal a previously unrecognized mechanism that regulates lipid absorption in enterocytes and identify ANKRD9 as a central component of this mechanism.
    DOI:  https://doi.org/10.1038/s41467-026-70332-3
  10. Nature. 2026 Mar 11.
    Ageing promotes metastasis via activation of the integrated stress response.
    Angana A H Patel, Jozefina J Dzanan, Kevin X Ali, Ella A Eklund, Samantha W Alvarez, Dorota Raj, Martin Dankis, Ilayda Altinönder, Maria Schwarz, Kristell Le Gal, Emre Bedel, Ahmed Ezat El Zowalaty, Emma Jonasson, Heba Albatrok, Nadia Gul, Jozef P Bossowski, Ray Pillai, Patrick Micke, Johan Botling, Levent M Akyürek, Davide Angeletti, Sama I Sayin, Anetta Härtlova, Thales Papagiannakopoulos, Roger Olofsson Bagge, Anders Ståhlberg, Andreas Hallqvist, Clotilde Wiel, Volkan I Sayin.
      Lung cancer predominantly affects older individuals, yet how physiological ageing influences tumour evolution remains poorly understood1. Here we show that ageing reprograms the evolutionary trajectory of KRAS-driven lung adenocarcinoma, limiting primary tumour growth while promoting metastatic dissemination through epigenetic activation of the integrated stress response (ISR). The ISR effector ATF4 drives epithelial and metabolic plasticity, conferring metastatic competence. Mechanistically, aged tumour cells show increased sensitivity to the PERK-eIF2α arm of the unfolded protein response, sustaining persistent ATF4 signalling. Targeting ISR-ATF4 genetically or pharmacologically abolishes these adaptations and limits dissemination, whereas ATF4 overexpression alone is sufficient to induce metastasis. The ageing-ATF4 axis imposes a dependency on glutamine metabolism, revealing a therapeutically actionable vulnerability. Clinical analyses confirm that ATF4 is enriched in aged tumours and correlates with poor survival and advanced-stage disease. Collectively, these results define epigenetic ISR-ATF4 activation as a causal driver of lineage plasticity and metastasis in aged tumours, revealing a therapeutic opportunity in older patients with lung adenocarcinoma, the most common yet understudied subset of lung cancer.
    DOI:  https://doi.org/10.1038/s41586-026-10216-0
  11. iScience. 2026 Mar 20. 29(3): 114863
    Selective inhibition of ALDH1A3 impedes breast cancer growth and metastasis by blocking ALDH1A3-driven transcriptional programs.
    Maya R MacLean, Bianca Laura Bernardoni, Wasundara Fernando, Giovanni Petrarolo, Ilaria D'Agostino, Cheryl A Dean, Jaganathan Venkatesh, Christopher S Hughes, Kerry B Goralski, Geetha Subramanian, Raj Pranap Arun, Hannah F Cahill, Olivia L Walker, Lynn N Thomas, Robert C Douglas, Concettina La Motta, Paola Marcato.
      Aldehyde dehydrogenase 1A3 (ALDH1A3) promotes tumor growth, metastasis, and chemoresistance in multiple cancers, including triple-negative breast cancer (TNBC), yet no clinically approved, isoform-selective inhibitors exist. Here, we present CLM296, a novel, rationally designed, highly potent ALDH1A3 inhibitor. CLM296 exhibits nanomolar inhibition of ALDH1A3 in TNBC cells (half-maximal inhibitory concentration = 2 nM) with no off-target effects on ALDH1A1. Transcriptomic analysis shows that CLM296 selectively suppresses ALDH1A3-driven gene expression, confirming on-target activity. Functionally, CLM296 impedes ALDH1A3-mediated cell invasion in vitro and, with daily dosing in vivo, significantly reduces only ALDH1A3-dependent tumor growth and lung metastasis in TNBC xenografts. These effects are accompanied by selective inhibition of ALDH1A3 target genes in tumors, while pharmacokinetic studies demonstrate broad tissue distribution to metastatic sites, sustained target engagement, and favorable oral bioavailability. CLM296 shows no observable toxicity in preclinical models, supporting its potential as a first-in-class ALDH1A3 inhibitor for ALDH1A3-positive cancers.
    Keywords:  Cancer; Molecular interaction; Molecular mechanism of gene regulation
    DOI:  https://doi.org/10.1016/j.isci.2026.114863
  12. Sci Adv. 2026 Mar 13. 12(11): eady9244
    Circadian reprogramming by timed sodium intake reveals transcriptional pathways of daily salt handling in the colon.
    Takuto Torimitsu, Kenichiro Kinouchi, Kousha Changizi Ashtiani, Sherif Abdelkarim, Tomoki Sato, Takahide Kozuma, Na Yao, Akihide Iwahara, Kyosuke Kato, Shun Tonomura, Toshifumi Nakamura, Kenichi Yokota, Isao Kurihara, Pierre Baldi, Hiroshi Itoh, Kaori Hayashi.
      Circadian misalignment of the feeding behavior and the terrestrial cycle is associated with obesity and metabolic perturbations. However, it remains unclear whether the quantity and timing of dietary salt intake influence temporal sodium handling and blood pressure regulation. Here, we demonstrate that the colonic mineralocorticoid receptor (MR) and peripheral clock affect the daily sodium absorption and blood pressure variations. Genes related to sodium handling display diurnal rhythms in synchrony with the daily rhythms of aldosterone and the colonic circadian clock. Cistromic analysis substantiated the overlap of occupancy between the MR and brain and muscle ARNT-like 1 (BMAL1). Diurnal oscillation of aldosterone and peripheral clocks, as well as blood pressure, was robustly driven by nighttime feeding of a low-salt diet but markedly disrupted by daytime feeding of a high-salt diet in nocturnal mice. These findings delineate the colonic temporal sensing of dietary sodium abundance and highlight the transcriptional mechanisms of daily salt handling and blood pressure variations.
    DOI:  https://doi.org/10.1126/sciadv.ady9244
  13. EMBO Rep. 2026 Mar 13.
    Paneth cell SIRT1 deficiency increases intestinal stress resistance by modulating the gut microbiota.
    Liz M Garcia-Peterson, Alicia S Wellman, Xiaojiang Xu, Ming Ji, Caroline Duval, Igor Shats, Xiaoyue Wu, Thomas A Randall, Hamed Bostan, David Cunefare, Charan K Ganta, Maria Sifre, Xin Xu, Richard S Blumberg, Jian-Liang Li, Xiaoling Li.
      Paneth cells, intestine-originated innate immune-like cells, are important for maintenance of the intestinal stem cell niche, gut microbiota, and gastrointestinal barrier. Dysfunctional Paneth cells under pathological conditions are a site of origin for intestinal inflammation. However, mechanisms underlying stress-induced Paneth cell dysregulation remain unclear. Here, we report that SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase and a well-known genetic repressor of inflammation, cell-autonomously suppresses Paneth cell function and sensitizes the gut epithelium to environmental stress. Specifically, deletion of Paneth cell SIRT1 in mice elevates Wnt signaling and ATF4/endoplasmic reticulum stress pathway in Paneth cells. These molecular alterations are coupled with increased Paneth cell abundance and enhanced anti-microbial peptide production in young mice, improved protection against intestinal immune cell expansion in aged mice, and increased resistance to chemically induced colitis. Using microbiota-depleted mice with or without fecal transplantation, we further demonstrate that Paneth cell SIRT1 deficiency ameliorates colitis by interacting with the gut microbiota. Collectively, our findings uncover an unanticipated function of Paneth cell SIRT1 in conferring stress sensitivity in the gut epithelium.
    Keywords:  Anti-microbial Peptides; ER Stress; Gut Microbiota; SIRT1; Wnt/β-catenin
    DOI:  https://doi.org/10.1038/s44319-026-00726-3
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