bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2026–09–20
eight papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Metabolic matching shapes organ-specific metastasis.
  2. Westernized diet related arachidonic acid metabolism expands DNA error-prone growth factor-dependent colonic quiescent stem cells in adolescent mice.
  3. Quantitative imaging of dynamic processes in intestinal organoids.
  4. Cysteine excess triggers a mitochondrial iron-dependent cell death.
  5. Single-cell gene regulatory networks characterize colonic stem and immune cell homeostasis in Nr4a1 knockout mice.
  6. PADI-dependent mitochondrial adaptation drives resistance to KRAS inhibitors.
  7. Defensive lipid droplets are PUFA reservoirs and suppliers driving bacterial clearance and inflammation.
  8. PDX-Atlas: A web-based portal to manage and share data from patient-derived xenograft models of cancer.
  1. Biochim Biophys Acta Rev Cancer. 2026 Sep 14. pii: S0304-419X(26)00177-0. [Epub ahead of print]1881(6): 189705
    Metabolic matching shapes organ-specific metastasis.
    Cristina Álvarez-Álvarez, Patricia Altea-Manzano.
      Metastasis is the leading cause of cancer-related mortality, yet the mechanisms driving organ-specific colonization remain incompletely understood. Increasing evidence suggests that metastatic success depends on a "metabolic match" between disseminated tumor cells and the microenvironment of the target organ. In this mini-review, we discuss how intrinsic metabolic programs inherited from the primary tumor interact with extrinsic factors such as nutrient availability, redox balance, extracellular matrix remodeling, and organ-resident cells to shape metastatic organotropism. We propose that the interplay between cancer cell metabolic plasticity and tissue-specific metabolic landscapes critically determines metastatic fitness and may uncover new therapeutic vulnerabilities.
    Keywords:  Metabolic match; Metabolic plasticity; Metastasis; Metastatic organotropism; Organ-resident cells; Pre-metastatic niche; Tumor metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189705
  2. Cell Death Dis. 2026 Sep 14. pii: 798. [Epub ahead of print]17(1):
    Westernized diet related arachidonic acid metabolism expands DNA error-prone growth factor-dependent colonic quiescent stem cells in adolescent mice.
    OUTLIVE-CRC consortium
      Given the association between early-onset colorectal cancer (eoCRC) and insulin resistance (IR), we investigated the effects of westernized diet (WD)-induced IR on intestinal stem cells (ISCs) by in-depth phenotyping three adolescent mouse models of escalating WD-driven IR. WD-related hyperlipidaemia and hyperglycaemia enhanced ω6-polyunsaturated fatty acid (PUFA) metabolism, while inhibiting glucose metabolism, resulting in colonic epithelial cell (EC) energy deficiency, hypoproliferation, and quiescent ISCs (qISC) expansion. WD-induced systemic IR provoked colonic EC IR, reduced ω6-PUFA metabolism, which was compensated by aberrated triglyceride metabolism and growth factor receptor signalling, causing hyperproliferation of expanded qISCs. Combined with single-cell transcriptomic data and colonic 3D-organoid analysis we revealed that the ω6-PUFA arachidonic acid inhibited glucose uptake, favouring colonic EC IR driven expansion of the lipid-dependent inherently DNA-mismatch prone qISC compartment in expense of the insulin-dependent LGR5+ ISCs. Overall, our findings may open new alleys for targeted nutritional interventions in eoCRC prevention.
    DOI:  https://doi.org/10.1038/s41419-026-09240-9
  3. Nat Protoc. 2026 Sep 15.
    Quantitative imaging of dynamic processes in intestinal organoids.
    Willem Kasper Spoelstra, Xuan Zheng, Rutger N U Kok, Guizela Huelsz-Prince, Max Betjes, Pascal Ender, Yvonne Goos, Kim A Kuentzelmann, Heidi E Klumpe, Daniel Krueger, Daisong Wang, Hans Clevers, Sander J Tans, Jeroen S van Zon.
      Organoids are powerful models for studying tissue dynamics across multiple cellular generations and offer key insights into organ homeostasis, cellular differentiation and disease. Live imaging of organoids is an essential tool for understanding dynamic processes on the cell level, while still in the tissue context. It allows for simultaneous quantification of gene expression and reconstruction of lineage trees, while tracking cells over space and time. Here, we present protocols for long-term imaging and quantitative analysis of intestinal organoids. Our workflow consists of sample preparation, experimental manipulations (such as drug treatments, laser ablations and fluorescence recovery after photobleaching), long-term live imaging (120 h), in situ fixation and permeabilization, multiplexed antibody staining and single-cell tracking with lineage reconstruction. The workflow is broadly applicable to studying dynamic cellular processes in both 2D and 3D organoids, at timescales from minutes to days. We outline strategies for optimizing organoid health, imaging conditions and experimental interventions to ensure efficient downstream analysis. In addition, we describe how this workflow enables real-time quantification of gene expression using fluorescent reporters and inferring cell type changes by combining multiplexed antibody staining with cell-tracking data. The skills required for following these protocols are organoid culturing and standard live-cell confocal microscopy, and the full experimental protocol takes ~2 weeks. Together, these protocols provide a comprehensive approach for studying cellular behavior, lineage trees, expression dynamics and cell-cell interactions in organoids.
    DOI:  https://doi.org/10.1038/s41596-026-01432-z
  4. Nat Metab. 2026 Sep 15.
    Cysteine excess triggers a mitochondrial iron-dependent cell death.
    Toshitaka Nakamura, Ayaka Inoki, Nupur K Das, Brandon Chen, Artem Khan, Yuyang Liu, Beste Uygur, Frederick S Yen, Gokhan Unlu, Yatrik M Shah, Kıvanç Birsoy.
      Thiol-containing metabolites are central to cellular redox homeostasis1. Among these, cysteine functions as a proteogenic amino acid, supports redox balance and iron-sulfur cluster biogenesis, and, when depleted, triggers ferroptosis2. Cells nevertheless maintain cysteine at low levels, reflecting its intrinsic toxicity, but the mechanisms by which excess cysteine causes cell death remain unclear3. Here we performed a genome-wide CRISPR screen and identified mitochondrial iron transporters as essential mediators of cysteine toxicity. Limiting mitochondrial iron availability suppresses cysteine-induced cell death and prevents impairment of iron-sulfur cluster proteins and respiration. Mechanistically, cysteine mobilizes iron from ferritin, expands the cytosolic iron pool and drives mitochondrial iron accumulation. Enhancing glutathione reductase activity specifically within mitochondria restores redox balance downstream of iron accumulation and protects cells by maintaining iron-sulfur cluster integrity. Our findings suggest that maintaining low cysteine levels safeguards mitochondrial iron homeostasis, and that excess cysteine triggers a distinct mitochondrial iron-dependent cell death under conditions of thiol imbalance.
    DOI:  https://doi.org/10.1038/s42255-026-01616-7
  5. iScience. 2026 Oct 16. 29(10): 117466
    Single-cell gene regulatory networks characterize colonic stem and immune cell homeostasis in Nr4a1 knockout mice.
    Selim Romero, Shreyan Gupta, Michael L Salinas, Destiny A Mullens, Jennifer Goldsby, Yang Y Fan, Laurie A Davidson, Jaileen Rivera-Rodriguez, Gus A Wright, Stephen H Safe, James J Cai, Robert S Chapkin.
      Recent findings suggest that the orphan nuclear receptor 4A (NR4A) can regulate cellular energetics and epithelial defenses, contributing to a resilient, disease-resistant phenotype. To further examine the effects of NR4A on intestinal epithelial, stromal, and immune cell homeostasis, we performed single-cell transcriptomics and differential gene network analysis in wild-type and whole-body Nr4a1 knockout mice. Here we observed a widespread effect of Nr4a1 deletion on intercellular communication involving intestinal stem cells, macrophages, T and B cells, and fibroblasts, indicating a complex and pervasive remodeling of the colonic epithelial and immune microenvironments and their regulatory networks. This alteration in cell-cell crosstalk was associated with an elevated single-cell entropy and colonic crypt-derived organoid growth, indicative of higher differentiation potential and stem-like properties in epithelial cells. Our work demonstrates that Nr4a1 serves as a critical regulatory factor in stem cell and immune homeostasis in the colon.
    Keywords:  differentiation potency; entropy; gene regulatory networks; immune cells; intestine; organoids; stem cells
    DOI:  https://doi.org/10.1016/j.isci.2026.117466
  6. Cell Rep. 2026 Sep 17. pii: S2211-1247(26)01094-6. [Epub ahead of print]45(10): 118016
    PADI-dependent mitochondrial adaptation drives resistance to KRAS inhibitors.
    Mariachiara Gani, Francesca Agostini, Luca Secco, Lavinia De Pino, Raffaella Picco, Danilo Licastro, Vanessa Tolotto, Francesca D'Este, Himanshi Choudhary, Annalisa Ferino, Valentina Rapozzi, Leonard Barasa, Yuhei Ohta, Hidehiko Nakagawa, Riccardo Sgarra, Paul R Thompson, Luigi E Xodo, Eros Di Giorgio.
      KRAS(ON) and KRAS(OFF) inhibitors have improved the treatment of KRAS-driven tumors, yet resistance remains a major challenge. Here, we identify PADI1 and PADI3 as negative prognostic markers in KRAS-mutant colorectal and pancreatic cancers. KRAS-driven metabolic rewiring sustains their expression through an enhancer within the PADI1 locus. Although KRAS inhibition suppresses PADI1/3 expression in sensitive cells, resistant models maintain elevated PADI1/3 expression and accumulate intracellular calcium, sustaining PADI-dependent adaptive survival. Pharmacological inhibition of PADIs synergizes with KRAS(ON) and KRAS(OFF) inhibitors in two- and three-dimensional cancer models, restores sensitivity in resistant cells, and enhances antitumor activity in vivo. Integrated transcriptomic and proteomic analyses identify HSPA9/Mortalin as a critical citrullinated effector. PADI3-mediated citrullination enhances Mortalin ATPase activity and ATP/ADP cycling, whereas loss of citrullination correlates with apoptosis. Disruption of this adaptive circuitry triggers mitochondrial dysfunction, caspase activation, and non-lytic apoptosis without detectable DAMP release, revealing a therapeutic vulnerability of KRAS-driven tumors.
    Keywords:  CP: cancer; KRAS; KRAS(OFF); KRAS(ON); Mortalin; PADI1; PADI3; citrullination; colorectal cancer; pancreatic ductal adenocarcinoma; zoldonrasib
    DOI:  https://doi.org/10.1016/j.celrep.2026.118016
  7. Cell Rep. 2026 Sep 16. pii: S2211-1247(26)01080-6. [Epub ahead of print]45(10): 118002
    Defensive lipid droplets are PUFA reservoirs and suppliers driving bacterial clearance and inflammation.
    Marta Bosch, Gyana-Lipsa Parida, Marina Sánchez-Quijada, Carles Ruiz-Mirapeix, Miguel Sánchez-Álvarez, Laura Pedró-Cos, Alba Fajardo, Harriet P Lo, Mariano Alonso-Bivou, Rémi Safi, Erika Pineda, James Rae, James E B Curson, Bernhard Keller, Jesús Balsinde, Anna M Planas, Matthew J Sweet, Albert Herms, Caroline Demangel, Robert G Parton, Albert Pol.
      Lipid droplets (LDs) rapidly form in infected cells to participate in the defense against microbes. Here, we investigate the involvement of LD lipids in the immune response. Comparative lipidomics demonstrate that in vivo host LDs accumulate polyunsaturated fatty acids (PUFAs) in LD-triglycerides and -phospholipids. Host lipid metabolism and the LD proteome are transcriptionally controlled by rapid, transient, and intricate immune programs initiated by pathogen-associated molecular patterns and relayed by cytokines such as interferons (type I and II), interleukins (IL-1β), and tumor necrosis factor. When this environment is reproduced in cultured macrophages, newly formed LDs accumulate defensive proteins, coordinate complex PUFA synthesis, and become PUFA reservoirs and suppliers. Among LD-PUFAs, the ω-6 arachidonic acid is the most actively metabolized during the initial phases of innate immunity. Released from LDs by adipose triglyceride lipase, arachidonic acid is used by macrophages for prostaglandin and thromboxane synthesis, bacterial phagocytosis, and elimination of microbes.
    Keywords:  CP: metabolism; CP: microbiology; adipose triglyceride lipase; arachidonic acid; inflammation; innate immunity; lipid droplets; polyunsaturated fatty acids
    DOI:  https://doi.org/10.1016/j.celrep.2026.118002
  8. Cancer Lett. 2026 Sep 16. pii: S0304-3835(26)00600-2. [Epub ahead of print]660 218836
    PDX-Atlas: A web-based portal to manage and share data from patient-derived xenograft models of cancer.
    Shivakumar Keerthikumar, Ashlee K Clark, Yuchen Wu, Bennett Anderson, Yijun Da, Lei Qin, Nicholas Choo, Laura H Porter, Jenna Kraska, Melissa Papargiris, Gail P Risbridger, Renea A Taylor, Mitchell G Lawrence, David L Goode.
      
    Keywords:  Bioinformatics; Database; Genomics; Patient-derived xenograft; Transcriptomics
    DOI:  https://doi.org/10.1016/j.canlet.2026.218836
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