bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2026–03–22
eight papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Extrinsic lipids are absorbed and accumulate in colorectal cancer.
  2. NSUN2 mediates intestinal stem cell expansion and colorectal tumour initiation via MAPK/ERK signalling.
  3. IL-17RA signaling promotes the dedifferentiation of Paneth progenitors through ADAM17 to regenerate gut epithelium post-irradiation.
  4. Epithelial-mesenchymal transition shapes the lipotoxic response of colon cancer cells to palmitic acid.
  5. Caspase-3/7 deficiency results in enhanced intestinal inflammation and reduced tumorigenesis.
  6. Frazzled/DCC directs spatial progenitor integration ensuring steady-state intestinal turnover.
  7. Multi-omics analysis reveals features improving outcomes and immunotherapy resistance in MSS colorectal cancer.
  8. Single cell transcriptomics reveals that air-liquid interface culture promotes goblet cell differentiation and inhibits glycolysis in organoid cell monolayers.
  1. Gut. 2026 Mar 19. pii: gutjnl-2025-336377. [Epub ahead of print]
    Extrinsic lipids are absorbed and accumulate in colorectal cancer.
    Klaus Peter Janssen, Marijana Basic, Silvia Bolsega, Amira Metwaly, Florian Jokisch, Sophia von Gamm, Josef Scheiber, Ralph Burkhardt, Gerhard Liebisch, Klaus Neuhaus, Sarah Brunner, Thomas Clavel, Esther Wortmann, Olivia I Coleman, Dirk Haller, Andre Bleich, Sabrina Krautbauer, Josef Ecker.
       BACKGROUND: Colorectal cancer (CRC) exhibits increased levels of arachidonic acid-derived pro-inflammatory derivatives indicating an uptake of dietary polyunsaturated fatty acids (PUFAs).
    OBJECTIVE: We aimed to investigate uptake of extrinsic fatty acids (FAs) in tumours and their relevance for CRC lipid metabolism and progression.
    DESIGN: Total FAs were quantified using gas chromatography-mass spectrometry in non-diseased mucosa and tumour tissue from patients with CRC of a discovery cohort (n=152), validated in an independent cohort (n=28) and associated with clinical, genomic and microbiome data. The genetic mouse tumour model Apc1638N was used to track the flux of stable isotope-labelled FAs in tumours from the intestinal lumen. The relationship between FA uptake and tumour progression was investigated in 2D and 3D cell models.
    RESULTS: Extrinsic long chain PUFAs, including arachidonic acid, accumulate in CRC, particularly in right-sided tumours, and in tumours of Apc1638N mice. The CRC-specific FA profiles were independent of sex, molecular subtypes, early-disease or late-disease onset. The absorption of FAs from the intestinal lumen in tumours was confirmed in specific pathogen-free Apc1638N mice. In the absence of the microbiome, in germ-free Apc1638N mice, fewer tumours were developed, and survival was increased. Inhibition of FA import or β-oxidation reduces cancer cell proliferation.
    CONCLUSION: Extrinsic FAs accumulate in CRC, verifying a central role of arachidonic acid-derived inflammatory mediators, but also suggesting a relevance of dietary FAs for cancer cell proliferation. It will be intriguing to explore to what extent targeting this flux pathway together with the interrelated microbiome opens new therapeutic avenues for CRC in humans.
    Keywords:  COLORECTAL CANCER; LIPID ABSORPTION; LIPID METABOLISM; MICROBIOME
    DOI:  https://doi.org/10.1136/gutjnl-2025-336377
  2. Cell Death Dis. 2026 Mar 19.
    NSUN2 mediates intestinal stem cell expansion and colorectal tumour initiation via MAPK/ERK signalling.
    Aslihan Bastem Akan, Caroline V Billard, Szu-Ying Chen, Po-Hsien Huang, Patrizia Cammareri, Vidya Rajasekaran, Adam E Hall, Paula Preyzner, Sebastian Öther-Gee Pohl, Susan M Farrington, Malcolm G Dunlop, Farhat V N Din, Kevin B Myant.
      Colorectal cancer is initiated by loss of APC, which drives expansion of LGR5+ intestinal stem cell (ISC) populations. Whilst LGR5 + ISC expansion is a critical step for tumour initiation and progression, its regulation is poorly understood. Emerging evidence suggests post-transcriptional RNA modifications play a key role in cancer biology, but their role in CRC initiation has not been explored. Here, we identify the m5C methyltransferase NSUN2 as a key regulator of ISC expansion and intestinal tumourigenesis. NSUN2 is upregulated in multiple CRC mouse models and human tumours, and its depletion impairs ISC expansion and hyperproliferation, leading to reduced tumour initiation. Transcriptome-wide bisulfite sequencing revealed that NSUN2 mediates m5C methylation on mRNAs encoding key ISC regulators and components of the MAPK/ERK pathway. Mechanistically, loss of NSUN2 reduces ERK phosphorylation in Apc-deficient models, and oncogenic KrasG12D expression is sufficient to restore ERK signalling and rescue ISC expansion. Together, this establishes a novel role for NSUN2 as a key regulator of ISC-driven CRC initiation and describes a critical molecular mechanism linking m5C methylation to MAPK-driven stem cell transformation.
    DOI:  https://doi.org/10.1038/s41419-026-08560-0
  3. Nat Commun. 2026 Mar 17.
    IL-17RA signaling promotes the dedifferentiation of Paneth progenitors through ADAM17 to regenerate gut epithelium post-irradiation.
    Cody G Kempen, Ankita Singh, Keith A Breau, Hafiz I Tariq, Yangle Yu, Stephen J Gaudino, Tej Bahadur, Emilia Orzechowska-Licari, Onur Eskiocak, Kiyoshi Shiomitsu, Richard Blumberg, Paula Denoya, Rebecca Martin, Agnieszka B Bialkowska, Semir Beyaz, Scott T Magness, Patrick Hearing, Hwan Keun Kim, Brian S Sheridan, Peter Dempsey, Pawan Kumar.
      Paneth cells and their antimicrobial products are critical in mediating small intestinal host defense under homeostatic conditions and after injury or infection. In addition, Paneth cells have also been shown to gain stem-like properties and repropagate intestinal crypts after intestinal injury. The specific role of intestinal IL-17A or its receptor (IL-17RA) signaling in Paneth cells to gain stem-like features has yet to be investigated. Using Paneth cell-specific IL-17RA (Il17rafl/fl;Defa6-cre) knockout mice, anti-IL-17A neutralizing studies and lineage tracer (Defa6-cre;mT/mG) mice, we show that after injury IL-17RA signaling is required for Paneth cell to gain stem-like properties to regenerate the intestinal epithelium. Increased susceptibility of Il17rafl/fl;Defa6-cre mice is associated with reduced expression Adam17 in the terminal ileum. Adam17 overexpression in Il17rafl/fl;Defa6-cre mice rescues the epithelial regeneration defect in these mice. IL-17A induces Nox1 in Paneth cells and H2O2 induces ADAM17 enzymatic activity. Finally, using Paneth cell-specific Adam17 (Adam17fl/fl;Defa6-cre) knockout mice, we show that ADAM17 in Paneth cells is required for tissue regeneration. Collectively, our data reveal an essential role of the IL-17RA-ADAM17 pathways in Paneth cells for tissue regeneration.
    DOI:  https://doi.org/10.1038/s41467-026-70479-z
  4. Mol Cell Proteomics. 2026 Mar 12. pii: S1535-9476(26)00050-2. [Epub ahead of print] 101554
    Epithelial-mesenchymal transition shapes the lipotoxic response of colon cancer cells to palmitic acid.
    Francesco Vari, Ilaria Serra, Elisa Bisconti, Eleonora Stanca, Antonella Raffo-Romero, Sarah Mehenni, Yanis Zirem, Daniele Vergara, Isabelle Fournier, Anna Maria Giudetti, Michel Salzet.
      Saturated fatty acids such as palmitic acid (PA) can induce lipotoxic stress, whereas monounsaturated fatty acids like oleic acid (OA) often promote adaptive responses through lipid droplets (LDs) formation. Here, we reveal that epithelial-mesenchymal transition (EMT) profoundly influences the lipotoxic response of colorectal cancer cells. Using the epithelial-like HCT15 and mesenchymal-like HCT116 cell lines, we combined proteomic, metabolic, and imaging analyses to elucidate how EMT status determines lipid storage capacity and resistance to PA-induced toxicity. A Basal proteomic profiling highlighted a striking divergence in metabolic changes: HCT15 cells displayed enhanced glycolysis and reduced expression of LDs biogenesis proteins, while HCT116 cells exhibited oxidative metabolism and a "lipid-rich" proteomic signature enriched in PLIN2, GPAT3, and DGAT1. Functionally, PA triggered massive cytotoxicity and failed to induce LDs in HCT15 cells, correlating with DGAT1/2 downregulation and suppressed triacylglycerol synthesis. In contrast, HCT116 cells showed modest LDs accumulation, preserved mitochondrial function, and strong resistance to lipotoxic stress. OA treatment restored LDs formation and cell viability in both models, underscoring the protective role of unsaturated fatty acids. Notably, forced EMT induction in HCT15 cells by PMA markedly enhanced LDs accumulation and reduced PA-induced death, confirming that EMT confers metabolic plasticity and lipid-buffering capacity. These findings demonstrate that EMT status modulates differential lipid handling and stress adaptation in colon cancer cells, linking mesenchymal transition to enhanced LDs biogenesis and survival under lipotoxic conditions. Data are available via ProteomeXchange with identifier PXD071641.
    Keywords:  EMT markers; lipid droplets; lipotoxicity; metabolic reprogramming; palmitic acid
    DOI:  https://doi.org/10.1016/j.mcpro.2026.101554
  5. Sci Adv. 2026 Mar 20. 12(12): eadz5906
    Caspase-3/7 deficiency results in enhanced intestinal inflammation and reduced tumorigenesis.
    Wei Xie, Laura Wyckaert, Mike Vadi, Bruno Verstraeten, Tatyana Divert, Jef Haerinck, Riet De Rycke, Femke Baeke, Mohamed Lamkanfi, Geert Berx, Adam Wahida, Peter Vandenabeele.
      Aberrant intestinal epithelial cell (IEC) death is common in inflammatory bowel disease (IBD) and related animal models. While various cell death pathways contribute to disease, the dominant modalities and their regulatory mechanisms in intestinal inflammation remain ill defined. Using the DSS colitis model, we examined the contribution of apoptosis (Casp3/7ΔIEC), necroptosis (MlklΔIEC), pyroptosis (GsdmeΔIEC, Gsdmd-/-), and ferroptosis (Gpx4iΔIEC) in IECs. Mice lacking caspase-3/7 in IECs showed worsened colitis, higher mortality, and impaired regeneration, not seen in the other transgenic mice. Caspase-3/7 deficiency in IECs hindered stem cell proliferation and increased inflammatory cell death, disrupting barrier integrity and delaying recovery. Despite heightened inflammation, Casp3/7ΔIEC mice had reduced tumor formation in the AOM/DSS-induced colorectal cancer model. These findings highlight a protective role for caspase-3/7 in controlling inflammation and tissue regeneration, while promoting tumorigenesis following intestinal injury, and suggest modulation of caspase-3/7 as a promising therapeutic strategy in IBD and colorectal cancer.
    DOI:  https://doi.org/10.1126/sciadv.adz5906
  6. Nat Commun. 2026 03 14. pii: 2491. [Epub ahead of print]17(1):
    Frazzled/DCC directs spatial progenitor integration ensuring steady-state intestinal turnover.
    Lisa Zipper, Pol Ramon-Cañellas, Filiz Akkas-Gazzoni, Tobias Reiff.
      Adult epithelial organs undergo continual steady-state turnover that is achieved by tight coupling of stem cell production with replacement of worn-out epithelial cells by local intercellular signalling1,2. Like many eukaryotic epithelia, absorptive enterocytes (EC) of the adult Drosophila midgut are arranged in a hexagonal, honeycomb-like pattern. On tricellular nexuses of EC, intestinal stem cells (ISC) are scattered in a way so that around two thirds of EC can be renewed directly by adjacent ISC. However, the mechanism for replacement of the remaining third of remotely located EC is unknown.Here, we show that a conserved axonal guidance cue directs enteroblasts (EB), the immediate ISC daughters, to selectively replace worn-out adjacent and remote EC with identical frequency. Worn-out EC express Netrin-B ligands that attract Frazzled/DCC-receptor dependent EB protrusions and subsequent EB migration towards the Netrin-B expressing EC. Our newly developed 'Hamelin' assay confirms Frazzled-dependent EB migration towards Netrin-B sources and hints to invasive progenitor behaviour as midgut progenitors cross the organ boundary into the hindgut. Together, we establish spatially directed EB migration and integration as essential for intestinal homeostasis and provide first mechanistic support for recent findings resuscitating conserved Netrins and Frazzled/DCC-signalling as therapeutic target in metastasis.
    DOI:  https://doi.org/10.1038/s41467-026-70704-9
  7. iScience. 2026 Mar 20. 29(3): 114817
    Multi-omics analysis reveals features improving outcomes and immunotherapy resistance in MSS colorectal cancer.
    Hui Xu, Anning Zuo, Yuhao Ba, Shutong Liu, Xinwei Han, Zaoqu Liu, Haidong Zhu.
      In contrast to the MSI-H subtype, most microsatellite-stable (MSS) colorectal cancer (CRC) patients exhibit poor prognosis and limited responsiveness to immunotherapy, highlighting the urgent need for robust biomarkers to stratify prognosis and predict immunotherapy responsiveness. Here, 68 single-cell and 3,767 bulk transcriptome samples were integrated to identify and validate MSS patients with high immune infiltration. Multidimensional, prognosis-related, and immunological features specific to MSS CRC were characterized at cellular and genetic levels. To reduce algorithm selection bias, 93 artificial intelligence algorithms were applied to construct a machine learning-derived MSS prognostic-immune signature (MLDMPIS). MLDMPIS demonstrated robust prognostic and immunotherapy response prediction performance in 1,323 MSS patients and six independent immunotherapy cohorts, outperforming clinical indicators, published prognostic signatures, and immune response models. Mechanistically, CADM1 was identified as a key molecule associated with MLDMPIS. Functional analyses revealed that CADM1 promotes tumor stemness, thereby enhancing proliferation, invasion, and metastasis in MSS CRC.
    Keywords:  bioinformatics; cancer; cancer systems biology; high-performance computing in bioinformatics; immunology; systems biology
    DOI:  https://doi.org/10.1016/j.isci.2026.114817
  8. Am J Physiol Gastrointest Liver Physiol. 2026 Mar 14.
    Single cell transcriptomics reveals that air-liquid interface culture promotes goblet cell differentiation and inhibits glycolysis in organoid cell monolayers.
    Tania Malonga, Emeline Lhuillier, Christelle Marrauld, Deborah Fourmy, Elodie Riant, Cédric Cabau, Nathalie Vialaneix, Martin Beaumont.
      Faithfully recapitulating the cellular heterogeneity of the intestinal epithelium is essential when using organoid models. Air-liquid interface (ALI) culture has been shown to promote secretory cell dif-ferentiation but its impact on gene expression in each epithelial cell type remains unclear. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize the cellular heterogeneity of rabbit caecum-derived organoid monolayers grown under immerged or ALI conditions. We then compared these organoid cell type-specific gene expression profiles to a scRNA-seq atlas of the rabbit caecal epithelium in vivo. We selected the rabbit model notably because, unlike mice, it pos-sesses BEST4+ epithelial cells, a newly discovered subset of mature absorptive cells. Our analysis revealed a high degree of transcriptomic similarity between in vivo and organoid-derived stem and transit-amplifying cells. ALI culture markedly enhanced the differentiation of the secretory lineage, especially goblet cells, which transcriptome closely resembled that of in vivo goblet cells. Further-more, ALI was the only condition allowing the detection of enteroendocrine cells. BEST4+ cells, however, were absent from organoids in immerged or ALI conditions despite their presence in vivo. In addition, ALI culture led to a consistent downregulation of hypoxia and glycolysis-associated genes across all cell types, which suggests a metabolic shift likely driven by increased oxygen avail-ability in ALI conditions. Cell-cell communication analyses further indicated that ALI more closely mirrored in vivo patterns than immerged condition. Altogether, these results demonstrate that ALI culture allows to better recapitulate the in vivo cellular heterogeneity and molecular signatures of the intestinal epithelium.
    Keywords:  Air-liquid interface; Epithelium; Goblet Cells; Hypoxia; Organoids
    DOI:  https://doi.org/10.1152/ajpgi.00251.2025
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