bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–08–24
ten papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Colorectal cancer heterogeneity co-evolves with tumor architecture to determine disease outcome.
  2. HIF-1 attenuates high-fiber diet-mediated proliferation and stemness of colonic epithelium.
  3. Auxilin in enterocytes controls intestinal homeostasis through inter-cell communication.
  4. Polyclonality and metabolic heterogeneity in a colorectal tumor model.
  5. Colorectal ALOX15 as a host factor determining the effects of EPA and DHA on colorectal tumorigenesis in mice.
  6. Prospects for ferroptosis therapies in cancer.
  7. Stearoyl-CoA desaturase 1: An important factor in lipid metabolism in colorectal cancer.
  8. Crosstalk between the circadian clock, intestinal stem cell niche, and epithelial cell fate decision.
  9. Targeting ferroptosis in cancer stem cells: A novel strategy to improve cancer treatment.
  10. Tracing the evolution of single-cell 3D genomes in Kras-driven cancers.
  1. bioRxiv. 2025 Aug 13. pii: 2025.08.11.669722. [Epub ahead of print]
    Colorectal cancer heterogeneity co-evolves with tumor architecture to determine disease outcome.
    iCAN
      Intratumoral heterogeneity, originating from genetic, epigenetic, and phenotypic cellular diversity, is pervasive in cancer. As these heterogeneous states employ diverse mechanisms to promote tumor progression, metastasis, and therapy resistance, emergence of cancer heterogeneity is one of the most significant barriers to curative treatment. Here we leverage deep learning approaches to develop a high-throughput image-analysis paradigm with subcellular resolution that quantifies and predicts colorectal cancer (CRC) patient outcome based on tissue architecture and nuclear morphology. We further combine this approach with spatial transcriptomics, multiplex immunohistochemistry, and patient-derived organoids to uncover a dynamic, co-evolutionary relationship between tumor architecture and cell states. We identify clinically relevant architectural interfaces in CRC tissue that diversify cellular identities by favoring distinct cancer stem cell states and thus promote evolution of tumor heterogeneity. Specifically, tissue fragmentation and associated compressive forces promote loss of classic stem cell signature and acquisition of fetal/regenerative stem cell states, which initially emerges as a hybrid state with features of epithelial-to-mesenchyme (EMT) transition. Additional tumor stroma communication then diversifies these states into distinct stem cell and EMT states at the invasive margins of tumors. Reciprocally, Wnt signaling state of tumor cells tunes their responsiveness to tissue architecture. Collectively, this work uncovers a feedback loop between cell states and tissue architecture that drives cancer heterogeneity and cell state diversification. Machine learning-based analyses harness this co-dependency, independently of mutational status or cancer stage, to predict patient outcome.
    DOI:  https://doi.org/10.1101/2025.08.11.669722
  2. Gut Microbes. 2025 Dec;17(1): 2543123
    HIF-1 attenuates high-fiber diet-mediated proliferation and stemness of colonic epithelium.
    Pollyana Ribeiro Castro, Renan Oliveira Corrêa, Monara Kaélle Sérvulo Cruz Angelim, Vinícius de Rezende Rodovalho, Mariane Font Fernandes, Vinícius Dias Nirello, Arilson Bernardo Dos Santos Pereira Gomes, Jaqueline de Souza Felipe, Lais Passarielo Pral, Sarah de Oliveira, Patrícia Brito Rodrigues, José Luís Fachi, Guilherme Reis-de-Oliveira, Bradley J Smith, Victor C Carregari, Nicolas G Shealy, Catherine Shelton, Daniel Martins-de-Souza, Pedro M Moraes-Vieira, Mariana Xavier Byndloss, Patrick Varga-Weisz, Marco Aurélio Ramirez Vinolo.
      The complex interplay between diet, microbiota, and host is exemplified by the effects of dietary fiber on the intestine. Inulin ingestion triggers epithelial changes in the colon that depend on microbiota-derived molecules, including enhanced proliferation, increased mucus production, and elevated antimicrobial peptide secretion. Here we employed a multilayered and multi-omics approach, including dietary interventions, intestinal organoids, and both genetic and pharmacological interventions to investigate the impact of inulin on two aspects of diet-microbiota-host interactions: intestinal hypoxia and hypoxia-inducible factor (HIF)-1 signaling in intestinal epithelial cells (IECs). We found that inulin, a soluble fiber, promotes intestinal hypoxia, stabilizing HIF-1 in IECs in a microbiota- and host-dependent manner. Furthermore, we show that HIF-1 stabilization modulates intestinal stem cell (ISC) function through metabolic reprogramming in a microbiota-dependent manner. Our findings reveal an unrecognized role for HIF-1 in orchestrating microbiota-dependent epithelial metabolism and proliferation in the colon, underscoring the complexity of diet-microbiota-host interactions.
    Keywords:  Hypoxia; dietary fiber; intestinal stem cells; inulin; metabolism; microbiota
    DOI:  https://doi.org/10.1080/19490976.2025.2543123
  3. Cell Death Dis. 2025 Aug 18. 16(1): 626
    Auxilin in enterocytes controls intestinal homeostasis through inter-cell communication.
    Runqi Wang, Zhengran Li, Jing Wei, Ruiyan Kong, Xuejing Ren, Hang Zhao, Danjie Zhang, Xiyue Tao Liu, Zhouhua Li.
      Residential stem cells sense extrinsic and intrinsic signals to proliferate accordingly to maintain homeostasis. However, how differentiated cells control stem cell proliferation still remains elusive. Here, we find that Auxilin (Aux) maintains enterocyte (EC) integrity to prevent unlimited intestinal stem cell (ISC) proliferation. Depleting aux in ECs leads to excessive ISC proliferation and intestinal homeostasis disruption. Ectopic cytokine production from dying aux-depleted ECs activates JAK/STAT signaling and promotes ISC proliferation. Mechanistically, Aux facilitates anterograde ER-to-Golgi apparatus (GA) vesicle transport by associating with COPII coatomer. Further, the presentation of cell adhesion molecules (CAMs) by ER-to-GA transport is required for intestinal homeostasis. Together, these data demonstrate that Aux maintains EC integrity by mediating ER-to-GA trafficking of CAMs to restrain excessive ISC proliferation. Thus our study uncovers the underlying mechanism of how differentiated cells control stem cell proliferation through inter-cell communication during tissue homeostasis and pathogenesis.
    DOI:  https://doi.org/10.1038/s41419-025-07954-w
  4. iScience. 2025 Aug 15. 28(8): 113090
    Polyclonality and metabolic heterogeneity in a colorectal tumor model.
    Pierre Delamotte, Mickael Poidevin, Yan Jaszczyszyn, Arnaud Le Rouzic, Jacques Montagne.
      The monoclonal origin of cancer is widely accepted, although numerous studies suggest that some are of polyclonal origin. Loss of checkpoints in transformed cells gives rise to carcinomas comprising a wide diversity of cell types that fulfill distinct, even complementary, metabolic functions, contrasting with a hypothetical monoclonal origin. Here, using a Drosophila intestinal tumor model, we show that, despite an identical genetic background, these tumors (1) comprise a conserved set of different metabolic-specialized clusters; (2) are always polyclonal and derive from several clones characterized by distinct metabolic specificity; (3) depend on motility of the founder clones for their growth; and (4) share metabolic needs similar to those of human cancers. In summary, our study indicates that, in this model, tumor formation always requires assembly between founder clones potentially providing distinct cellular functions, as visualized by their metabolic heterogeneity. Thus, this polyclonal assembly would constitute a critical step of tumor progression.
    Keywords:  Cancer; Experimental models in systems biology; Metabolic flux analysis
    DOI:  https://doi.org/10.1016/j.isci.2025.113090
  5. Cell Mol Gastroenterol Hepatol. 2025 Aug 14. pii: S2352-345X(25)00148-1. [Epub ahead of print] 101607
    Colorectal ALOX15 as a host factor determining the effects of EPA and DHA on colorectal tumorigenesis in mice.
    Xiangsheng Zuo, Yoshiyuki Kiyasu, Yi Liu, Yasunori Deguchi, Fuyao Liu, Micheline Moussalli, Lin Tan, Bo Wei, Daoyan Wei, Peiying Yang, Imad Shureiqi.
       BACKGROUND AND AIMS: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the major omega-3 polyunsaturated fatty acids (ω-3 PUFAs), derived from fish oil are widely used as dietary supplements and are FDA-approved for treating hypertriglyceridemia. However, studies evaluating their effects on colorectal tumorigenesis (CRT) have produced conflicting results, and the underlying reasons for this variability remain unclear. 15-Lipoxygenase-1 (ALOX15), a key enzyme involved in the generation of resolvins from EPA and DHA, is frequently lost in the human colon during CRT. We therefore investigated whether ALOX15 expression in the colon influences the effects of EPA and DHA on resolvin production and CRT.
    METHODS: The effects of intestinal transgenic ALOX15 expression on resolvin generation and colorectal tumor formation in response to various formulations of EPA and DHA dietary supplementations were evaluated using multiple mouse models that closely recapitulate human CRT. Transgenic human ALOX15 was expressed in colonic epithelial cells under the control of various promoters in the mice. EPA, DHA and their metabolite resolvin levels were assessed in colonic epithelial cells and sera by liquid chromatography and tandem mass spectrometry, while production of chemokines and cytokines (e.g., CCL3-5, IL-1β, IL-6) was measured. Abundance of tumor-associated macrophage and CD8+ T cell was evaluated by immunohistochemistry and immunofluorescence staining.
    RESULTS: Dietary EPA and DHA supplementation in control mice lacking transgenic human ALOX15 expression resulted in minimal changes in resolvin production and had variable effects on CRT. In contrast, EPA and DHA uniformly inhibited colorectal tumor formation in mice engineered to express human ALOX15 in their intestinal epithelial cells. These antitumorigenic effects were associated with increased resolvin production, reduced colonic expression of CCL2, IL-1β and IL-6, decreased tumor-associated macrophages, and enhanced infiltration of CD8α+ T cells in the tumor microenvironment. In vitro, RvE1 and RvD5-the predominant resolvins generated by ALOX15-suppressed CCL2, IL-1β and IL-6 production and promoted phagocytic activity in murine macrophages.
    CONCLUSIONS: Colonic ALOX15 expression is essential for enabling EPA and DHA to generate resolvins and consistently suppress CRT. The status of colonic ALOX15 expression should be taken into account when developing prevention strategies that utilize EPA and DHA to decrease the risk of colon cancer.
    Keywords:  ALOX15; DHA; EPA; colorectal tumorigenesis; resolvins
    DOI:  https://doi.org/10.1016/j.jcmgh.2025.101607
  6. Nat Cancer. 2025 Aug 18.
    Prospects for ferroptosis therapies in cancer.
    Jessalyn M Ubellacker, Scott J Dixon.
      Ferroptosis is a nonapoptotic form of cell death characterized by lethal membrane lipid peroxidation. This mechanism was first characterized in cancer cells well over a decade ago, and there is much enthusiasm for the concept that certain cancers may be treated by inducing ferroptosis. However, therapies that engage ferroptosis have yet to enter clinical testing. In this Review, we highlight the gap between our rapidly expanding knowledge of the ferroptosis mechanism and its translation into cancer therapies. We discuss the known challenges that may be slowing ferroptosis therapies from reaching the clinic.
    DOI:  https://doi.org/10.1038/s43018-025-01037-7
  7. Biochem Pharmacol. 2025 Aug 14. pii: S0006-2952(25)00504-0. [Epub ahead of print]242(Pt 1): 117239
    Stearoyl-CoA desaturase 1: An important factor in lipid metabolism in colorectal cancer.
    Xinzhu Xue, Fang Zhu, Yinnan Chen.
      Colorectal cancer is among the most prevalent cancers globally. It is frequently accompanied by alterations in three metabolic pathways, of which lipid metabolism is particularly important. Recent studies have found that stearoyl-CoA desaturase 1, an important desaturase in lipid metabolism, is crucial in the progression of most tumor cells. This review summarizes the structure and function of stearoyl-CoA desaturase 1, its role in lipid metabolism, its effect on tumor progression, upstream factors regulating stearoyl-CoA desaturase 1 expression, stearoyl-CoA desaturase 1-related reports in colorectal cancer research in the past 5 years, and the potential use of stearoyl-CoA desaturase 1 in future clinical treatment.
    Keywords:  Colorectal cancer; Drug resistant; Ferroptosis; Lipid metabolism; Stearoyl-CoA desaturase 1; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bcp.2025.117239
  8. Genes Dis. 2025 Nov;12(6): 101650
    Crosstalk between the circadian clock, intestinal stem cell niche, and epithelial cell fate decision.
    Ji Liu, Zhihui Jiang, Juanmin Zha, Qiong Lin, Weiqi He.
      The circadian rhythm, a 24-h cycle, plays a crucial role in regulating gut physiological processes, particularly the proliferation and differentiation of intestinal epithelial cells, which are essential for gut homeostasis and repair. This review discusses the complex interactions between circadian rhythms, cell cycle regulation, and key signaling pathways (Wnt, Notch, and Hippo) in the context of the intestinal stem cell niche and epithelial cell fate decisions. Key molecules such as brain and muscle ARNT-like 1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), hairy and enhancer of split 1 (Hes1), and Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) coordinate stem cell functions with circadian rhythms. We discuss how Notch signaling regulates the cell cycle and interacts with circadian rhythms. Additionally, we explore the role of Hippo-Wnt signaling in balancing cell proliferation and differentiation. Furthermore, we highlight the intricate relationships between circadian clock components and signaling pathways, emphasizing the importance of temporal coordination in determining epithelial cell fate. We also discuss shared enzymes, including casein kinase 1 delta (CK1δ), glycogen synthase kinase 3 (GSK3), and AMP-activated protein kinase (AMPK), which play a role in regulating the cell cycle, circadian rhythm, and signaling pathways. In summary, this review offers valuable insights into the regulatory mechanisms that control stem cell behavior and epithelial cell differentiation, suggesting promising directions for future research in intestinal biology and tissue homeostasis.
    Keywords:  Cell cycle regulation; Circadian clock; Epithelial differentiation; Intestinal stem cell; Signaling pathways
    DOI:  https://doi.org/10.1016/j.gendis.2025.101650
  9. Genes Dis. 2025 Nov;12(6): 101678
    Targeting ferroptosis in cancer stem cells: A novel strategy to improve cancer treatment.
    Luyao Wang, Ye Zhu, Chengying Huang, Qiuming Pan, Junxi Wang, Hongrui Li, Yudi Huang, Guozhong Yi, Zhiyong Li, Songtao Qi, Guanglong Huang, Shanqiang Qu.
      Ferroptosis, a distinct regulated cell death process characterized by iron retention and lipid peroxidation, plays a crucial role in the survival of cancer stem cells (CSCs), key contributors to cancer initiation, progression, and recurrence. CSCs exhibit enhanced iron uptake and altered lipid metabolism, allowing them to evade conventional therapies and persist within the cancer microenvironment. Their resilience is linked to low reactive oxygen species levels, aiding survival under oxidative stress. Key regulatory pathways, including the cystine/glutathione axis, significantly modulate CSCs' sensitivity to ferroptosis by maintaining a balance between antioxidant defenses and pro-oxidative stressors. Targeting ferroptosis in CSCs offers promising therapeutic avenues for enhancing treatment efficacy and overcoming resistance. Strategies such as pharmacological inhibition of the SLC7A11 transporter, which reduces cysteine availability and glutathione levels, can potentiate ferroptosis in CSCs. Additionally, inducing dysregulation of iron metabolism or lipid peroxidation can selectively compromise CSCs' survival. Nanoparticle drug delivery systems that increase intracellular iron and reactive oxygen species levels are proving effective in targeting CSCs with minimal impact on normal cells. Ultimately, a comprehensive understanding of the interplay between ferroptosis and CSCs' biology is essential for developing innovative strategies aimed at eradicating these elusive cells, thereby improving cancer treatment outcomes and reducing recurrence rates.
    Keywords:  Cancer stemcells (CSCs); Cell signaling; Drug target; Ferroptosis; Iron metabolism
    DOI:  https://doi.org/10.1016/j.gendis.2025.101678
  10. Nat Genet. 2025 Aug 18.
    Tracing the evolution of single-cell 3D genomes in Kras-driven cancers.
    Miao Liu, Shengyan Jin, Sherry S Agabiti, Tyler B Jensen, Tianqi Yang, Jonathan S D Radda, Christian F Ruiz, Gabriel Baldissera, Moein Rajaei, Fang-Yong Li, Jeffrey P Townsend, Mandar Deepak Muzumdar, Siyuan Wang.
      Although three-dimensional (3D) genome structures are altered in cancer, it remains unclear how these changes evolve and diversify during cancer progression. Leveraging genome-wide chromatin tracing to visualize 3D genome folding directly in tissues, we generated 3D genome cancer atlases of oncogenic Kras-driven mouse lung adenocarcinoma (LUAD) and pancreatic ductal adenocarcinoma. Here we define nonmonotonic, stage-specific alterations in 3D genome compaction, heterogeneity and compartmentalization as cancers progress from normal to preinvasive and ultimately to invasive tumors, discovering a potential structural bottleneck in early tumor progression. Remarkably, 3D genome architectures distinguish morphologic cancer states in single cells, despite considerable cell-to-cell heterogeneity. Analyses of genome compartmentalization changes not only showed that compartment-associated genes are more homogeneously regulated but also elucidated prognostic and dependency genes in LUAD, as well as an unexpected role for Rnf2 in 3D genome regulation. Our results highlight the power of single-cell 3D genome mapping to identify diagnostic, prognostic and therapeutic biomarkers in cancer.
    DOI:  https://doi.org/10.1038/s41588-025-02297-w
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