bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2026–08–30
eleven papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Ketogenic Diet Promotes Intestinal Tumorigenesis Via Lipid Oxidation.
  2. Lipid metabolism and chromatin-associated sirtuin-dependent epigenetic reprogramming in cancer.
  3. Oncofetal cell states: cell plasticity drives invasion in premetastatic colorectal tumors.
  4. Goblet cells mechanically breach the epithelial barrier in gut homeostasis.
  5. Proliferation and differentiation in intestinal organoids are balanced by ligand-modulated EGFR trafficking.
  6. Intestinal fructose catabolism promotes obesity and insulin resistance via ileal lacteal remodeling.
  7. The hybrid energy metabolism profile of human colorectal cancer cells.
  8. Cell competition driven by secreted ligands: Modeling liver metastasis of colorectal cancer.
  9. LTBP4 deficiency induces MRC1+/CD44+ macrophages to drive cancer progression in preclinical colorectal cancer models.
  10. Serotonin receptor agonist suppresses colorectal cancer.
  11. Long-lasting extracellular matrix modifications reshape intestinal stem cell fate and promote chronic inflammation.
  1. Cancer Discov. 2026 Aug 26. OF1
    Ketogenic Diet Promotes Intestinal Tumorigenesis Via Lipid Oxidation.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2026-076
  2. Mol Biol Rep. 2026 Aug 25. pii: 1458. [Epub ahead of print]53(1):
    Lipid metabolism and chromatin-associated sirtuin-dependent epigenetic reprogramming in cancer.
    Francisco Alejandro Lagunas-Rangel.
      Lipids are essential components of cancer biology, serving not only as sources of energy and biomass but also as signalling molecules that influence gene regulation and cellular plasticity. Increasing evidence suggests that lipid metabolic rewiring can shape epigenetic states through the activity of sirtuins, a family of NAD+-dependent enzymes with deacetylase, deacylase and ADP-ribosyltransferase activities that couple metabolic cues to chromatin regulation. This narrative review examines how alterations in fatty acid oxidation, lipid uptake, cholesterol metabolism and lipid-derived metabolites converge on the sirtuin family of NAD+-dependent enzymes to regulate epigenetic states in cancer. Lipid metabolism shapes sirtuin function by influencing NAD+/NADH balance, acetyl-CoA availability and the production of diverse acyl-CoA species, thereby modulating histone acetylation, non-canonical lysine acylations and DNA methylation programmes. In parallel, lipid metabolites can directly regulate sirtuin abundance, activity and subcellular localization, with context-dependent consequences for chromatin regulation and transcriptional plasticity. Emerging evidence indicates that this lipid-sirtuin-epigenetic axis contributes to metabolic adaptation and tumour cell fitness, stemness, antitumour immunity and metastatic dissemination. The dual nature of sirtuin signalling is also discussed, as these enzymes can either promote or constrain tumour progression depending on the metabolic and microenvironmental context. Therapeutic opportunities targeting lipid metabolism and sirtuins are considered, together with the potential of lipid, sirtuin and epigenetic signatures as biomarkers for prognosis, patient stratification and precision oncology.
    Keywords:  Cancer stem cells; Chromatin regulation; Fatty acid oxidation; Histone deacylation; Tumour microenvironment
    DOI:  https://doi.org/10.1007/s11033-026-12653-6
  3. Signal Transduct Target Ther. 2026 Aug 28. pii: 352. [Epub ahead of print]11(1):
    Oncofetal cell states: cell plasticity drives invasion in premetastatic colorectal tumors.
    Mahmoud N A Amer, Florian R Greten.
      
    DOI:  https://doi.org/10.1038/s41392-026-02941-9
  4. Nat Commun. 2026 07 25. pii: 9078. [Epub ahead of print]17(1):
    Goblet cells mechanically breach the epithelial barrier in gut homeostasis.
    Justine Creff, Yuan He, Sandra Bernat-Fabre, Etienne Buscail, Salomé Neuvendel, Vishnu Krishnakumar, Dhriti Saumya, Laurent Malaquin, Thomas Mangeat, Shi-Lei Xue, Denis Krndija.
      The intestinal epithelium forms a tight barrier against the harsh luminal environment. Absorptive enterocytes have a polygonal, columnar morphology, while mucus-producing goblet cells exhibit a rounded apical shape and a voluminous cell body, raising the question of how epithelial integrity is preserved in tissues with such morphological heterogeneity. Here, we show that, under homeostatic conditions in vivo, goblet cells mechanically induce tight-junction fractures between neighboring enterocytes. This effect is exacerbated by goblet cell hypertrophy and is associated with increased gut permeability. Using in vivo and organoid models, combined with pharmacological, genetic and mechanical perturbations and theoretical modeling, we demonstrate that these fractures arise from a force imbalance at cell interfaces: goblet cells exert pressure on adjacent enterocytes, whose junctional rupture depends on tissue rheology controlled by myosin II. Our findings uncover a mechanical role for goblet cells in epithelial cohesion and barrier regulation, revealing how cellular heterogeneity shapes tissue integrity.
    DOI:  https://doi.org/10.1038/s41467-026-76034-0
  5. Life Sci Alliance. 2026 Nov;pii: e202603733. [Epub ahead of print]9(11):
    Proliferation and differentiation in intestinal organoids are balanced by ligand-modulated EGFR trafficking.
    Mario O Caracci, Sabrina Seidler, Luis M Muñoz-Nava, Birga Soetje, Kirsten Michel, Philippe Ih Bastiaens.
      Epidermal growth factor (EGF) signaling is associated with proliferation and tumorigenesis. Conversely, EGF-family ligands can also trigger a differentiation program, an effect attributed to ligand affinity and EGF receptor (EGFR) activity. Most of these observations have been made in immortalized cell culture experiments, whereas the mechanisms underlying EGF/EGFR-driven proliferation-differentiation dynamics in complex development and tissue self-renewal have not been addressed. We show that culturing mouse small intestinal organoids (mSIOs) without EGF enhanced EGFR expression and basal phosphorylation while maintaining a balanced development of proliferative crypts and differentiated villi. Addition of EGF or Epiregulin (EREG) triggered receptor endocytosis, reducing cell-surface levels and expression. While EGF promoted crypt proliferation, EREG promoted both proliferation and villus differentiation compared with untreated controls. Removal or re-introduction of EGF or EREG proved sufficient to induce development comparable to the constant presence of ligands over 96 h. Sub-saturating concentrations of EGF led to increased villus differentiation, resembling EREG treatments, suggesting that control over EGFR endocytic cycle regulates its plasma membrane localization shaping the balance of proliferation and differentiation in mSIOs.
    DOI:  https://doi.org/10.26508/lsa.202603733
  6. Sci Adv. 2026 Aug 28. 12(35): eaec0481
    Intestinal fructose catabolism promotes obesity and insulin resistance via ileal lacteal remodeling.
    Miranda L Lopez, Taekyung Kang, Ana M Espeleta, Varvara I Rubtsova, Jongwon Baek, Jakob Songcuan, Elena M Moyer, Joohwan Kim, Won-Suk Song, Sunhee Jung, Rochelle W Lai, Aiyana Binuya, Christopher H Lee, Amy R Lantz, Nicholas D'Sa, Alexis Anica, Elise Tran, Yujin Chun, Wonsuk Choi, Ki-Hong Jang, Sungji Cho, Miranda E Kelly, Ian J Tamburini, Yasmine H Alam, Johnny Le, Cuauhtemoc B Ramirez, Raghu P Kataru, Seon Pyo Hong, Thomas Q de Aguiar Vallim, Dequina A Nicholas, Katherine S Xue, Gina Lee, Hosung Bae, Cholsoon Jang.
      High-fructose corn syrup (HFCS) consumption is a risk factor for obesity and diabetes, yet the underlying mechanisms, especially at the specific organ level, are incompletely understood. Catabolism of dietary fructose primarily occurs in the small intestine and liver, with fructose breakdown in the liver being pathological, while small intestinal fructose clearance protects the liver. Here, we report that inhibition of fructose catabolism specifically in the murine small intestine unexpectedly mitigates fructose-induced obesity and insulin resistance. Such phenotypes are attributed to decreased dietary fat absorption by the shortening of ileal lacteals. Fecal transplantation experiments revealed that the microbiome altered by blunted host intestinal fructose catabolism decreases ileal macrophages essential for lacteal growth. Thus, altered intestinal lacteal architecture likely contributes to the synergistic effects of high fat and sugar on metabolic disorders. It may also be relevant to the clinical evidence that pharmacologic suppression of fructose catabolism mitigates diet-induced obesity.
    DOI:  https://doi.org/10.1126/sciadv.aec0481
  7. Biochimie. 2026 Aug 22. pii: S0300-9084(26)00202-6. [Epub ahead of print]
    The hybrid energy metabolism profile of human colorectal cancer cells.
    Rafael Moreno-Sánchez, Emma Verónica Moreno-Saavedra, Emma Saavedra, Jorge Luis Vargas-Navarro, Sara Rodríguez-Enríquez.
      In a continuous effort to characterize the energy metabolism of colorectal cancer, the glycolytic and oxidative phosphorylation fluxes of human colorectal cancer Caco2 cells, cultured and incubated under various conditions, were assessed. Furthermore, the activities and kinetic parameters of several glycolytic and antioxidant enzymes were determined. Both pathways made similar contributions to the cell ATP supply, indicating a hybrid energy metabolism in these colorectal cancer cells, rather than the widely assumed "glycolytic phenotype" commonly associated with this type of cancer. The kinetic analysis of glycolysis and antioxidant pathway revealed no significant differences in enzyme activities and kinetic parameters among Caco2 cells grown under different conditions. However, (a) the glycolytic LDH/PyK, PyK/PFK-1 and PFK-1/HK, and antioxidant G6PD/IDH and CAT/SOD activity ratios, and (b) the strong HPI inhibition exerted by Ery4P indicated clear regulatory differences between cancer and non-cancer cells, which may be considered as potential metabolic biomarkers and suitable drug targets.
    Keywords:  Caco2 cells; antioxidant pathway; glycolysis; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.biochi.2026.08.014
  8. Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2531078123
    Cell competition driven by secreted ligands: Modeling liver metastasis of colorectal cancer.
    Hossein Nemati, Saskia Jacoba Elisabeth Suijkerbuijk, Joost de Graaf.
      Cell competition in multicellular organisms has been shown to play a critical role during the development of organisms, cancer progression, and in the establishment and maintenance of tissue homeostasis. Various mechanisms of cell competition have been identified, including active elimination via mechanical forces or induced apoptosis, as well as competition for nutrients and other beneficial factors. A recent experiment demonstrated hallmarks of cell competition, associated with cell cycle dynamics, between liver progenitor cells and colorectal cancer cells [A. Krotenberg Garcia et al., iScience 27, 109718 (2024)]. However, a mechanistic explanation for this form of competition remains lacking. Here, we present a mean-field model of competition for signaling ligands, coupled with cell cycle dynamics, to provide such an understanding. Our model captures the salient features of the experiment, including population dynamics and cell cycle variations. We demonstrate that secretion of a beneficial factor by cells, coupled with the enhanced uptake efficiency of cancer cells, suffices to reproduce the experimental outcome. Our model, reminiscent of competition for secreted growth factors, provides insight into the minimal level of complexity required to achieve the observed competitive outcome as well as its link to cell cycle dynamics. It can also serve as a general framework for studying biological populations with growth-stage-dependent competition over consumer-produced products.
    Keywords:  cell competition; cell cycle; consumer–resource modeling; mean-field model; physical modeling
    DOI:  https://doi.org/10.1073/pnas.2531078123
  9. Sci Transl Med. 2026 Aug 26. 18(864): eaeb2189
    LTBP4 deficiency induces MRC1+/CD44+ macrophages to drive cancer progression in preclinical colorectal cancer models.
    Songtao Ji, Shuya Du, Ge Miao, Xiaohua Yang, Haojia Wang, Xuemei Li, Wanqi Ma, Dan Wei, Tianyu Cao, Mingzhen Zhou, Jianing Yu, Xiangshu Cheng, Yuanci Zhang, Hua Han, Yongzhan Nie, Jipeng Li, Hongyan Qin, Liang Wang, Xin Wang, Yuanyuan Lu, Xiaodi Zhao.
      The tumor microenvironment is crucial for cancer progression, but the mechanisms underlying the tumor-immune cell interactions in it remain poorly understood. Here, we identified latent transforming growth factor-β (TGFβ) binding protein 4 (LTBP4) deficiency in colorectal cancer (CRC) as a critical driver that reprogrammed tumor-associated macrophages (TAMs) and induced a distinct subset, which promoted tumor progression by coordinating immune evasion and extracellular matrix (ECM) remodeling. Clinically, LTBP4 deficiency correlated with CRC progression and poor patient survival. Ltbp4 knockout markedly promoted tumor growth and metastasis in immunocompetent mice, an effect attenuated in immunodeficient hosts, establishing the essential role of host immunity in mediating the effects of LTBP4 deficiency. Single-cell RNA sequencing revealed that LTBP4 deficiency induced a mannose receptor C-type 1-positive (MRC1+)/CD44+ TAM subset and correlated with reduced CD8+ T cell infiltration. Mechanistically, LTBP4 deficiency increased active TGFβ1 levels, which acted in a paracrine manner to up-regulate MRC1 in TAMs, whereas autocrine signaling induced HAS2 (hyaluronan synthase 2) expression and hyaluronan production to increase CD44. CD44 signaling in TAMs up-regulated matrix metalloproteinases for collagen degradation, whereas MRC1 mediated collagen internalization, cooperatively remodeling the ECM to facilitate tumor invasion. The TGFβ1-driven MRC1+/CD44+ TAMs further suppressed CD8+ T cell function by diminishing the C-X-C motif chemokine ligand 16-C-X-C motif chemokine receptor 6 (CXCL16-CXCR6) axis. Therapeutically, targeted depleting MRC1+/CD44+ TAMs enhanced the efficacy of PD-1 (programmed cell death-1) blockade in LTBP4-deficient tumors. Our study positions LTBP4 as a key modulator of tumor progression and reveals a therapeutic strategy for LTBP4-deficient CRC.
    DOI:  https://doi.org/10.1126/scitranslmed.aeb2189
  10. Nat Rev Drug Discov. 2026 Aug 28.
    Serotonin receptor agonist suppresses colorectal cancer.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-026-00144-z
  11. Immunity. 2026 Aug 26. pii: S1074-7613(26)00321-3. [Epub ahead of print]
    Long-lasting extracellular matrix modifications reshape intestinal stem cell fate and promote chronic inflammation.
    Idan Adir, Carmel Sochen, Sivan Gelb, Aviya Habshush Menachem, Sacha Lebon, Barak Toval, Vladyslav Holiar, Natalia Davidzohn, Tomer-Meir Salame, Irit Rosenhek-Goldian, Simonas Savickas, Fabio Sabino, Valerio Izzi, Bella Ungar, Alon Abend, Inna Solomonov, Ehud Zigmond, Taina Pihlajaniemi, Ulrich Auf dem Keller, Moshe Biton, Irit Sagi.
      Tissue regeneration is viewed as a return to homeostasis, but whether the extracellular matrix (ECM) reverts during recovery from gut inflammation is unclear. Using temporal multi-omics, biomechanical profiling, and spatial fate mapping in colitis models, we showed that colonic ECM underwent lasting pathological reprogramming following inflammation, which we termed modified (mod)ECM. Characterized by collagen XVIII accumulation and immune-driven proteolysis, modECM redirected intestinal stem cells (ISCs) toward a wound-associated epithelial state with a pro-inflammatory transcriptional program. Ex vivo, modECM alone reshaped ISC fate by suppressing Wnt signaling and activating immune recruitment pathways. In vivo, modECM-rich zones sustained T cell infiltration and KRT14+ epithelial cell emergence from Lgr5+ progenitors. This aberrant epithelial program was mirrored in inflamed rectal biopsies from individuals with ulcerative colitis. Our findings redefine the ECM as a long-lived instructive compartment that encodes injury memory and promotes maladaptive regeneration, positioning it as a therapeutic target in chronic inflammatory diseases.
    Keywords:  ECM; ECM remodeling; ISC; T cell recruitment; collagen XVIII; colon; extracellular matrix; intestinal stem cell; pathological reprogramming; tissue regeneration; wound-associated epithelia
    DOI:  https://doi.org/10.1016/j.immuni.2026.07.022
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