bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–05–11
thirteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Stemness in flux: Dissecting intestinal crypt organization with multimodal approaches.
  2. Clonal dispersal is associated with tumor heterogeneity and poor prognosis in colorectal cancer.
  3. EGFR controls transcriptional and metabolic rewiring in KRASG12D colorectal cancer.
  4. Extrusion of BMP2+ surface colonocytes promotes stromal remodeling and tissue regeneration.
  5. Ligand-activated EGFR/MAPK signaling but not PI3K, are key resistance mechanisms to EGFR-therapy in colorectal cancer.
  6. Activation of lysosomal iron triggers ferroptosis in cancer.
  7. Inhibition of Glutathione Pathway by Oleanolic Acid via PSAT1 Leads to Ferroptosis in Colorectal Cancer.
  8. Colorectal Cancer Cells-Derived Exosomal PIK3CA Mutation DNA Promotes Tumor Metastasis by Activating Fibroblast and Affecting Tumor Metastatic Microenvironment.
  9. Modular regulation of the stem cell transcriptome defines self-renewal, differentiation, and dedifferentiation.
  10. Molecular basis of cell fate plasticity - insights from the privileged cells.
  11. Lipid-degrading small molecule kills cancer cells by ferroptosis.
  12. Cellular metabolomics study in colorectal cancer cells and media following treatment with 5-fluorouracil by gas chromatography-tandem mass spectrometry.
  13. The Curated Cancer Cell Atlas provides a comprehensive characterization of tumors at single-cell resolution.
  1. Dev Cell. 2025 May 05. pii: S1534-5807(25)00205-9. [Epub ahead of print]60(9): 1275-1276
    Stemness in flux: Dissecting intestinal crypt organization with multimodal approaches.
    Maria Azkanaz, Dimitrios Laskaris, Jacco van Rheenen.
      In this issue of Developmental Cell, Banjac et al. integrate lineage tracing, single-cell RNA sequencing, and mathematical modeling to reveal that stem cells at the crypt base drive the decision between secretory and absorptive lineage commitment. Their findings highlight the central role of crypt-bottom Lgr5+ cells in maintaining intestinal epithelium homeostasis.
    DOI:  https://doi.org/10.1016/j.devcel.2025.04.003
  2. iScience. 2025 May 16. 28(5): 112403
    Clonal dispersal is associated with tumor heterogeneity and poor prognosis in colorectal cancer.
    Selami Baglamis, Vivek M Sheraton, Sanne M van Neerven, Adrian Logiantara, Lisanne E Nijman, Laura A Hageman, Nicolas Léveillé, Clara C Elbers, Maarten F Bijlsma, Louis Vermeulen, Przemek M Krawczyk, Kristiaan J Lenos.
      Clonal dispersal, resulting from the intermingling of tumor cell subpopulations, is thought to be a key driver of tumor heterogeneity. Despite advances in spatial modeling of cancer biology, quantification of clonal dispersal has been challenging. This study introduces a straightforward method, relying on fluorescent cell barcoding, to quantify clonal dispersal in various in vitro and in vivo models of colorectal cancer (CRC). Our approach allows for precise localization of clones and uncovering the degree of clonal mixing across different CRC models. Our findings suggest that clonal dispersal is correlated with the expression of genes involved in epithelial-mesenchymal transition and CMS4-related signaling pathways. We further identify a dispersal gene signature, associated with intratumor heterogeneity, which is a robust clinical predictor of poor prognosis and recurrence in CRC, highlighting its potential as a prognostic marker and a putative direction for therapeutic targeting.
    Keywords:  Bioinformatics; Cancer; Cell biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112403
  3. EMBO Mol Med. 2025 May 06.
    EGFR controls transcriptional and metabolic rewiring in KRASG12D colorectal cancer.
    Dana Krauß, Veronica Moreno-Viedma, Emi Adachi-Fernandez, Cristiano de Sá Fernandes, Jakob-Wendelin Genger, Ourania Fari, Bernadette Blauensteiner, Dominik Kirchhofer, Nikolina Bradaric, Valeriya Gushchina, Georgios Fotakis, Thomas Mohr, Ifat Abramovich, Inbal Mor, Martin Holcmann, Andreas Bergthaler, Arvand Haschemi, Zlatko Trajanoski, Juliane Winkler, Eyal Gottlieb, Maria Sibilia.
      Inhibition of the epidermal growth factor receptor (EGFR) shows clinical benefit in metastatic colorectal cancer (CRC) patients, but KRAS-mutations are known to confer resistance. However, recent reports highlight EGFR as a crucial target to be co-inhibited with RAS inhibitors for effective treatment of KRAS mutant CRC. Here, we investigated the tumor cell-intrinsic contribution of EGFR in KRASG12D tumors by establishing murine CRC organoids with key CRC mutations (KRAS, APC, TP53) and inducible EGFR deletion. Metabolomic, transcriptomic, and scRNA-analyses revealed that EGFR deletion in KRAS-mutant organoids reduced their phenotypic heterogeneity and activated a distinct cancer-stem-cell/WNT signature associated with reduced cell size and downregulation of major signaling cascades like MAPK, PI3K, and ErbB. This was accompanied by metabolic rewiring with a decrease in glycolytic routing and increased anaplerotic glutaminolysis. Mechanistically, following EGFR loss, Smoc2 was identified as a key upregulated target mediating these phenotypes that could be rescued upon additional Smoc2 deletion. Validation in patient-datasets revealed that the identified signature is associated with better overall survival of RAS mutant CRC patients possibly allowing to predict therapy responses in patients.
    Keywords:  CRC-organoids; EGFR; KRAS; Metabolism; Stemness-WNT
    DOI:  https://doi.org/10.1038/s44321-025-00240-4
  4. Nat Commun. 2025 May 03. 16(1): 4131
    Extrusion of BMP2+ surface colonocytes promotes stromal remodeling and tissue regeneration.
    Julian Heuberger, Lichao Liu, Hilmar Berger, Joop van den Heuvel, Manqiang Lin, Stefanie Müllerke, Safak Bayram, Giulia Beccaceci, Hugo de Jonge, Ermanno Gherardi, Michael Sigal.
      The colon epithelium frequently incurs damage through toxic influences. Repair is rapid, mediated by cellular plasticity and acquisition of the highly proliferative regenerative state. However, the mechanisms that promote the regenerative state are not well understood. Here, we reveal that upon injury and subsequent inflammatory response, IFN-γ drives widespread epithelial remodeling. IFN-γ promotes rapid apoptotic extrusion of fully differentiated surface colonocytes, while simultaneously causing differentiation of crypt-base stem and progenitor cells towards a colonocyte-like lineage. However, unlike homeostatic colonocytes, these IFN-γ-induced colonocytes neither respond to nor produce BMP-2 but retain regenerative capacity. The reduction of BMP-2-producing epithelial surface cells causes a remodeling of the surrounding mesenchymal niche, inducing high expression of HGF, which promotes proliferation of the IFN-γ-induced colonocytes. This mechanism of lineage replacement and subsequent remodeling of the mesenchymal niche enables tissue-wide adaptation to injury and efficient repair.
    DOI:  https://doi.org/10.1038/s41467-025-59474-y
  5. Nat Commun. 2025 May 09. 16(1): 4332
    Ligand-activated EGFR/MAPK signaling but not PI3K, are key resistance mechanisms to EGFR-therapy in colorectal cancer.
    Xueping Qu, Habib Hamidi, Radia M Johnson, Ethan S Sokol, Eva Lin, Cathy Eng, Tae Won Kim, Johanna Bendell, Smruthy Sivakumar, Benjamin Kaplan, Felipe de Sousa E Melo, Andrew Mancini, Matthew Wongchenko, Yi Shi, David Shames, Yibing Yan, Fortunato Ciardiello, Carlos Bais.
      Understanding mechanisms of resistance to active therapies is crucial for developing more effective treatments. Here, we investigate resistance to anti-EGFR and anti-VEGF plus chemotherapy treatment in colorectal cancer (CRC) patients from the IMblaze370 trial (NCT02788279). While anti-VEGF does not select for secondary mutations, anti-EGFR leads to simultaneous mutations in EGFR and MAPK, but not PI3K pathway genes. Notably, we observe frequent acquired mutations in the EGFR extracellular but not intracellular domain and that patients with higher baseline expression of EGFR-ligands are prone to acquire resistant mutations. This data reveals a ligand-activated EGFR/MAPK-signaling dependency in CRC. We also observe enrichment for 8q gains in anti-EGFR treated patients, potentially linked to MYC amplification, a finding further supported by baseline expression analysis. This work adds to the evidence supporting broader evaluation of EGFR and pan-KRAS inhibitor combinations in CRC patients. It also underscores the utility of EGFR ligands as anti-EGFR efficacy biomarkers and provides a rationale for developing ligand blockers to complement and/or improve conventional anti-EGFR therapies in CRC.
    DOI:  https://doi.org/10.1038/s41467-025-59588-3
  6. Nature. 2025 May 07.
    Activation of lysosomal iron triggers ferroptosis in cancer.
    Tatiana Cañeque, Leeroy Baron, Sebastian Müller, Alanis Carmona, Ludovic Colombeau, Antoine Versini, Stéphanie Solier, Christine Gaillet, Fabien Sindikubwabo, Julio L Sampaio, Marie Sabatier, Eikan Mishima, Armel Picard-Bernes, Laurène Syx, Nicolas Servant, Bérangère Lombard, Damarys Loew, Jiashuo Zheng, Bettina Proneth, Leishemba K Thoidingjam, Laurence Grimaud, Cameron S Fraser, Krystina J Szylo, Emma Der Kazarian, Caroline Bonnet, Emmanuelle Charafe-Jauffret, Christophe Ginestier, Patricia Santofimia-Castaño, Matias Estaras, Nelson Dusetti, Juan Lucio Iovanna, Antonio Sa Cunha, Gabriella Pittau, Pascal Hammel, Dimitri Tzanis, Sylvie Bonvalot, Sarah Watson, Vincent Gandon, Aditya Upadhyay, Derek A Pratt, Florêncio Porto Freitas, José Pedro Friedmann Angeli, Brent R Stockwell, Marcus Conrad, Jessalyn M Ubellacker, Raphaël Rodriguez.
      Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death called ferroptosis1. Defining where this chemistry occurs in the cell can inform the design of drugs capable of inducing or inhibiting ferroptosis in various disease-relevant settings. Genetic approaches have revealed suppressors of ferroptosis2-4; by contrast, small molecules can provide spatiotemporal control of the chemistry at work5. Here we show that the ferroptosis inhibitor liproxstatin-1 exerts cytoprotective effects by inactivating iron in lysosomes. We also show that the ferroptosis inducer RSL3 initiates membrane lipid oxidation in lysosomes. We designed a small-molecule activator of lysosomal iron-fentomycin-1-to induce the oxidative degradation of phospholipids and ultimately ferroptosis. Fentomycin-1 is able to kill iron-rich CD44high primary sarcoma and pancreatic ductal adenocarcinoma cells, which can promote metastasis and fuel drug tolerance. In such cells, iron regulates cell adaptation6,7 while conferring vulnerability to ferroptosis8,9. Sarcoma cells exposed to sublethal doses of fentomycin-1 acquire a ferroptosis-resistant cell state characterized by the downregulation of mesenchymal markers and the activation of a membrane-damage response. This phospholipid degrader can eradicate drug-tolerant persister cancer cells in vitro and reduces intranodal tumour growth in a mouse model of breast cancer metastasis. Together, these results show that control of iron reactivity confers therapeutic benefits, establish lysosomal iron as a druggable target and highlight the value of targeting cell states10.
    DOI:  https://doi.org/10.1038/s41586-025-08974-4
  7. Drug Dev Res. 2025 May;86(3): e70097
    Inhibition of Glutathione Pathway by Oleanolic Acid via PSAT1 Leads to Ferroptosis in Colorectal Cancer.
    Qing Sun, Ruolin Sun, Bokun He, Hongjie Meng, Jie Jin, Juhui He.
      Phosphoserine aminotransferase 1 (PSAT1), a pivotal regulator of serine metabolism, is overexpressed in a variety of cancers, yet its role in colorectal cancer (CRC) remains to be elucidated. Oleanolic acid (OA), a naturally occurring pentacyclic triterpenoid, is suspected to have the potential to regulate ferroptosis, though this capability has not been confirmed. Utilizing bioinformatics tools, we conducted an analysis of PSAT1 expression in CRC, pathway enrichment, and its correlation with proteins pivotal to glutathione metabolism and the induction of ferroptosis. Expression levels of PSAT1 were validated by Quantitative Polymerase Chain Reaction (qPCR) and western blot analysis (WB). Cell Counting Kit-8 (CCK-8) was employed to measure the viability of CRC cells. Ferroptosis was assessed via flow cytometry, Fe2+ detection, malondialdehyde (MDA) levels, and WB. The metabolic pathway of glutathione was examined by analyzing the levels of reduced glutathione (GSH) and glutathione disulfide (GSSG), glutamate, glutamine, and α-ketoglutarate, and by assessing the expression of rate-limiting enzymes in glutamine metabolism. The interaction between OA and PSAT1 was predicted by molecular docking and validated with the cellular thermal shift assay (CETSA) -WB assay. The results showed that PSAT1 was found to be highly expressed in CRC and enriched in pathways associated with ferroptosis and glutathione metabolism, instrumental in preserving the vitality of CRC cells. PSAT1 knockdown increased cellular lipid reactive oxygen species (ROS) and MDA, and ferrous ion accumulation, while also inhibiting the expression of ferroptosis markers Solute carrier family 7, membrane 11 (SLC7A11) and Glutathione peroxidase 4 (GPX4). Overexpression of PSAT1 raised the levels of glutathione metabolic intermediates and the GSH ratio, inhibiting ferroptosis, and these effects were reversed by methionine sulfoximine. OA was identified through molecular docking and CETSA-WB to effectively dock with PSAT1 and target it to inhibit glutathione metabolism, enhancing lipid peroxidation and Fe2+ accumulation in CRC cells. In conclusion, OA, upon binding to PSAT1, curbs its expression, which in turn downregulates glutathione metabolism and enhances ferroptosis in CRC cells.
    Keywords:  PSAT1; colorectal cancer; ferroptosis; glutathione metabolism; oleanolic acid
    DOI:  https://doi.org/10.1002/ddr.70097
  8. Adv Sci (Weinh). 2025 May 08. e2501792
    Colorectal Cancer Cells-Derived Exosomal PIK3CA Mutation DNA Promotes Tumor Metastasis by Activating Fibroblast and Affecting Tumor Metastatic Microenvironment.
    Rui Wang, Wanming Li, Yuqiong Lv, Wei Ba, Ying Jiang, Xiaoshuai Li, Jin Fang.
      Exosomes participate in the formation of the tumor metastatic microenvironment (TME) by delivering tumor-specific substances. However, current studies mostly focus on exosomal RNA and proteins and lack an in-depth exploration of exosomal DNA. It is discovered that PIK3CAH1047R mutant DNA in colorectal cancer (CRC) cell-derived exosomes can be delivered into recipient fibroblasts, where they are transcribed and translated, ultimately leading to the activation of fibroblasts into cancer-associated fibroblasts (CAFs) through interaction with the endogenous P85 regulatory subunit of the phosphatidylinositol 3-kinase (PI3K) pathway. CAFs have facilitated tumor cell migration in vitro and promote lung metastasis in vivo by secreting elevated levels of IL6. Additionally, the PIK3CAH1047R mutation is detected in CAFs at both the primary and metastatic sites, suggesting that it may play a role in promoting metastasis by influencing the TME. Moreover, patients with CRC harboring the PIK3CAH1047R mutation and exhibiting elevated levels of IL6 are significantly more likely to metastasize. These findings suggest that the simultaneous detection of serum-derived exosomal PIK3CAH1047R mutation and serum IL6 secretion may serve as a promising diagnostic and prognostic tool for CRC and simultaneous targeting of PIK3CAH1047R mutation and IL6 may serve as a novel approach for the treatment of CRC.
    Keywords:  cancer‐associated fibroblasts; colorectal cancer; exosomal PIK3CAH1047R mutation DNA; peritumoral microenvironment; tumor metastatic microenvironment
    DOI:  https://doi.org/10.1002/advs.202501792
  9. bioRxiv. 2025 Apr 14. pii: 2025.04.10.648217. [Epub ahead of print]
    Modular regulation of the stem cell transcriptome defines self-renewal, differentiation, and dedifferentiation.
    Amelie A Raz, Hafidh Hassan, Yukiko M Yamashita.
      Adult stem cells maintain tissue homeostasis by balancing self-renewal and differentiation. Stem cells themselves are frequently replenished by dedifferentiation of partially differentiated progeny. It is a paradox how stem cells and progeny retain the same potential to be or become stem cells, while undergoing different trajectories of self-renewal, differentiation, and dedifferentiation. Here, we show that Drosophila male germline stem cells (GSCs) solve this paradox via two parallel mechanisms. First, differentiating progeny (spermatogonia) may maintain dedifferentiation-competence by inheriting the transcriptome from GSCs in the form of perdurant mRNA, without actively transcribing these genes. Second, two niche signaling pathways (Bmp and Jak-Stat) activate overlapping but distinct subsets of transcriptional targets, and their combinatorial activity allows equally-potent cells to choose different trajectories. Together, this study reveals how a pool of dedifferentiation-competent progeny is maintained to regenerate stem cells as needed without resulting in tumorigenic stem cell overproduction.
    DOI:  https://doi.org/10.1101/2025.04.10.648217
  10. Curr Opin Genet Dev. 2025 May 05. pii: S0959-437X(25)00046-2. [Epub ahead of print]93 102354
    Molecular basis of cell fate plasticity - insights from the privileged cells.
    Stephen Maxwell Scalf, Qiao Wu, Shangqin Guo.
      In the post-Yamanaka era, the rolling balls on Waddington's hilly landscape not only roll downward, but also go upward or sideways. This new-found mobility implies that the tantalizing somatic cell plasticity fueling regeneration, once only known to planarians and newts, might be sparking in the cells of mice and humans, if only we knew how to fully unlock it. The hope for ultimate regeneration was made even more tangible by the observations that partial reprogramming by the Yamanaka factors reverses many hallmarks of aging [76], even though the underlying mechanism remains unclear. We intend to revisit the milestones in the evolving understanding of cell fate plasticity and glean molecular insights from an unusual somatic cell state, the privileged cell state that reprograms in a manner defying the stochastic model. We synthesize our view of the molecular underpinning of cell fate plasticity, from which we speculate how to harness it for regeneration and rejuvenation. We propose that senescence, aging and malignancy represent distinct cell states with definable biochemical and biophysical parameters.
    DOI:  https://doi.org/10.1016/j.gde.2025.102354
  11. Nature. 2025 May 07.
    Lipid-degrading small molecule kills cancer cells by ferroptosis.
    Mike Lange, James A Olzmann.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-025-01337-z
  12. Metabolomics. 2025 May 07. 21(3): 62
    Cellular metabolomics study in colorectal cancer cells and media following treatment with 5-fluorouracil by gas chromatography-tandem mass spectrometry.
    Songjin Oh, Hyun Bo Sim, Hyeongyeong Kim, Seul-Ki Mun, Moongi Ji, Byeongchan Choi, Doo-Young Kim, Jong-Jin Kim, Man-Jeong Paik.
       BACKGROUND: Metabolic reprogramming is a distinctive characteristic of colorectal cancer (CRC) which provides energy and nutrients for rapid proliferation. Although numerous studies have explored the rewired metabolism of CRC, the metabolic alterations occurring in CRC when the cell cycle is arrested by treatment with 5-fluorouracil (5-FU), an anticancer drug that arrests the S phase, remain unclear.
    METHODS: A systematic profiling analysis was conducted as ethoxycarbonyl/methoxime/tert-butyldimethylsilyl derivatives using gas chromatography-tandem mass spectrometry in HT29 cells and media following 5-FU treatment in a concentration- and time-dependent manner.
    RESULTS: In HT29 cells of 24 h after 5-FU treatment (3-100 μM) and 48 h after 5-FU treatment (1-10 μM), six amino acids, including valine, leucine, isoleucine, serine, glycine, and alanine and two organic acids, including pyruvic acid and lactic acid, were significantly increased compared to the DMSO-treated group. However, 48 h after 5-FU treatment (30-100 μM) in HT29 cells, the levels of these metabolites decreased along with an approximately 50% reduction in viability, an increase in the level of reactive oxygen species, induction of cycle arrest in the G1 phase, and the induction of apoptosis. On the other hand, the levels of fatty acids showed a continuous increase in HT29 cells 48 h after 5-FU treatment (1-100 μM). In the media, the decreased availabilities in the cellular uptake of nutrient metabolites, including valine, leucine, isoleucine, serine, and glutamine, were observed at 48 h after 5-FU treatment in a dose-dependent manner.
    CONCLUSION: It is assumed that there is a possible shift in energy dependence from the tricarboxylic acid cycle to fatty acid metabolism. Thus, metabolic profiling analysis revealed altered energy metabolism in CRC cells following 5-FU treatment.
    Keywords:  5-Fluorouracil; Colorectal cancer; HT29 cells; Mass spectrometry; Metabolite profiling analysis; Metabolomics
    DOI:  https://doi.org/10.1007/s11306-025-02263-x
  13. Nat Cancer. 2025 May 08.
    The Curated Cancer Cell Atlas provides a comprehensive characterization of tumors at single-cell resolution.
    Michael Tyler, Avishai Gavish, Chaya Barbolin, Roi Tschernichovsky, Rouven Hoefflin, Michael Mints, Sidharth V Puram, Itay Tirosh.
      Recent years have seen a rapid proliferation of single-cell cancer studies, yet most of these studies profiled few tumors, limiting their statistical power. Combining data and results across studies holds great promise but also involves various challenges. We recently began to address these challenges by curating a large collection of cancer single-cell RNA-sequencing datasets, leveraging it for systematic analyses of tumor heterogeneity. Here we greatly extend this repository to 124 datasets for over 40 cancer types, together comprising 2,836 samples, with improved data annotations, visualizations and exploration. Using this vast cohort, we generate an updated map of recurrent expression programs in malignant cells and systematically quantify context-dependent gene expression and cell-cycle patterns across cell types and cancer types. These data, annotations and analysis results are all freely available for exploration and download through the Curated Cancer Cell Atlas, a central community resource that opens new avenues in cancer research.
    DOI:  https://doi.org/10.1038/s43018-025-00957-8
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