bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2026–09–06
fifteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Spatiotemporal lineage tracing reveals the dynamic spatial architecture of tumor growth and metastasis.
  2. Maternal metabolic stress regulates progeny intestinal stem cell niche signaling through heritable changes in redox metabolites.
  3. Tumor evolution shapes metastatic competence in colorectal cancer.
  4. Integrated clinicogenomic analysis reveals the evolution and metastatic tropisms of advanced colorectal cancer.
  5. Opposing effects of Lrig1 and Lrig3 on EGFR maintain intestinal homeostasis and mitigate likelihood of colonic neoplasia.
  6. High-fat diet remodels plasma membrane rigidity to potentiate colonocyte stemness in mice.
  7. Building and regenerating intestines by manipulating intestinal stem cells.
  8. Chrono-atlas of cell-type specific daily gene expression rhythms in the regenerating colon.
  9. Host metabolism rewrites metastatic fate.
  10. Real-time tracking of cell death in human intestinal organoids: A quantitative imaging approach.
  11. New Studies Showcase Capabilities of Organoids.
  12. Overall survival of immunotherapy versus standard of care in chemorefractory microsatellite stable metastatic colorectal cancer: a propensity score matched analysis of 708 patients.
  13. Colorectal Cancer Deaths Increase Among Younger Adults.
  14. Tumor immune microenvironment remodeling predicts response to checkpoint inhibitor therapy.
  15. TIME in motion: How response takes shape.
  1. Nat Genet. 2026 Sep 02.
    Spatiotemporal lineage tracing reveals the dynamic spatial architecture of tumor growth and metastasis.
    Matthew G Jones, Dawei Sun, Kyung Hoi Joseph Min, William N Colgan, Haoyu Wang, Tivadar Török, Juliano Ribeiro, Jessie Xue, Erik C Cardoso, Yao Rong, Luyi Tian, Jackson A Weir, Victor Z Chen, Luke W Koblan, Kathryn E Yost, Nicolas Mathey-Andrews, Edridge D'Souza, Andrew J C Russell, Robert R Stickels, Karol S Balderrama, William M Rideout, Min Dai, Giovanni Marrero, Vipin Kumar, Anjali Saqi, Benjamin Herzberg, Benjamin Izar, Howard Y Chang, Joo-Hyeon Lee, Tyler Jacks, Fei Chen, Jonathan S Weissman, Nir Yosef, Dian Yang.
      Tumor progression is driven by dynamic interactions between cancer cells and their surrounding microenvironment. Here we integrate high-resolution spatial transcriptomics and evolving lineage-tracing technologies to elucidate how tumor expansion, plasticity and metastasis co-evolve with microenvironmental remodeling in a Kras;Trp53-driven mouse model of lung adenocarcinoma. We find that subclonal expansion contributes to a hypoxic, immunosuppressive and fibrotic microenvironment that is associated with the emergence of prometastatic cancer cell states. We use tumor phylogeography to delineate intercellular interactions that are rewired in the expanding tumor niche and use co-culture systems to dissect how intercellular interactions and hypoxia influence cancer cell state. Furthermore, we find that metastases arise from spatially confined primary tumor subclones and remodel the distant metastatic niche into a fibrotic, collagen-rich microenvironment. Together, we present a comprehensive dataset integrating spatial assays and lineage tracing to elucidate how sequential changes in cancer cell state and microenvironmental structures cooperate to promote tumor progression.
    DOI:  https://doi.org/10.1038/s41588-026-02739-z
  2. Nat Commun. 2026 08 03. pii: 9338. [Epub ahead of print]17(1):
    Maternal metabolic stress regulates progeny intestinal stem cell niche signaling through heritable changes in redox metabolites.
    Helin Hocaoglu, Shenlu Qin, Leah Eller, Farhan Abu, Benjamin Ohlstein, Lei Wang, Matthew H Sieber.
      Maternal metabolic stress is a major determinant of progeny health and disease susceptibility, yet the mechanisms linking germline metabolism to lifelong changes in tissue physiology remain poorly defined. Here, we show that maternal metabolic stress alters the cellular composition of the progeny intestinal epithelium through a conserved metabolic pathway. Germline metabolic dysfunction depletes NAD⁺ in mature oocytes, reprogramming progeny redox metabolism and impairing the methionine cycle. This metabolic shift reduces protein levels of the Notch ligand Delta, disrupting intestinal stem cell niche signaling and altering progeny intestinal physiology. Across insect and mammalian models, our findings reveal that maternal metabolic health has conserved effects on progeny metabolism and intestinal function. Together, this work identifies heritable redox-metabolic changes as a mechanistic link between maternal metabolic stress, stem cell regulation, and intestinal disease susceptibility.
    DOI:  https://doi.org/10.1038/s41467-026-76249-1
  3. Cancer Cell. 2026 Sep 01. pii: S1535-6108(26)00351-X. [Epub ahead of print]
    Tumor evolution shapes metastatic competence in colorectal cancer.
    Mathijs P Verhagen, Louis Vermeulen.
      In this issue of Cancer Cell, Manca et al. investigate the genomic evolution and metastatic tropism of over 7,000 colorectal cancers. Integrating primary tumor location, genomic alterations, and clinical variables, they reveal how distinct patterns of tumor evolution shape metastatic competence and impact organ tropism, offering a framework to refine surveillance.
    DOI:  https://doi.org/10.1016/j.ccell.2026.07.013
  4. Cancer Cell. 2026 Sep 01. pii: S1535-6108(26)00360-0. [Epub ahead of print]
    Integrated clinicogenomic analysis reveals the evolution and metastatic tropisms of advanced colorectal cancer.
    Paolo Manca, Henry Walch, Jierui Xu, Natalie Small, Ayush Kris, Evan Seffar, Allison Richards, Tiffany Xue, Adam Price, Mark T A Donoghue, Christopher Fong, Michele Waters, Justin Jee, Sachin Kumar Deshmukh, George W Sledge, Midhun Malla, Andrea Cercek, Leonard Saltz, Neil H Segal, Zsofia K Stadler, Maliha Nusrat, Michael B Foote, Avni Desai, Sree Chalasani, Devika Rao, Louise Connell, Richard K G Do, Karuna Ganesh, Martin R Weiser, Michael F Berger, David B Solit, Jinru Shia, Efsevia Vakiani, Julio Garcia-Aguilar, Nikolaus Schultz, Francisco Sanchez-Vega, Walid K Chatila, Rona Yaeger.
      We performed an integrated clinical and genomic analysis of over 7,000 consecutively sequenced colorectal cancer (CRC) samples to comprehensively characterize genetic drivers and metastatic tropisms of CRC. We find that genomic evolutionary changes, such as clonal mutations and oncogenic mutant allelic imbalance, selectively enhance the impact of recurrent oncogenic alterations. We identify the relative timing of organ-specific metastasis, showing sequential metastatic progression in microsatellite stable CRC with brain and adrenal metastases as late events; metastatic sites that cluster together, such as lung, bone, and brain metastases; and genomic events that enhance or decrease risk for each metastatic site, with WNT pathway activation as overall protective while RAS pathway activation increased risk for spread to all metastatic sites. Our data suggest that despite the heterogeneity in CRC, genomic evolution increases the impact of recurrent alterations, and integrating information about tumor primary location and genomics can be used to predict organ-specific metastasis risk.
    Keywords:  colorectal cancer; metastatic tropisms; tumor genomics
    DOI:  https://doi.org/10.1016/j.ccell.2026.08.004
  5. Cell Mol Gastroenterol Hepatol. 2026 Aug 31. pii: S2352-345X(26)00151-7. [Epub ahead of print] 101873
    Opposing effects of Lrig1 and Lrig3 on EGFR maintain intestinal homeostasis and mitigate likelihood of colonic neoplasia.
    Matthew E Bechard, Zhengyi Chen, Ping Zhao, Radhika Aramandla, Yilin Yang, Alan J Simmons, M Kay Washington, Jeffery L Franklin, Ken S Lau, Robert J Coffey.
       BACKGROUND AND AIMS: EGFR signaling maintains intestinal homeostasis by modulating proliferation and differentiation within the stem cell compartment with excess EGFR signaling predisposing to neoplasia. EGFR protein levels are central to EGFR function. These levels are negatively regulated by LRIG1, which accelerates receptor internalization and degradation, supporting a tumor suppressor role for LRIG1. LRIG3 is a less studied family member that has been reported, in a context-dependent manner, to both cooperate with and oppose the effects of LRIG1 on EGFR.
    METHODS: To examine the function of LRIG3 relative to LRIG1 on EGFR levels and downstream signaling in vivo, we generated an Lrig3 floxed allele and intercrossed these mice with Lrig1CreERT2 mice that are Lrig1 null in the homozygous state. This allowed us to assess the effects of Lrig3 loss in Lrig1-null intestinal cells. We also tested how LRIG3 depletion in Lrig1-expressing cells affects colorectal tumors in Lrig1CreERT2/+; Apcfl/+ mice.
    RESULTS: Unlike the heightened EGFR and Wnt activity caused by Lrig1 loss, loss of Lrig3 in Lrig1Null cells markedly reduced activity in both pathways. In this setting, a widening of the intestinal crypt base was observed with the appearance of intermediate-lineage secretory cells at the expense of stem cells. In marked contrast to multiple distal colonic tumors in Lrig1CreERT2/+; Apcfl/+ mice, deletion of a single Lrig3 allele in Lrig1 haploinsufficient mice decreased EGFR signaling and markedly reduced colonic tumor formation.
    CONCLUSIONS: These findings indicate that LRIG3 and LRIG1 oppose one another to balance EGFR signaling, maintain intestinal homeostasis and minimize the likelihood colonic neoplasia.
    DOI:  https://doi.org/10.1016/j.jcmgh.2026.101873
  6. Cell Mol Gastroenterol Hepatol. 2026 Sep 03. pii: S2352-345X(26)00156-6. [Epub ahead of print] 101878
    High-fat diet remodels plasma membrane rigidity to potentiate colonocyte stemness in mice.
    Michael L Salinas, Natividad R Fuentes, Xiaoli Wang, Ellen Ruth Alexander Morris, Yang-Yi Fan, Madison E Edwards, Xin Yan, Evelyn S Callaway, Kerstin K Landrock, James J Cai, Robert S Chapkin.
       BACKGROUND & AIMS: Obesity and consumption of a high-fat diet (HFD) are established risk factors for colorectal cancer (CRC). However, the cellular mechanisms linking dietary lipid exposure to intestinal stem cell (ISC) dysregulation remain incompletely defined. We therefore investigated whether HFD perturbs plasma membrane homeostasis to potentiate colonocyte stemness in mice.
    METHODS: Mice were placed on a chronic 12-week HFD or control (low-fat diet; LFD) feeding regimen, or a short-term 1-week HFD exposure. In addition, genetically obese leptin receptor-deficient (db/db) versus (db/+) wildtype mice were examined. Membrane free cholesterol and rigidity were quantified in colonic crypts and Lgr5+ ISCs utilizing Filipin III and Di-4-ANEPPDHQ dyes, respectively. Membrane receptor nanoclustering of epidermal growth factor receptor (EGFR) and low-density lipoprotein receptor-related protein 6 (LRP6) was assessed by super-resolution microscopy. β-catenin activation, stem cell frequency, proliferation, and organoid-forming efficiency were also evaluated by immunostaining, flow cytometry, and ex vivo organoid assays.
    RESULTS: Chronic HFD feeding in mice increased membrane free cholesterol content and rigidity in colonic stem cells, and enhanced EGFR and LRP6 receptor nanoclustering. This alteration in plasma membrane homeostasis resulted in the overactivation of β-catenin and expansion of the ISC niche, e.g., stem cell proliferation and organoid-forming efficiency. Notably, genetically induced obesity in db/db mice did not recapitulate the HFD membrane phenotype, highlighting a diet-specific effect.
    CONCLUSIONS: Collectively, these findings identify plasma membrane remodeling as a previously unrecognized mechanism linking dietary lipids to aberrant ISC homeostasis and CRC risk.
    Keywords:  cholesterol; obesity; receptor nanoclustering; single cell transcriptomics
    DOI:  https://doi.org/10.1016/j.jcmgh.2026.101878
  7. Nat Rev Gastroenterol Hepatol. 2026 Sep 03.
    Building and regenerating intestines by manipulating intestinal stem cells.
    Calvin J Kuo, Sarah Blutt, Mark Donowitz, Mary K Estes, Chandan Guha, Ophir D Klein, Linheng Li, Joyce C Niland, António J M Santos, Ramesh A Shivdasani, Jason R Spence, Carol J Swanson, Timothy C Wang, Kelley S Yan, Nicholas C Zachos, Michael A Helmrath.
      Perturbations of the multifaceted functions of the human intestine can manifest in an extraordinarily diverse range of disease pathologies that span developmental, infectious, inflammatory and neoplastic conditions. Accordingly, there is substantial interest in treating intestinal disorders by harnessing the promise of intestinal stem cells (ISCs). From 2009 to 2024, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a multi-institution collaborative, the Intestinal Stem Cell Consortium (ISCC), that sought to leverage advances in ISC biology for clinical translation to accelerate in vivo mucosal repair and eventually generate functioning intestinal tissue ex vivo. In this Roadmap, ISCC members summarize the latest advances and current knowledge gaps both from within the ISCC working group and across the field as a whole as relevant to understanding the human ISC niche, stem cell interactions with and in response to pathogens, and cellular and humoral regenerative strategies, towards realizing stem cell-based therapy for intestinal diseases.
    DOI:  https://doi.org/10.1038/s41575-026-01242-4
  8. Nat Commun. 2026 Aug 06. pii: 9438. [Epub ahead of print]17(1):
    Chrono-atlas of cell-type specific daily gene expression rhythms in the regenerating colon.
    Vania Carmona-Alcocer, Cédric Gobet, Jessie MacDonald, Zainab Taleb, Felix Naef, Phillip Karpowicz.
      The circadian clock is present throughout the body, including the intestine, where it regulates daily physiology through rhythmic gene expression. The large intestine (colon) is composed of many functionally distinct cell types; how daily rhythms in transcript abundance are coordinated in specific cells is not known. Using single-cell transcriptomics, we analyzed 24-hour gene expression rhythms in all major cell types of the colon following injury. Such rhythms are not uniformly distributed: rhythmic genes, including circadian clock components, clock targets, and systemic response programs, differ in their timing, and are cell-type-, region-, or injury- specific. Compared to stromal and muscle cells, which exhibit robust circadian clock rhythms, epithelial cells show weaker oscillations. During regeneration, cells of the epithelium, stroma, and immune system display strong biphasic rhythms in metabolic, protein processing, and temperature response genes, and epithelial clocks are reprogrammed to become 12-hours antiphasic in timing. Our data reveal unexpected complexity in the colon and provide a resource by identifying the cellular source of 24-hour transcript rhythms.
    DOI:  https://doi.org/10.1038/s41467-026-76318-5
  9. Trends Cancer. 2026 Sep 02. pii: S2405-8033(26)00189-5. [Epub ahead of print]
    Host metabolism rewrites metastatic fate.
    Zihan Qiu, Xinyu Li, Pengfei Xu.
      Metastatic heterogeneity has traditionally been explained by tumor-intrinsic evolution. A recent study by Peng-Winkler et al. challenges this paradigm by demonstrating that hepatic steatosis instructs colorectal cancer liver metastasis through fatty acid-dependent myelocytomatosis oncogene protein (MYC) activation. These findings identify host metabolism as an independent determinant of metastatic fate and suggest that precision oncology should extend beyond tumor genomics.
    Keywords:  colorectal cancer; hepatic steatosis; host metabolism; metastasis
    DOI:  https://doi.org/10.1016/j.trecan.2026.08.004
  10. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00160-3. [Epub ahead of print]210 137-156
    Real-time tracking of cell death in human intestinal organoids: A quantitative imaging approach.
    Jiyi Pang, Hojin Chang, Lachlan Whitehead, James E Vince.
      Organoids are self-renewing three-dimensional tissue models that can be derived from patient samples. Their recapitulation of the structure and function of native tissues makes them powerful tools for studying development, physiology, disease mechanisms and personalized medicine in vitro. However, quantitative assessment of cell death in organoid systems remains challenging due to their structural complexity and dynamic responses. Here, we present a robust pipeline combining real-time Incucyte® live-cell imaging with ImageJ-based quantitative analysis to measure cell death kinetics in human intestinal organoids. Organoids are cultured in the low-viscosity matrix suspension culture method, labelled with cell death-specific Incucyte® Cytotox Red Dye, and imaged via brightfield and fluorescence channels. A custom ImageJ analysis pipeline enables calculation of cell death overtime with high sensitivity and reproducibility. This approach overcomes the limitations of endpoint assays, delivering precise kinetic quantification of organoid cell death in response to cytokine stimulation, drug treatments, or genetic perturbations. The workflow is broadly applicable across diverse organoid systems and offers a scalable, standardized platform for interrogating cell death dynamics in basic and translational research.
    Keywords:  Apoptosis; Cell death; Intestinal organoids; Live cell imaging; Necroptosis; Pyroptosis
    DOI:  https://doi.org/10.1016/bs.mcb.2026.05.004
  11. Cancer Discov. 2026 Sep 04. OF1
    New Studies Showcase Capabilities of Organoids.
      Three recent papers show the potential benefits of several hundred new organoids, spheroids, and other cancer models. One study demonstrates that more than 600 of the models mirror their parent tumors. A second study uses organoids to uncover new cancer dependencies, or essential genes, in 147 organoids from 10 cancer types. The third study also identifies new cancer dependencies and shows that organoids from individual patients might lead to new treatment choices.
    DOI:  https://doi.org/10.1158/2159-8290.CD-NW2026-0086
  12. J Immunother Cancer. 2026 Sep 02. pii: e015414. [Epub ahead of print]14(9):
    Overall survival of immunotherapy versus standard of care in chemorefractory microsatellite stable metastatic colorectal cancer: a propensity score matched analysis of 708 patients.
    Guglielmo Vetere, Emerik Osterlund, Mahmoud M G Yousef, Songwit Payapwattanawong, Giulia Maddalena, Jumanah Alshenaifi, Kristin D Alfaro, Mark Knafl, Van K Morris, Christine M Parseghian, Kanwal P S Raghav, Robert A Wolff, Arvind Dasari, Michael J Overman, Scott Kopetz, John Paul Shen.
       BACKGROUND: Immune checkpoint inhibitors (ICIs) have limited efficacy in proficient mismatch repair/microsatellite stable (pMMR/MSS) metastatic colorectal cancer (mCRC). However, selected patients with specific metastatic patterns may derive benefit.
    METHODS: Patients with chemorefractory pMMR/MSS mCRC treated with ICI-based regimens were retrospectively identified. A comparison cohort treated with trifluridine/tipiracil±bevacizumab, regorafenib, or fruquintinib as standard of care (SOC) was generated through 1:1 propensity score matching by age, sex, Eastern Cooperative Oncology Group performance status (ECOG PS), liver metastases (present/absent), and RAS/BRAF status. Overall survival (OS) was compared using Cox regression.
    RESULTS: A total of 354 patients treated with ICIs and 354 treated with SOC were matched. Median age was 55 years, 52% male, 32% ECOG PS 0, 30% right-sided, and 69% RAS mutated in both groups, while 61% and 60% had liver metastases, respectively. Median OS (mOS) was 10.8 months with ICIs and 9.0 months with SOC (HR 0.76, 95% CI 0.64 to 0.92, p=0.004). In patients without liver metastases, mOS was longer with ICIs than SOC (19.1 vs 13.2 months, HR 0.59, 95% CI 0.43 to 0.80, p<0.001), whereas outcomes were similar in patients with liver metastases (6.4 vs 6.5 months, p=0.303). In univariable analyses, age, sex, primary tumor site, and RAS/BRAF status were not associated with OS. Treatment with ICIs, absence of liver metastases, one prior line of therapy, less than three metastatic sites, and ECOG PS 0 were associated with the most favorable outcomes in univariable and multivariable models.
    CONCLUSIONS: In chemorefractory pMMR/MSS mCRC without liver metastases, ICI-based regimens yielded longer OS than SOC. Further investigation of ICIs in this patient population is warranted.
    Keywords:  Biomarker; Colorectal Cancer; Immunotherapy; Microsatellite; Mismatch repair - MMR
    DOI:  https://doi.org/10.1136/jitc-2026-015414
  13. JAMA. 2026 Sep 04.
    Colorectal Cancer Deaths Increase Among Younger Adults.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2026.12071
  14. Cancer Cell. 2026 Sep 01. pii: S1535-6108(26)00384-3. [Epub ahead of print]
    Tumor immune microenvironment remodeling predicts response to checkpoint inhibitor therapy.
    Zhongyang Lin, Mitalee Chandra, Nalini Srinivas, Selma Ugurel, Jürgen C Becker, Dvir Aran.
      Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet the basis of variable patient responses remains unclear. We assemble a longitudinal single-cell RNA sequencing atlas of 441 samples from 241 patients across ten cancer entities to map treatment-associated remodeling of the tumor immune microenvironment (TIME). With a hierarchical reference-guided deep-phenotyping framework, we define 77 immune and stromal subtypes and resolve four conserved TIME subtypes. Approximately 40% of tumors shift between states during therapy, and the transition is more predictive of outcome than the baseline state. Favorable transitions toward inflamed or B cell-enriched subtype track with improved response and survival, while persistence in or shifts toward myeloid dominance indicate resistance. We derive a 59-gene signature that predicted response and survival for 1,383 baseline tumors across 19 independent cohorts. These findings establish immunotype transitions as a central determinant of ICI efficacy, offering new avenues for response prediction and rational immunotherapy design.
    Keywords:  immunotherapy; pan-cancer; single-cell RNA sequencing; treatment response; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2026.08.007
  15. Cancer Cell. 2026 Sep 01. pii: S1535-6108(26)00303-X. [Epub ahead of print]
    TIME in motion: How response takes shape.
    Wee Loong Chin, Willem Joost Lesterhuis.
      Biomarkers for immune checkpoint inhibitors have largely treated the tumor immune microenvironment as a fixed property. In this issue of Cancer Cell, Lin et al. assemble a longitudinal pan-cancer single-cell atlas and show that the direction of immune-state remodeling during therapy is more informative than baseline composition.
    DOI:  https://doi.org/10.1016/j.ccell.2026.06.016
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