bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–05–25
ten papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Phenotypic heterogeneity and plasticity in colorectal cancer metastasis.
  2. Early immune evasion in colorectal cancer: interplay between stem cells and the tumor microenvironment.
  3. Recharacterization of the Tumor Suppressive Mechanism of RSL3 Identifies the Selenoproteome as a Druggable Pathway in Colorectal Cancer.
  4. TGF-β signaling redirects Sox11 gene regulatory activity to promote partial EMT and collective invasion of oncogenically transformed intestinal organoids.
  5. Cancer-associated fibroblast-derived SEMA3C facilitates colorectal cancer liver metastasis via NRP2-mediated MAPK activation.
  6. Targeting SLC7A11 with sorafenib sensitizes stereotactic body radiotherapy in colorectal cancer liver metastasis.
  7. Low-density Lipoprotein Regulates Intestinal Stem Cell Homeostasis via PPAR Pathway.
  8. CDX1 and CDX2 suppress colon cancer stemness by inhibiting β-catenin-facilitated formation of Pol II-DSIF-PAF1C complex.
  9. Heterogeneity and evolution of DNA mutation rates in microsatellite stable colorectal cancer.
  10. Metformin reverses 5-FU resistance induced by radiotherapy through mediating folate metabolism in colorectal cancer.
  1. Cell Genom. 2025 May 15. pii: S2666-979X(25)00137-5. [Epub ahead of print] 100881
    Phenotypic heterogeneity and plasticity in colorectal cancer metastasis.
    Cancer Tissue Bank
      Phenotypic heterogeneity and plasticity in colorectal cancer (CRC) has a crucial role in tumor progression, metastasis, and therapy resistance. However, the regulatory factors and the extrinsic signals driving phenotypic heterogeneity remain unknown. Using a combination of single-cell multiomics and spatial transcriptomics data from primary and metastatic CRC patients, we reveal cancer cell states with regenerative and inflammatory phenotypes that closely resemble metastasis-initiating cells in mouse models. We identify an intermediate population with a hybrid regenerative and stem phenotype. We reveal the transcription factors AP-1 and nuclear factor κB (NF-κB) as their key regulators and show localization of these states in an immunosuppressive niche both at the invasive edge in primary CRC and in liver metastasis. We uncover ligand-receptor interactions predicted to activate the regenerative and inflammatory phenotype in cancer cells. Together, our findings reveal regulatory and signaling factors that mediate distinct cancer cell states and can serve as potential targets to impair metastasis.
    Keywords:  AP-1; NOTUM; colorectal cancer; metastasis; phenotypic heterogeneity; plasticity; single-cell multiomics; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.xgen.2025.100881
  2. Trends Cancer. 2025 May 16. pii: S2405-8033(25)00112-8. [Epub ahead of print]
    Early immune evasion in colorectal cancer: interplay between stem cells and the tumor microenvironment.
    Norihiro Goto, Judith Agudo, Ömer H Yilmaz.
      Most colorectal cancers (CRCs) are characterized by a low mutational burden and an immune-cold microenvironment, limiting the efficacy of immune checkpoint blockade (ICB) therapies. While advanced tumors exhibit diverse immune evasion mechanisms, emerging evidence suggests that aspects of immune escape arise much earlier, within precancerous lesions. In this review, we discuss how early driver mutations and epigenetic alterations contribute to the establishment of an immunosuppressive microenvironment in CRC. We also highlight the dynamic crosstalk between cancer cells, stromal niche cells, and immune cells driving immune evasion and liver metastasis. A deeper understanding of these early events may guide the development of more effective preventive and therapeutic strategies for CRC.
    Keywords:  colorectal cancer; immune evasion; niche cell; stem cell
    DOI:  https://doi.org/10.1016/j.trecan.2025.04.016
  3. Cancer Res. 2025 May 20.
    Recharacterization of the Tumor Suppressive Mechanism of RSL3 Identifies the Selenoproteome as a Druggable Pathway in Colorectal Cancer.
    Stephen L DeAngelo, Liang Zhao, Sofia Dziechciarz, Myungsun Shin, Sumeet Solanki, Andrii Balia, Marwa O El-Derany, Cristina Castillo, Yao Qin, Nupur K Das, Hannah N Bell, Joao A Paulo, Yuezhong Zhang, Nicholas J Rossiter, Elizabeth C McCulla, Jianping He, Indrani Talukder, Billy Wai-Lung Ng, Zachary T Schafer, Nouri Neamati, Joseph D Mancias, Markos Koutmos, Yatrik M Shah.
      Ferroptosis is a non-apoptotic form of cell death driven by iron-dependent lipid peroxide accumulation. Colorectal cancer (CRC) cells feature elevated intracellular iron and reactive oxygen species (ROS) that heighten ferroptosis sensitivity. The ferroptosis inducer (S)-RSL3 ([1S,3R]-RSL3) is widely described as a selective inhibitor of the selenocysteine-containing enzyme (selenoprotein) glutathione peroxidase 4 (GPX4), which detoxifies lipid peroxides utilizing glutathione. However, through chemical controls utilizing the (R) stereoisomer of RSL3 ([1R,3R]-RSL3) that does not bind GPX4, combined with inducible genetic knockdowns of GPX4 in CRC cell lines, we revealed here that GPX4 dependency does not always align with (S)-RSL3 sensitivity, questioning the current characterization of GPX4 as the primary target of (S)-RSL3. Affinity pull-down mass spectrometry with modified (S)-RSL3 probes identified multiple selenoprotein targets, indicating broad selenoprotein inhibition. Further investigation of the therapeutic potential of broadly disrupting the selenoproteome as a therapeutic strategy in CRC showed that the selenoprotein inhibitor auranofin, an FDA-approved gold-salt, chemically induced oxidative cell death and ferroptosis in CRC models in vitro and in vivo. Similarly, genetic perturbation of ALKBH8, a tRNA-selenocysteine methyltransferase required for selenoprotein translation, suppressed CRC growth. In summary, these findings recharacterize the mechanism of (S)-RSL3 beyond GPX4 inhibition and establish selenoproteome disruption as a CRC therapeutic strategy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3478
  4. Oncogenesis. 2025 May 20. 14(1): 17
    TGF-β signaling redirects Sox11 gene regulatory activity to promote partial EMT and collective invasion of oncogenically transformed intestinal organoids.
    Yu-Hsiang Teng, Bismark Appiah, Geoffroy Andrieux, Monika Schrempp, Katja Rose, Angelika Susanna Hofmann, Manching Ku, Sven Beyes, Melanie Boerries, Andreas Hecht.
      Cancer cells infiltrating surrounding tissue frequently undergo partial epithelial-mesenchymal transitions (pEMT) and employ a collective mode of invasion. How these phenotypic traits are regulated and interconnected remains underexplored. Here, we used intestinal organoids with colorectal cancer (CRC) driver mutations as model system to investigate the mechanistic basis of TGF-β1-induced pEMT and collective invasion. By scRNA-seq we identified multiple cell subpopulations representing a broad pEMT spectrum, where the most advanced pEMT state correlated with the transcriptional profiles of leader cells in collective invasion and a poor prognosis mesenchymal subtype of human CRC. Bioinformatic analyses pinpointed Sox11 as a transcription factor gene whose expression peaked in the potential leader/pEMThigh cells. Immunofluorescence staining confirmed Sox11 expression in cells at the invasive front of TGF-β1-treated organoids. Loss-of-function and overexpression experiments showed that Sox11 is necessary, albeit not sufficient, for TGF-β1-induced pEMT and collective invasion. In human CRC samples, elevated SOX11 expression was associated with advanced tumor stages and worse prognosis. Unexpectedly, aside from orchestrating the organoid response to TGF-β1, Sox11 controlled expression of genes related to normal gut function and tumor suppression. Apparently, Sox11 is embedded in several distinct gene regulatory circuits, contributing to intestinal tissue homeostasis, tumor suppression, and TGF-β-mediated cancer cell invasion.
    DOI:  https://doi.org/10.1038/s41389-025-00560-7
  5. Proc Natl Acad Sci U S A. 2025 May 27. 122(21): e2423077122
    Cancer-associated fibroblast-derived SEMA3C facilitates colorectal cancer liver metastasis via NRP2-mediated MAPK activation.
    Yuyuan Zhang, Anning Zuo, Yuhao Ba, Shutong Liu, Jingqi Chen, Shuaixi Yang, Siyuan Weng, Yukang Chen, Hui Xu, Peng Luo, Quan Cheng, Bufu Tang, Benyu Liu, Chuhan Zhang, Jingkuan Yang, Xinwei Han, Zaoqu Liu.
      Liver metastasis remains the predominant cause of mortality in patients with colorectal cancer (CRC). Nevertheless, the mechanisms underlying the initiation of colorectal cancer liver metastasis remain poorly elucidated. During the metastatic process of CRC cells from the primary site to the liver, we performed time-resolved analyses and identified a subset of tumor cells spatially located in the primary tumor and temporally distributed in the early stages of liver metastasis. These cells were termed liver metastasis-initiating cells (LMICs). LMICs exhibit high stemness, low proliferation, active interaction with surrounding stromal components, and a close association with liver metastasis. Notably, we found significant interactions between cancer-associated fibroblasts (CAFs) and LMICs via the SEMA3C-NRP2 receptor-ligand pair. Further in vivo and in vitro experiments confirmed that CAF-secreted SEMA3C could bind to the NRP2 receptor, which activates the MAPK pathway and promotes colorectal cancer liver metastasis. Our findings suggest potential therapeutic strategies for the early prevention of colorectal cancer liver metastasis.
    Keywords:  colorectal cancer; liver metastasis; metastasis-initiating; single-cell
    DOI:  https://doi.org/10.1073/pnas.2423077122
  6. Drug Resist Updat. 2025 May 10. pii: S1368-7646(25)00051-2. [Epub ahead of print]81 101250
    Targeting SLC7A11 with sorafenib sensitizes stereotactic body radiotherapy in colorectal cancer liver metastasis.
    Jiashuai He, Yiran Zhang, Simin Luo, Zhan Zhao, Tianmu Mo, Hanyang Guan, Haoquan Li, Zili Bian, Xiangwei Zhang, Shenghui Qiu, Shijin Liu, Wang Tang, Bo Shi, Minfeng Chen, Dongmei Zhang, Yunlong Pan, Jinghua Pan.
      Colorectal cancer (CRC) with hepatic metastasis is associated with poor prognosis. Stereotactic body radiotherapy (SBRT) can provide local control for unresectable hepatic metastases of patients with CRC. However, the mechanisms of responsiveness to SBRT in metastatic CRC (mCRC) remain unclear. We aimed to identify a strategy to enhance the efficacy of SBRT in patients with CRC liver metastases and its mechanisms. Transcriptomic sequencing of CRC cells exposed to SBRT revealed that SBRT inhibited SLC7A11 expression. Downregulation of SLC7A11 enhanced the sensitivity of CRC cells to SBRT via ferroptosis. SBRT diminished the ability of tumor cells to sustain oxidative stress by impeding the phosphorylation of JNK and c-Jun and the transcription of NRF2. Furthermore, sorafenib, which targets SLC7A11, exerted inhibitory effects on tumor growth when used in combination with SBRT. A phase II clinical trial confirmed that sorafenib combined with SBRT overcame the resistance of liver mCRC with high SLC7A11 expression by inducing ferroptosis. The combination of SBRT and sorafenib demonstrated favorable clinical effects and safety, making it a good option for patients with CRC liver metastasis. STATEMENT OF SIGNIFICANCE: A novel strategy using the combination of SBRT and sorafenib for the treatment of patients with CRC hepatic metastasis was investigated. This strategy overcomes the radiation therapy resistance of mCRC by inhibiting SLC7A11 expression and promoting ferroptosis.
    Keywords:  Colorectal cancer; Cystine/glutamate antiporter xCT; Liver metastasis; Phase II single-arm clinical trial; SBRT; Sorafenib, Ferroptosis
    DOI:  https://doi.org/10.1016/j.drup.2025.101250
  7. J Lipid Res. 2025 May 14. pii: S0022-2275(25)00086-0. [Epub ahead of print] 100826
    Low-density Lipoprotein Regulates Intestinal Stem Cell Homeostasis via PPAR Pathway.
    Ruicheng Shi, Wei Lu, Zhiming Zhao, Bo Wang.
      Epidemiological studies have highlighted a strong association between hyperlipidemia and an increased risk of cancer in the gut. Intestinal stem cells (ISCs) have been demonstrated as the cells of origin for tumorigenesis in the gut. However, the impact of hyperlipidemia on ISC homeostasis remains unclear. Here, we show that hyperlipidemia induced by low-density lipoprotein receptor (Ldlr) deficiency enhances ISC proliferation in vivo. Additionally, LDL treatment impairs organoid survival but increases ISC stemness ex vivo, as evidenced by the formation of poorly differentiated spheroid and higher ISC self-renewal capacity. Mechanistically, LDL treatment activates PPAR pathways, and pharmacological inhibition of PPAR and its downstream targets, including CPT1A and PDK4, mitigates the effect of LDL on ISCs. These findings demonstrate that hyperlipidemia modulates ISC homeostasis, providing new insights into the mechanism linking hyperlipidemia with tumorigenesis in the gut.
    Keywords:  ISCs; LDL; PPAR; fatty acid oxidation; hyperlipidemia
    DOI:  https://doi.org/10.1016/j.jlr.2025.100826
  8. Cell Death Dis. 2025 May 21. 16(1): 408
    CDX1 and CDX2 suppress colon cancer stemness by inhibiting β-catenin-facilitated formation of Pol II-DSIF-PAF1C complex.
    Koji Aoki, Akari Nitta, Ayumi Igarashi.
      Homeobox transcription factors CDX1 and CDX2 (hereafter, CDX1/2) play key roles in determining the identity of intestinal epithelial cells and regulating their stem cell functions. However, the role of CDX1/2 in regulating colon cancer stemness and the underlying mechanisms are unclear. Here, we show that complete loss of Cdx1 or concurrent loss of Cdx1/2 increased the stemness and malignancy of intestinal tumors. Consistently, CDX1/2 reduced the expression of cancer stemness-related genes, including LGR5. CDX1/2 bound to the downstream region of the LGR5 transcription start site (TSS), a region where β-catenin also binds. Despite increased H3 acetylation and an open chromatin structure, CDX1/2 reduced the occupancy of DRB sensitivity-inducing factor (DSIF), RNA polymerase II-associated factor 1 (PAF1), and RNA polymerase II (Pol II) complexes around the LGR5 TSS. Through their homeodomains, CDX1/2 inhibited the β-catenin-facilitated formation of active Pol II complexes containing DSIF and PAF1 complexes by preventing the interaction between β-catenin and these complexes, in an additive manner. Our findings suggest that CDX1/2 cooperatively suppressed colonic tumorigenesis and cancer stemness by antagonizing β-catenin via the DSIF and PAF1 complexes. Additionally, DSIF and PAF1 complexes acted as transcriptional platforms that integrated and funneled both tumor-suppressive and oncogenic signals into the expression of genes that control colon cancer stemness.
    DOI:  https://doi.org/10.1038/s41419-025-07737-3
  9. Sci Transl Med. 2025 May 21. 17(799): eado1641
    Heterogeneity and evolution of DNA mutation rates in microsatellite stable colorectal cancer.
    Elena Grassi, Valentina Vurchio, George D Cresswell, Irene Catalano, Barbara Lupo, Francesco Sassi, Francesco Galimi, Sofia Borgato, Martina Ferri, Marco Viviani, Simone Pompei, Gianvito Urgese, Bingjie Chen, Eugenia R Zanella, Francesca Cottino, Mariangela Russo, Gianluca Mauri, Filippo Pietrantonio, Maria Giulia Zampino, Luca Lazzari, Silvia Marsoni, Alberto Bardelli, Marco Cosentino Lagomarsino, Andrea Sottoriva, Livio Trusolino, Andrea Bertotti.
      Historically, DNA sequence mutability has been considered relatively uniform and low in tumors with chromosomal instability (CIN), based on the assumption that high mutability would be detrimental in karyotypically aberrant contexts. Recent in silico analyses have challenged this view, suggesting some heterogeneity in mutation rates across CIN tumors; however, these predictions lack experimental validation. It also remains unclear how the intertumor variability of mutation rates compares to intratumor diversification and evolves along disease progression, whether mutation rates are functionally relevant in CIN cancers, and which mutational processes shape mutational accrual during CIN tumor onset and evolution. To address these gaps, we performed mutation accumulation experiments using clonal populations of patient-derived tumoroids from seven CIN, microsatellite-stable colorectal cancers (CRCs), and one microsatellite-unstable CRC. Each tumor exhibited a distinctive mutation rate footprint that was conserved among different clones from the same ancestor. In contrast, mutation rates diverged markedly across different tumors, with variations in magnitude within microsatellite-stable tumors as prominent as those distinguishing them from microsatellite-unstable tumors. New mutations reflected mutational processes associated with defective DNA replication and repair, which were not detected in normal tissues. Last, both mutation accumulation assays and high-depth whole-exome sequencing of subclonal variants showed higher mutation rates in metastatic lesions compared with matched primary tumors, suggesting positive selection for cells with increasing mutability during cancer dissemination. By providing an empirical assessment of mutation rates in human cancer, our data delineate heterogeneity, heritability, and progression-associated evolvability of DNA mutational instability as hallmarks of microsatellite-stable CRC.
    DOI:  https://doi.org/10.1126/scitranslmed.ado1641
  10. Mol Med. 2025 May 21. 31(1): 199
    Metformin reverses 5-FU resistance induced by radiotherapy through mediating folate metabolism in colorectal cancer.
    Shuxuan Wang, Yanyan Lin, Qianqian Zhao, Huanliang Chen, Shisuo Du, Zhaochong Zeng.
       PURPOSE: Radiation therapy has revolutionized the treatment of primary or liver metastases in colorectal cancer (CRC). In colorectal cancer, conventional fractionation (1.8 ~ 2.0 Gy daily) is typically used for treatment. Nevertheless, there is a paucity of research investigating the potential implications of radiation therapy-induced alterations in the expression levels of regulatory genes on resistance to chemotherapy agents. Herein, we explored the mechanism by which conventional fractionation drives 5-fluorouracil (5-FU) resistance and metformin (Met) rescued 5-FU resistance in CRC.
    METHODS AND MATERIALS: RNA sequencing, differential genes expression analysis was performed to identify the 5-FU resistance genes after irradiation (according to the convention of cell irradiation, 2 Gy × 8 scheme was selected). Drug sensitivity assay, immunofluorescence staining, folate analogs concentration measurement was used to explore the biological function of histocompatibility minor 13 (HM13) and γ-Glutamyl Hydrolase (GGH). Combined chemosensitivity test and xenograft mouse model has been used to gain insights into the underlying clinical value of the combination of 5-FU and Met.
    RESULTS: The conventional fractionation scheme (2 Gy × 8) induced resistance to 5-FU in the CRC cell line HCT-15, accompanied by an elevated RNA expression level of peptidase HM13. Mechanistically, the increased expression of HM13 caused an abnormal shearing of the N-terminal signal peptide of γ-Glutamyl Hydrolase (GGH), which resulted in decreased intracellular content of 5, 10-methylenetetrahydrofolate (5,10-CH2-THF).
    CONCLUSION: We revealed a new mechanism of 5-FU resistance induced by irradiated with 2 Gy × 8 through the HM13-GGH-5,10-CH2-THF axis. The synergistic effect of Met and 5-FU can rescue 5-FU resistance after conventional fractionated irradiation. In summary, this work will help to reveal the mechanisms of IR-induced 5-FU resistance, which is important for finding new therapeutic targets and improving the efficacy of chemotherapy regimens after radiotherapy.
    Keywords:  5-FU; Folate metabolism; Histocompatibility minor 13; Irradiation; Metformin
    DOI:  https://doi.org/10.1186/s10020-025-01206-5
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