bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–11–02
thirteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. FSP1-mediated lipid droplet quality control prevents neutral lipid peroxidation and ferroptosis.
  2. Distinct Molecular Responses of Human Intestinal Organoids to Proton and Photon Radiation.
  3. Fuelling resistance: Lipid metabolic rewiring in cancer response to chemotherapy and radiotherapy.
  4. Obese adipose tissue-derived extracellular vesicles enriched with glycolytic cargo promote colorectal cancer tumorigenesis.
  5. A single-chain derivative of an integrin-activating antibody potentiates organoid growth in Matrigel and collagen hydrogels.
  6. Phenotypic plasticity including drug efflux drives reversible irinotecan resistance in LIM1215 colorectal cancer cells.
  7. Deciphering organotropism reveals therapeutic targets in metastasis.
  8. Intestinal fibroblast heterogeneity: unifying RNA-seq studies and introducing consensus-driven nomenclature.
  9. Acquired high tumor mutational burden and activity of immunotherapy after targeted therapy in microsatellite stable colorectal cancer.
  10. Lysosome heterogeneity and diversity mapped through its distinct cellular functions.
  11. RUNX2 cooperates with SREBP1 to rewire cancer metabolism and promote aggressiveness.
  12. Genomic profiling of high tumor mutational load in microsatellite-stable colorectal cancer uncovers MAPK signaling pathway alterations following anti-EGFR therapy.
  13. The Emerging Role of Peroxisome Proliferator-Activated Receptors in Cancer Stemness.
  1. Nat Cell Biol. 2025 Oct 29.
    FSP1-mediated lipid droplet quality control prevents neutral lipid peroxidation and ferroptosis.
    Mike Lange, Michele Wölk, Vivian Wen Li, Cody E Doubravsky, Joseph M Hendricks, Shunji Kato, Yurika Otoki, Benjamin Styler, Sean L Johnson, Cynthia A Harris, Kiyotaka Nakagawa, Isabel F Snodgrass, Dohee Kim, John W Newman, Maria Fedorova, James A Olzmann.
      Lipid droplets (LDs) are organelles that store and supply lipids, based on cellular needs. Although mechanisms preventing oxidative damage to membrane phospholipids are established, the vulnerability of LD neutral lipids to peroxidation and protective mechanisms are unknown. Here we identify LD-localized ferroptosis suppressor protein 1 (FSP1) as a critical regulator that prevents neutral lipid peroxidation by recycling coenzyme Q10 (CoQ10) to its lipophilic antioxidant form. Lipidomics reveal that FSP1 loss leads to the accumulation of oxidized triacylglycerols and cholesteryl esters, and biochemical reconstitution of FSP1 with CoQ10 and NADH suppresses triacylglycerol peroxidation in vitro. Notably, inducing polyunsaturated fatty acid-rich LDs triggers triacylglycerol peroxidation and LD-initiated ferroptosis when FSP1 activity is impaired. These findings uncover the first LD lipid quality-control pathway, wherein LD-localized FSP1 maintains neutral lipid integrity to prevent the build-up of oxidized lipids and induction of ferroptosis.
    DOI:  https://doi.org/10.1038/s41556-025-01790-y
  2. Am J Physiol Gastrointest Liver Physiol. 2025 Oct 30.
    Distinct Molecular Responses of Human Intestinal Organoids to Proton and Photon Radiation.
    Victoria Poplaski, Tajhal D Patel, Hoa Nguyen-Phuc, Amal Kambal, Lawrence Bronk, Mary K Estes, Cristian Coarfa, Sarah E Blutt.
      Radiation exposure impairs rapidly renewing tissues like the intestinal epithelium, yet translational insights from murine models have been limited by species-specific responses. Here, we use human intestinal organoids (HIOs) derived from jejunal epithelium to evaluate human epithelial responses to low dose proton and photon (gamma) radiation. Gamma irradiation induces a unique developmental and metabolic shift in crypt-like organoids, including enrichment of amino acid metabolism pathways and activation of fetal-associated transcription factors and morphology. Integrated multi-omic profiling reveals serotonin biosynthesis as a central regenerative node. Human intestinal organoids can complement animal models and are emerging as a powerful tool in modeling human radiation responses and identifying candidate biomarkers for intestinal injury.
    Keywords:  intestine; organoid; radiation; stem cell reversion
    DOI:  https://doi.org/10.1152/ajpgi.00186.2025
  3. Biomed Pharmacother. 2025 Oct 30. pii: S0753-3322(25)00909-6. [Epub ahead of print]193 118715
    Fuelling resistance: Lipid metabolic rewiring in cancer response to chemotherapy and radiotherapy.
    Viktoria Piatrikova, Eva Kocianova, Lucia Skvarkova, Tereza Golias.
      Resistance to chemotherapy and radiotherapy remains a major challenge in cancer treatment and is closely linked to treatment failure and poor patient outcome. While metabolic rewiring is a well-established hallmark of cancer, the specific role of lipid metabolism in promoting therapy resistance has only recently gained attention. Cancer cells modulate lipid metabolic pathways to support survival, maintain redox balance, enable membrane remodelling, enhance DNA repair, and evade cell death under therapeutic stress. They do so by altering fatty acid synthesis, fatty acid oxidation, and lipid storage, ultimately contributing to resistance to genotoxic therapies. These adaptations also intersect with non-apoptotic cell death pathways such as ferroptosis and cuproptosis, and are regulated in part by post-translational modifications including acetylation and lipidation. Moreover, chemotherapy and radiotherapy can further promote metabolic adaptations that increase lipid dependence and reinforce resistant phenotypes. Recognizing these metabolic dependencies has revealed potential molecular targets within lipid metabolism, offering new opportunities to overcome resistance by co-targeting metabolic plasticity alongside standard therapies. Therapeutic strategies that disrupt lipid-driven adaptations may therefore help re-sensitise resistant tumours, enhance therapeutic efficacy, and expand treatment options.
    Keywords:  Cuproptosis; Fatty acids; Ferroptosis; Lipid droplets; Lipid metabolism; Lipidation; Therapy resistance
    DOI:  https://doi.org/10.1016/j.biopha.2025.118715
  4. Cancer Lett. 2025 Oct 28. pii: S0304-3835(25)00676-7. [Epub ahead of print] 218104
    Obese adipose tissue-derived extracellular vesicles enriched with glycolytic cargo promote colorectal cancer tumorigenesis.
    Parsa S Haque, Shere L Paris, Rhonda F Souza, Joseph C Onyiah, Christina Coughlan, David J Orlicky, Janos Zempleni, Arianne L Theiss.
      Obesity increases the risk of colorectal cancer (CRC) development, accelerates disease progression and is associated with decreased disease-free survival. Obesity adversely affects the visceral adipose tissue (VAT) leading to increased secretion of extracellular vesicles (EVs). However, the crosstalk between VAT and CRC tumor cells still remains unclear. EVs are lipid-membraned particles that transfer cargo to and/or induce signaling in other cells. Here, we characterized human VAT-derived non-obese (N-OB) and obese (OB) EVs and investigated the functional interaction between CRC cells and VAT-derived EVs. EVs were isolated from VAT obtained from obese (BMI>30) and non-obese patients (BMI<30). Unbiased proteomics revealed that compared to N-OB EVs, OB EVs were enriched with glycolytic enzymes like triose phosphate isomerase (TPI1). This enrichment was associated with increased TPI1 protein levels in CRC cells and elevated glycolytic activity. OB EV-treated cells also exhibited increased stemness-associated genes, 3D-spheroid formation and Apcmin/+ tumoroid self-renewal capacity. In vivo, mice with an adipocyte-specific knockout of EV cargo sorting protein, Tsg101 (Tsg101ΔAd), have altered EV cargo composition with reduced glycolytic enzyme levels. Functionally, Tsg101ΔAd-EVs were able to protect against high-fat diet (HFD)-induced increase in glycolysis and stem-like ability. Moreover, Apcmin/+:Tsg101ΔAd mice were protected against HFD-induced enhanced tumorigenesis. Collectively, this study identifies adipocyte EVs, and its metabolic cargo, as an important regulator of CRC cell metabolism and function, promoting intestinal tumorigenesis.
    Keywords:  CRC; EV; Tsg101; glycolysis; obesity; stem
    DOI:  https://doi.org/10.1016/j.canlet.2025.218104
  5. Nat Biotechnol. 2025 Oct 28.
    A single-chain derivative of an integrin-activating antibody potentiates organoid growth in Matrigel and collagen hydrogels.
    Wim B M de Lau, Joost J A P M Wijnakker, Gijs J F van Son, Daniel Krueger, Daisong Wang, Matthijs S Abendroth, Robin Schreurs, Claudia Y Janda, Fenna L H van Rijt, Benjamin J P Chalopin, Emma Bokobza, Johan H van Es, Timothy A Springer, Arnoud Sonnenberg, Hans Clevers.
      Current methods of culturing human epithelial organoids from adult stem cells may not be compatible with clinical applications as they rely on xenogeneic, chemically undefined or non-standardized components such as the basement membrane extract Matrigel. Matrigel provides a source of extracellular matrix molecules, including laminins and collagen IV, which interact with β1 integrins expressed on organoid cells. Here we describe a single-chain (sc) version of antibody TS2/16 that allosterically activates integrin β1 function in organoids. The addition of monomeric scTS2/16 to organoid medium results in up to a fivefold increase in the yield of all gastrointestinal organoids grown in Matrigel. Moreover, scTS2/16 supports a six- to sevenfold increase in the yield of these organoids when cultured in collagen I hydrogels, both in 3D and 2D. Collagen I is well defined, available in clinical-grade formulations and, when combined with scTS2/16, may support the clinical application of epithelial organoids derived from gastrointestinal tissues and other epithelial sources.
    DOI:  https://doi.org/10.1038/s41587-025-02874-8
  6. FEBS Lett. 2025 Oct 28.
    Phenotypic plasticity including drug efflux drives reversible irinotecan resistance in LIM1215 colorectal cancer cells.
    Tugce Dilber, Gizem Damla Yalcin, Kubra Celikbas Yilmaz, Ahmet Acar.
      Colorectal cancer (CRC) presents significant therapeutic challenges, particularly due to the development of resistance to standard chemotherapeutic agents such as irinotecan. In this study, we aimed to investigate the molecular and phenotypic mechanisms underlying irinotecan resistance in CRC using the LIM1215 cell line model. Transcriptomic analysis demonstrated that drug withdrawal induced major transcriptional reprogramming, characterized by downregulation of ABC transporters (ABCB1 and ABCG2), extracellular matrix-related genes, and markers of epithelial-to-mesenchymal transition (EMT), alongside reactivation of cell cycle pathways. Drug screening further indicated that resistant cells maintained under irinotecan pressure exhibited a multidrug-resistant phenotype, while withdrawn cells regained sensitivity, particularly to tyrosine kinase inhibitors. Supplementation with the efflux inhibitor Elacridar partially restored drug sensitivity in resistant cells, emphasizing the role of transporter-mediated efflux in maintaining resistance.
    Keywords:  ABC transporters; colorectal cancer; irinotecan resistance; phenotypic plasticity
    DOI:  https://doi.org/10.1002/1873-3468.70208
  7. Front Cell Dev Biol. 2025 ;13 1677481
    Deciphering organotropism reveals therapeutic targets in metastasis.
    Jhommara Bautista, Andrés López-Cortés.
      Metastasis remains the principal cause of cancer-related mortality, yet its distribution across organs is far from random. Instead, tumor cells exhibit organotropism, a consistent preference for colonizing specific distant tissues, a phenomenon shaped by anatomical constraints, molecular crosstalk, and microenvironmental compatibility. Far beyond mere mechanical entrapment in vascular beds, metastatic dissemination reflects a coordinated interplay between tumor-intrinsic programs and organ-specific niches. Tumor-derived extracellular vesicles, cytokines, and matrix-remodeling enzymes actively precondition distant sites through pre-metastatic niche formation, creating permissive microenvironments primed for colonization. Simultaneously, tissue-specific immune landscapes, stromal compositions, and mechanical architectures determine the fate of disseminated tumor cells, whether they are eliminated, enter dormancy, or form macrometastases. Phenotypic plasticity, metabolic reprogramming, and immune evasion mechanisms equip subclones with the capacity to exploit these unique niches. Across cancer types, reproducible patterns of organotropic metastasis not only guide clinical surveillance and therapeutic stratification but also reveal vulnerabilities in the metastatic cascade. This review synthesizes emerging mechanistic insights across anatomical, immunological, and molecular domains to construct a comprehensive framework of organotropism, highlighting therapeutic opportunities to intercept metastasis at organ-specific checkpoints.
    Keywords:  immune evasion; metabolic reprogramming; metastasis; organotropism; phenotypic plasticity; pre-metastatic niche
    DOI:  https://doi.org/10.3389/fcell.2025.1677481
  8. J Cell Sci. 2025 Oct 31. pii: jcs.264147. [Epub ahead of print]
    Intestinal fibroblast heterogeneity: unifying RNA-seq studies and introducing consensus-driven nomenclature.
    Neda Glisovic, Aleksandra Chikina, Noémie Robil, Sonia Lameiras, Reda Bouras, Danijela Matic Vignjevic.
      In the colon, the single-layered epithelium forms crypts that extend into the mucosa and are surrounded by a fibroblast network essential for extracellular matrix (ECM) production, remodeling, and epithelial support. Fibroblasts are heterogeneous, but inconsistent nomenclature and lack of markers have hindered their classification. Using single-cell RNA sequencing (scRNA-seq), we identified six distinct fibroblast subpopulations in mouse colonic mucosa, each with unique molecular profiles and specialized functions. Some fibroblasts focus on ECM production and remodeling, while others show high contractility. Certain subsets secrete cytokines promoting epithelial differentiation or maintaining the stem cell niche. Spatial mapping revealed their organization within the mucosa, and trajectory analysis suggested distinct differentiation pathways. Cell cycle scoring confirmed that fibroblasts remain largely non-proliferative under homeostasis. By integrating our dataset with published ones, we identified conserved fibroblast populations and propose a standardized nomenclature for intestinal fibroblasts. This framework enhances communication and understanding of fibroblast diversity and their roles in gut homeostasis and disease.
    Keywords:  Colon; Fibroblasts; Homeostasis
    DOI:  https://doi.org/10.1242/jcs.264147
  9. Clin Cancer Res. 2025 Oct 30.
    Acquired high tumor mutational burden and activity of immunotherapy after targeted therapy in microsatellite stable colorectal cancer.
    Celine Yeh, Oliver Artz, Haochen Zhang, Elias-Ramzey Karnoub, Peter Ntiamoah, Caroline Weipert, Henry Walch, Emily Harrold, Fergus Keane, Sree Chalasani, Neil H Segal, Michael B Foote, Andrea Cercek, Andrew Pagano, Steven B Maron, Luis A Diaz, Christine A Iacobuzio-Donahue, Jinru Shia, Benoit Rousseau, Rona Yaeger.
       PURPOSE: Microsatellite stable (MSS) colorectal cancers (CRCs), in contrast to microsatellite instability-high (MSI-H) CRCs, have few mutations and are insensitive to immune checkpoint blockade (ICB). CRCs treated with targeted agents often acquire a high number of genomic alterations at progression. We asked if targeted therapy could be used to generate a high tumor mutational burden (TMB) in MSS CRC and sensitize these tumors to ICB.
    PATIENTS AND METHODS: In patients with MSS metastatic CRC treated with targeted therapy, we evaluated baseline and progression TMB and response to ICB for patients whose tumors developed high TMB. We determined types of alterations, mutational signatures, neoantigenicity, and clonality associated with emergent genomic alterations in cases of acquired high TMB.
    RESULTS: Among 26 cases, nine acquired high TMB at progression. Three of these patients received ICB but none had a response. In the TMB-high cases, we found no induction of tumor-infiltrating lymphocytes or programmed death-ligand 1 expression. Acquired genomic alterations consisted predominantly of single nucleotide variants, were enriched for single-base substitution 17a/b mutational signature, and did not enhance predicted major histocompatibility complex class I binding. TMB was higher in plasma, driven by highly subclonal acquired alterations, compared to tissue samples which harbored few resistance alterations.
    CONCLUSION: A substantial number of MSS CRCs acquire high TMB following targeted therapy. However, this change is not associated with sensitization to ICB. The high TMB is due to subclonal alterations unique to individual disease sites that are inadequate to elicit a robust antitumor immune response.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-2566
  10. Cell Mol Life Sci. 2025 Oct 30. 82(1): 380
    Lysosome heterogeneity and diversity mapped through its distinct cellular functions.
    Indira Chavan, Arindam Bhattacharjee.
      Lysosomes respond to cellular nutrient availability and diverse oncoming vesicle traffic such as endocytosis and autophagy by switching between anabolic signaling or catabolic hydrolase activity, which coincides with a drastic shift in their cellular distribution, organelle contacts, ion homeostasis, membrane proteome and lipidome. Emerging evidence now reveals a dynamic remodeling of lysosomal membrane to counter membrane damage, acting via extensive lipid transfer from the endoplasmic reticulum or by localized membrane repair. Functionally, lysosomes play a key role in lipid metabolism and intracellular calcium signaling. Unsurprisingly, disease-associated lysosomes are either often hyperactive- thus promoting abnormal tissue growth, or hypoactive, promoting storage. Taken together, this presents an incredible functional diversity among the cellular population of lysosomes. Here, we discuss this intracellular heterogeneity and intercellular diversity in context of lysosomal function in health and disease.
    Keywords:  Lipid storage disorders; Lysosome plasticity; Lysosome quality control; Lysosome subpopulations; Phosphoinositides
    DOI:  https://doi.org/10.1007/s00018-025-05883-7
  11. J Exp Clin Cancer Res. 2025 Oct 31. 44(1): 298
    RUNX2 cooperates with SREBP1 to rewire cancer metabolism and promote aggressiveness.
    Emanuele Vitale, Mila Gugnoni, Veronica Manicardi, Silvia Muccioli, Federica Torricelli, Benedetta Donati, Simonetta Piana, Gloria Manzotti, Elisa Salviato, Francesca Reggiani, Cristian Ascione, Rebecca Vezzani, Moira Ragazzi, Mattia Forcato, Oriana Romano, Silvio Bicciato, Aaron R Goldman, Marco Tigano, Alessia Ciarrocchi.
      Embryonic Transcription Factors (TFs) are often reactivated in cancer, driving developmental gene programs that support phenotypic plasticity. Metabolic adaptation fuels this plasticity by supplying energy and molecular building blocks for growth. RUNX2, the master regulator of bone morphogenesis, is ectopically expressed in epithelial cancer, promoting metastasis through trans-differentiation processes like Epithelial-to-Mesenchymal Transition (EMT) and osteomimicry. By combining omics data with functional validation, we demonstrated that RUNX2 drives cancer cell metabolic rewiring by repressing mitochondrial respiration while promoting anabolic processes. We showed that RUNX2 upregulates key genes of lipid biosynthesis by regulating and cooperating with SREBP1. In vivo expression analysis in thyroid and breast cancer patients confirmed that lipid metabolism and SREBF1 expression are associated with increased metastatic potential and clinical aggressiveness. These findings emphasize the RUNX2 role in cancer plasticity and indicate metabolic adaptation as an integral part of the trans-differentiation program induced by this TF during cancer progression.
    Keywords:  Cancer cell metabolic rewiring; Embryonic transcription factors; Lipid biosynthesis; Oncogenic gene expression programs
    DOI:  https://doi.org/10.1186/s13046-025-03549-7
  12. ESMO Open. 2025 Oct 28. pii: S2059-7029(25)01746-6. [Epub ahead of print]10(11): 105877
    Genomic profiling of high tumor mutational load in microsatellite-stable colorectal cancer uncovers MAPK signaling pathway alterations following anti-EGFR therapy.
    L Boscolo Bielo, S Napolitano, A Avallone, F Pietrantonio, R Bordonaro, E Maiello, S Pisconti, E Tamburini, C Lotesoriere, G Tortora, A Zaniboni, L Blasi, L Antonuzzo, R Berardi, P Tagliaferri, C Cremolini, S Lonardi, C Garufi, C Pinto, E Ongaro, G Santabarbara, M Scartozzi, V De Falco, A De Stefano, C Cardone, A Iacovucci, M F Bosco, A E Russo, T P Latiano, C Nisi, M Messina, N Salmistraro, A Sartore-Bianchi, S Siena, M G Zampino, N Fazio, N Normanno, A Febbraro, L P Guerrera, P Parente, F De Vita, E Martinelli, T Troiani, G Curigliano, F Ciardiello, G Martini, D Ciardiello.
       BACKGROUND: Translational studies have provided evidence that targeted therapies and chemotherapy might induce a status of adaptive mutability with an increase in the tumor mutational load.
    PATIENTS AND METHODS: We conducted an analysis of pathogenic variants (PVs) detected by liquid biopsy (LBx)-based comprehensive genomic profiling in patients with chemo-refractory microsatellite-stable metastatic colorectal cancer (mCRC) pretreated with anti-epidermal growth factor receptor (EGFR) within the VELO and CAVE-2 GOIM studies compared with anti-EGFR naïve mCRC included in the CAPRI-2 GOIM trial.
    RESULTS: Overall, 559 patients with available samples for LBx analysis were included. EGFR pretreated tumors had significant enrichment for PVs in the MAPK signaling pathway with a median tumor mutational burden (TMB) [6 interquartile range (IQR 4-11) versus 4 (IQR 3-9), P < 0.0001]; 33.8% pretreated patients had TMB with ≥10 mutations per megabase compared with 9.7% patients before first-line anti-EGFR treatment. Higher mutational load correlated with KRAS (q = 0.07), BRAFV600 (q = 0.01), ERBB2 AMP (q = 0.06) and EGFR ECD (q = 0.07) PVs. Such association was not observed in patients naïve to anti-EGFR drugs. MAPK mutations were associated with higher TMB in anti-EGFR pretreated samples (beta = 4.0, P < 0.0001), but not in anti-EGFR-naïve samples (beta 1.2, P = 0.4).
    CONCLUSION: These findings might support the investigation of immunotherapy in patients with mCRC pretreated with EGFR inhibitors with high mutational load.
    Keywords:  MAPK; TMB; anti-EGFR; comprehensive genomic profiling; liquid biopsy
    DOI:  https://doi.org/10.1016/j.esmoop.2025.105877
  13. Cells. 2025 Oct 16. pii: 1610. [Epub ahead of print]14(20):
    The Emerging Role of Peroxisome Proliferator-Activated Receptors in Cancer Stemness.
    Beatriz Parejo-Alonso, Marta Mascaraque, Alba Royo-García, Patricia Sancho.
      The peroxisome proliferator-activated receptors (PPAR-α, PPAR-δ, and PPAR-γ) are transcription factors that belong to the nuclear hormone receptor superfamily. Upon activation by specific lipids, they regulate gene expression by directly binding to PPAR response elements (PPREs) in the DNA. Although the functions of the different PPARs are specific to the isoform, tissue, and context, all three PPARs are generally involved in energy homeostasis through lipid sensing in physiological conditions. Importantly, there is increasing evidence linking PPARs with malignant behavior in cancer, regulating features frequently attributed to the aggressive subpopulation of cancer stem cells (CSCs): self-renewal, tumor initiation, chemoresistance, metastasis, and immune evasion. However, contradictory effects have been described for each isoform in various cancer types, and their implication in these malignant features may not consistently follow a pro- or anti-tumoral pattern. In this review, we revise the current knowledge on the role of the PPAR family members in cancer, with a special focus on cancer stemness, and discuss the potential for PPARs as therapeutic targets in CSC-driven relapse and resistance.
    Keywords:  PPARs; cancer stem cells; chemoresistance; immune evasion; metastasis; self-renewal
    DOI:  https://doi.org/10.3390/cells14201610
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