bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2026–06–14
seven papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. High-plasticity oncofetal cell states in early pre-metastatic colorectal cancer.
  2. Dynamic transitioning between MAPK-driven and WNT-driven cell states drives intestinal cancer and shapes therapy response.
  3. Recurrent COPA mutation drives R-spondin-independent Wnt activation in intestinal tumors.
  4. Cell size modulates ferroptosis susceptibility.
  5. Intracellular lipid droplets positively regulate the dormancy of colorectal cancer cells depending on ELF1-ACSL5 signaling.
  6. Collective cell migration plasticity in patient-derived digestive cancer organoids is dictated by environment sensing and contractility.
  7. RUNX2 promotes chromatin accessibility and WNT signaling in inflamed intestinal epithelial cells.
  1. Cancer Cell. 2026 Jun 11. pii: S1535-6108(26)00256-4. [Epub ahead of print]
    High-plasticity oncofetal cell states in early pre-metastatic colorectal cancer.
    Manon Bulliard, Yakov Perlov, Ömer H Yilmaz, Bing Shui.
      In Nature, Buissant des Amorie et al. demonstrate that colorectal cancer acquires oncofetal cell states that resemble embryonic intestines, confer stem-like features, reshape epithelial identity, and prime cells for invasion and metastasis. Oncofetal cells are essential for metastasis and ubiquitous in non-metastatic tumors, with cancer-associated fibroblasts as key microenvironmental drivers.
    DOI:  https://doi.org/10.1016/j.ccell.2026.05.011
  2. Nat Genet. 2026 Jun;58(6): 1331-1340
    Dynamic transitioning between MAPK-driven and WNT-driven cell states drives intestinal cancer and shapes therapy response.
    Amanda R Moore, Brian Biehs, Noelyn Kljavin, Thi Thu Thao Nguyen, Akansha Shah, Jeremy Burton, Honglin Jiang, Jenille Tan, Deepankar Chakroborty, Lisa Wang, Nayan Chaudhary, Dongze He, William Lin, Kathryn Mesh, Xin Ye, Kamakoti P Bhat, Lisa Tai, Shiqi Xie, Weilan Ye, Lisa McGinnis, Shiva Malek, Sandra P Melo, Frederic J de Sauvage.
      Colorectal cancer (CRC) frequently harbors activating mutations in the WNT and MAPK pathways. While KRAS mutations alone can drive tumor initiation in many tissues, they are insufficient in the intestine. Leveraging allele-specific properties of RAS, we developed a mouse model to investigate MAPK hyperactivation. Here we show that KRAS mutations drive a regenerative state while antagonizing the Lgr5+ intestinal stem cell state; however, this regenerative state cannot initiate tumorigenesis. Instead, tumor initiation requires a stem-like state dependent on mutational activation of the WNT pathway. We identify two aberrant states-a WNT-driven stem-like state for tumor initiation and MAPK-driven transit-amplifying-like state for tumor growth. These plastic states, essential for tumorigenesis, also impact drug response, potentially explaining lower response rates and shorter duration of response to KRAS-G12C inhibitors in CRC compared to non-small cell lung cancer. These findings highlight the need to target both pathways and their associated cell states for effective CRC treatment.
    DOI:  https://doi.org/10.1038/s41588-026-02611-0
  3. Nat Genet. 2026 Jun;58(6): 1341-1352
    Recurrent COPA mutation drives R-spondin-independent Wnt activation in intestinal tumors.
    Masayuki Fujii, Naoko Abeto, Shotaro Kishimoto, Kouya Shiraishi, Taiki Hashimoto, Nobuyoshi Hiraoka, Satoru Nonaka, Motohiro Kojima, Mami Matano, Sirirat Takahashi, Gabriele Colozza, Bon-Kyoung Koo, Yasushi Yatabe, Motohiko Kato, Toshiro Sato, Shigeki Sekine.
      The majority of intestinal tumors harbor mutations in canonical Wnt pathway genes such as APC, whereas the lack of such alterations in a subset of tumors implies alternative tumorigenic routes. Here we identify recurrent in-frame deletion in COPA, frequently co-occurring with USP9X-truncating mutation, in small intestinal adenoma and adenocarcinoma. Patient-derived and CRISPR-engineered small intestinal organoids carrying COPA in-frame deletions exhibit R-spondin-independent yet Wnt ligand-dependent growth, maintaining LGR5 expression without canonical Wnt drivers. Mechanistically, COPA mutation stabilizes the Frizzled coreceptor LRP6 irrespective of R-spondin, sustaining Wnt pathway activation under growth factor-restricted conditions. USP9X loss further potentiates this phenotype. Unlike canonical Wnt pathway members, COPA encodes the α-subunit of coatomer complex I, which engages in vesicle trafficking with little prior linkage to intestinal tumorigenesis. Our findings establish COPA mutation as a unique and atypical intestinal tumor driver and implicate USP9X loss as a cooperating lesion.
    DOI:  https://doi.org/10.1038/s41588-026-02616-9
  4. Elife. 2026 Jun 10. pii: RP111544. [Epub ahead of print]15
    Cell size modulates ferroptosis susceptibility.
    Evgeny Zatulovskiy, Magdalena B Murray, Shuyuan Zhang, Scott J Dixon, Jan M Skotheim.
      Size is a fundamental property of cells that influences many aspects of their physiology. This is because cell size sets the scale for all subcellular components and drives changes in the composition of the proteome. Given that large and small cells differ in their biochemical composition, we hypothesized that they should also differ in how they respond to signals and make decisions. Here, we investigated how cell size affects the susceptibility of human cells to cell death. We found that large cells are more resistant to ferroptosis caused by system xc- inhibition. Ferroptosis is a type of cell death characterized by the iron-dependent accumulation of toxic lipid peroxides. This process is opposed by cysteine-dependent lipid peroxide detoxification mechanisms. We found that larger cells exhibit higher concentrations of the cysteine-containing metabolite glutathione and lower concentrations of membrane lipid peroxides. Mechanistically, this can be explained by the fact that larger cells had lower concentrations of an enzyme that enriches cellular membranes with peroxidation-prone polyunsaturated fatty acids, ACSL4, and increased concentrations of the glutathione-producing enzymes glutamate-cysteine ligase and glutathione synthetase, the iron-chelating protein ferritin, and the lysosomal protease cathepsin B, which can catabolize cysteine-rich extracellular proteins to produce additional cystine for fueling the synthesis of glutathione. Taken together, our results highlight the significant impact of cell size on cellular function and survival, revealing a size-dependent vulnerability to ferroptosis that could influence therapeutic strategies based on this cell death pathway.
    Keywords:  biochemistry; cell biology; cell death; cell size; chemical biology; erastin2; ferroptosis; glutathione; heterogeneous response; human; scaling
    DOI:  https://doi.org/10.7554/eLife.111544
  5. J Exp Clin Cancer Res. 2026 Jun 11.
    Intracellular lipid droplets positively regulate the dormancy of colorectal cancer cells depending on ELF1-ACSL5 signaling.
    Wancheng Liao, Rui Yin, Fan Zuo, Yangkun Li, Jiao Deng, Yanqi Li, Xiaolan Li, Deding Tao, Xuelai Luo, Weike Ji, Jichao Qin.
       BACKGROUND: Colorectal cancer recurrence is largely attributed to dormant tumor cells that evade therapy. The role of organelle metabolism, particularly lipid droplets (LDs) accumulation, in maintaining tumor dormancy remains poorly understood. This study aimed to investigate how LDs contribute to dormancy and to identify key regulatory mechanisms.
    METHODS: Using patient-derived xenograft models and colorectal cancer cell lines, we established chemotherapy-induced dormant, proliferative, and recurrent cells. Transcriptomic profiling identified key regulatory genes and lipidomics of LDs was performed by Liquid Chromatography‑Tandem Mass Spectrometry. Functional validation was performed via genetic knockdown/overexpression, pharmacological inhibition, and mutational analysis. Lipid droplet content, reactive oxygen species levels, and dormancy markers were assessed using staining, flow cytometry, and immunoblotting. Clinical correlation was evaluated using patient datasets and survival analysis.
    RESULTS: Dormant cells exhibited elevated LD levels compared to proliferative or recurrent cells. Transcriptomic analysis identified ACSL5 as a key upregulated gene in dormant cells. ACSL5 promoted LD accumulation, which in turn reduced intracellular reactive oxygen species and stabilized dormancy by sequestering oxidized lipids. The transcription factor ELF1 directly bound the ACSL5 promoter, establishing the ELF1-ACSL5 regulatory axis. Disruption of this axis depleted LDs, increased ROS, and forced dormant cells to exit dormancy. Clinically, high ACSL5 expression correlated with poor prognosis in colorectal cancer patients.
    CONCLUSION: This study defines a novel ELF1-ACSL5-lipid droplet axis that maintains colorectal cancer dormancy by promoting lipid sequestration and redox homeostasis. These findings reveal organelle-centric metabolic reprogramming as a fundamental dormancy mechanism and nominate this axis as a promising therapeutic target to prevent cancer recurrence.
    Keywords:  Dormant cancer cells; Lipid droplets; Tumor recurrence
    DOI:  https://doi.org/10.1186/s13046-026-03754-y
  6. Cell Rep. 2026 Jun 09. pii: S2211-1247(26)00601-7. [Epub ahead of print]45(6): 117523
    Collective cell migration plasticity in patient-derived digestive cancer organoids is dictated by environment sensing and contractility.
    Clémence Nguyen-Vigouroux, Elise Carraz-Billat, Tatiana Cetenovic, Célia Galleri-Paris, Johanna Protin, Charlotte Canet-Jourdan, Emmanuel Dornier, Mélanie Polrot, Jérôme Cartry, Alice Boilève, Sabrina Bedja, Raphaël Mérand, Mohamed-Amine Bani, Antoine Hollebecque, Michel Ducreux, Jacques R R Mathieu, Fanny Jaulin, Florent Peglion.
      The metastatic dissemination of individual cells or cell collectives is a decisive step in the progression of cancers. Migrating single cells dynamically switch between mesenchymal traction-based and amoeboid propulsion-based modes of migration in a mechanism named plasticity. Collective cell migration has mainly been described as a traction-dependent mode of locomotion. While a propulsive collective cell migration has recently been reported, we question whether cell clusters are also endowed with plasticity. Here, we report that patient-derived digestive cancer organoids exhibit a preferred mode of migration but transition to the alternate strategy to adapt to external stimuli or to the manipulation of intrinsic determinants. We show that the tumor cell cluster plasticity observed in vitro ensures efficient metastatic seeding in a murine model of peritoneal carcinomatosis. These findings reveal an adaptive mechanism at play during tumor invasion that must further be decrypted to enable the design of therapeutic strategies halting metastatic progression.
    Keywords:  CP: cancer; CP: cell biology; actomyosin contractility; collective cell migration; colorectal and pancreatic tumor organoids; mouse peritoneal carcinomatosis model; plasticity; β1-integrin
    DOI:  https://doi.org/10.1016/j.celrep.2026.117523
  7. Mucosal Immunol. 2026 Jun 11. pii: S1933-0219(26)00063-2. [Epub ahead of print] 100361
    RUNX2 promotes chromatin accessibility and WNT signaling in inflamed intestinal epithelial cells.
    Rodolfo I Cabrera-Silva, Zachary S Wilson, Jael Miranda, Shuling Fan, Michael Dame, Shrinivas Bishu, Jason R Spence, Jennifer C Brazil, Justin Colacino, Asma Nusrat, Charles A Parkos.
      Ulcerative colitis (UC) is characterized by chronic mucosal inflammation, recurrent epithelial injury, and impaired colonic mucosal wound healing. While WNT/β-catenin dysregulation has been reported in UC, the mechanisms of such abnormalities remain unclear. To investigate epithelial intrinsic alterations associated with UC, we performed single-nucleus RNA-seq (snRNA-seq) and ATAC-seq (snATAC-seq) multiomics on human primary colonic epithelial cells (colonoids) from healthy donors and patients with inactive or active UC. Colonoids were cultured in a 3D matrix recapitulating crypt base cells or grown as 2D monolayers in differentiation medium to recapitulate luminal epithelial cells. Colonoids from active UC had a unique cell population with elevated CTNNB1 and reduced APC expression. Chromatin profiling identified enrichment of RUNX2 motifs in this UC-associated cell population. Active UC colonoids exhibited reduced OLFM4 expression in 3D and the differentiation marker VIL1 in 2D, suggesting impaired epithelial stem-cell maintenance and maturation. RUNX2 inhibition using CADD522 reduced β-catenin levels in 3D colonoids and restored VIL1 expression and junctional β-catenin localization in 2D cultures. These findings reveal an intrinsic defect in epithelial renewal in UC, driven in part by RUNX2-dependent WNT dysregulation. Our study identifies RUNX2 as a transcriptional regulator of epithelial stem cell function and WNT signaling in the inflamed human colon.
    Keywords:  Colonoids; Multi-omics; RUNX2; Stem-cell maintenance; Ulcerative colitis; WNT signaling
    DOI:  https://doi.org/10.1016/j.mucimm.2026.100361
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