bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–05–04
fifteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Shaping intestinal organoids: Engineering crypt curvature to guide stem cell niches.
  2. Blood metabolic biomarkers and colorectal cancer risk: results from large prospective cohort and Mendelian randomisation analyses.
  3. Direct Inhibition of RAS Reveals the Features of Oncogenic Signaling Driven by RAS G12 and Q61 Mutations.
  4. Does side matter? Deciphering mechanisms that underpin side-dependent pathogenesis and therapy response in colorectal cancer.
  5. Signaling switches: Metabolism regulates gastruloid self-organization.
  6. Fatty acid metabolism: The crossroads in intestinal homeostasis and tumor.
  7. EZH2 promotes chemoresistance in colorectal cancer by inhibiting autophagy through NRP1 suppression.
  8. NAG-1/GDF15 as a tumor suppressor in colorectal cancer: inhibition of β-catenin and NF-κB pathways via interaction with EpCAM.
  9. Glucose-6-phosphate-dehydrogenase on old peroxisomes maintains self-renewal of epithelial stem cells after asymmetric cell division.
  10. Spatial heterogeneity, stromal phenotypes, and therapeutic vulnerabilities in colorectal cancer peritoneal metastasis.
  11. From blockage to biology: Unveiling the role of extracellular matrix dynamics in obstructive colorectal cancer pathogenesis.
  12. Hepatic iNKT cells facilitate colorectal cancer metastasis by inducing a fibrotic niche in the liver.
  13. Colon Cancer: The Young, the Old, and the Ugly.
  14. PI3K Signaling Enhances Intestinal Crypt Epithelial Cell Recovery after Radiation.
  15. Untargeted LC-MS/MS- based metabolomics profiling of colorectal cancer cell lines reveals potential hypoxia-associated biomarkers.
  1. Cell Stem Cell. 2025 May 01. pii: S1934-5909(25)00135-3. [Epub ahead of print]32(5): 678-680
    Shaping intestinal organoids: Engineering crypt curvature to guide stem cell niches.
    Riccardo Barrile, Magdalena Kasendra.
      Yavitt et al.1 introduce a photodegradable hydrogel platform to control crypt curvature in intestinal organoids, revealing how epithelial morphology directs Paneth cell localization. This innovative approach advances organoid engineering, providing a reproducible method to study stem cell niche interactions and model intestinal development and disease.
    DOI:  https://doi.org/10.1016/j.stem.2025.03.015
  2. Br J Cancer. 2025 Apr 30.
    Blood metabolic biomarkers and colorectal cancer risk: results from large prospective cohort and Mendelian randomisation analyses.
    Fangcheng Yuan, Guochong Jia, Wanqing Wen, Shuai Xu, Valerie Gunchick, Kui Deng, Jirong Long, Danxia Yu, Xiao-Ou Shu, Wei Zheng.
       BACKGROUND: Emerging evidence suggests metabolic dysregulation may contribute to colorectal cancer (CRC) aetiology. We aimed to identify pre-diagnostic metabolic biomarkers for CRC risk in 230,420 UK Biobank participants.
    METHODS: Nuclear magnetic resonance spectroscopy was used to quantify 249 metabolic biomarkers in plasma samples collected at baseline. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals (CIs) for associations of metabolic biomarkers with CRC risk after adjusting for potential confounders. To infer the potential causality of biomarkers that were associated with CRC independent of the others, we performed genome-wide association analyses among 199,732 UK Biobank participants of European ancestry to identify biomarker-associated genetic variants, followed by two-sample Mendelian randomization (MR) analyses using summary statistics of 78,473 CRC cases and 107,143 controls of European ancestry.
    RESULTS: During a median follow-up time of 9.7 years, 2,410 incident primary CRC cases were identified. Among 43 CRC-associated (P-value < 0.001) metabolic biomarkers, ten biomarkers including fatty acids (FAs), inflammation, ketone bodies, and lipoprotein lipids were associated with CRC risk after mutual adjustment. MR analyses provided strong evidence for potential causal associations of CRC risk with percentages of linolic acid [odds ratio (OR) = 0.89, 95% CI = 0.83-0.96, P-value = 3 × 10-3] and saturated FAs (OR = 1.14, 95% CI = 1.03-1.25, P-value = 9  ×  10-3) to total FAs.
    CONCLUSIONS: We identified multiple CRC-associated metabolic biomarkers. Perturbed lipid and lipoprotein metabolism may promote colorectal carcinogenesis.
    DOI:  https://doi.org/10.1038/s41416-025-02997-4
  3. Cancer Discov. 2025 Apr 28. OF1-OF18
    Direct Inhibition of RAS Reveals the Features of Oncogenic Signaling Driven by RAS G12 and Q61 Mutations.
    Michelangelo Marasco, Dinesh Kumar, Santiago Garcia Borrego, Tessa Seale, Giulia Maddalena, Riccardo Mezzadra, Kylie Belanger, Soren Cole, Brayan Perez, Wei Luan, Radha Mukherjee, Ilinca Aricescu, Vladimir Markov, Yuxin Zhu, Sabrina Arena, Alberto Bardelli, Elisa de Stanchina, Scott W Lowe, Richard A Burkhart, Jacquelyn W Zimmerman, Rona Yaeger, Scott E Kopetz, Neal Rosen, Sandra Misale.
       SIGNIFICANCE: RAS inhibition in multiple tumor types reveals the difference between G12 mutants and Q61 mutants in their cooperation with upstream regulators and downstream effectors to promote oncogenic signaling. Our findings provide the rationale for combinatorial approaches and contribute to explaining the nonuniform distribution of RAS mutations, de novo and at resistance.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0614
  4. Mol Cancer. 2025 May 02. 24(1): 130
    Does side matter? Deciphering mechanisms that underpin side-dependent pathogenesis and therapy response in colorectal cancer.
    Harrison J Boka, Rebekah M Engel, Christine Georges, Paul J McMurrick, Helen E Abud.
      Colorectal cancer (CRC) is stratified by heterogeneity between disease sites, with proximal right-sided CRC (RCRC) multifactorial in its distinction from distal left-sided CRC (LCRC). Notably, right-sided tumors are associated with aggressive disease characteristics which culminate in poor clinical outcomes for these patients. While factors such as mutational profile and patterns of metastasis have been suggested to contribute to differences in therapy response, the exact mechanisms through which RCRC resists effective treatment have yet to be elucidated. In response, recent analyzes, including those utilizing whole genome sequencing, transcriptional profiling, and single-cell analyses, have demonstrated that key molecular differences exist between disease sites, with differentially expressed genes spanning a diverse range of cellular functions. Here, we review and contextualize the most recent data on molecular biomarkers found to exhibit discordance between RCRC and LCRC, and highlight candidates for further investigation, including those which present promise for future clinical application. Given the present disparity in survival outcomes for RCRC patients, we expect the prognostic biomarkers presented in our review to be useful in establishing future directions for the side-specific treatment of CRC.
    DOI:  https://doi.org/10.1186/s12943-025-02327-5
  5. Cell Stem Cell. 2025 May 01. pii: S1934-5909(25)00140-7. [Epub ahead of print]32(5): 673-675
    Signaling switches: Metabolism regulates gastruloid self-organization.
    María J Rodríguez Colman, Katharina F Sonnen.
      Metabolic regulation of embryonic development is increasingly recognized. Villaronga-Luque et al.1 and Stopornwongkul et al.2 show that metabolic activity influences gastruloid formation from mouse embryonic stem cells, revealing that the balance between glycolysis and oxidative phosphorylation regulates cell fate decisions during gastruloid self-organization.
    DOI:  https://doi.org/10.1016/j.stem.2025.04.005
  6. Metabolism. 2025 Apr 23. pii: S0026-0495(25)00142-8. [Epub ahead of print]169 156273
    Fatty acid metabolism: The crossroads in intestinal homeostasis and tumor.
    Yao Lu, Lining Chen, Yingying Lin, Yafei Zhang, Yuqi Wang, Weiru Yu, Fazheng Ren, Huiyuan Guo.
      Fatty acids (FAs) have various functions on cell regulation considering their abundant types and metabolic pathways. In addition, the relation between FA and other nutritional metabolism makes their functions more complex. As the first place for diet-derived FA metabolism, intestine is significantly influenced despite lack of clear conclusions due to the inconsistent findings. In this review, we discuss the regulation of fatty acid metabolism on the fate of intestinal stem cells in homeostasis and disorders, and also focus on the intestinal tumor development and treatment from the aspect of gut microbiota-epithelium-immune interaction. We summarize that the balances between FA oxidation and glycolysis, between oxidative phosphorylation and ketogenesis, between catabolism and anabolism, and the specific roles of individual FA types determine the diverse effects of intestinal FA metabolism in different cases. We hope this will inspire further dissection and suggest precise dietary/metabolic intervention for different demands related to intestinal health.
    Keywords:  Fatty acid metabolism; Fatty acids; Intestinal stem cells; Intestinal tumor; Lipogenesis
    DOI:  https://doi.org/10.1016/j.metabol.2025.156273
  7. Biochem J. 2025 May 02. pii: BCJ20240607. [Epub ahead of print]
    EZH2 promotes chemoresistance in colorectal cancer by inhibiting autophagy through NRP1 suppression.
    Hong Deng, Qin Xu, Qiang Zhang, Chunfeng Liu, Lei Ren.
      Colorectal cancer (CRC) is characterized by aggressive tumor growth and chemoresistance, with Enhancer of zeste homolog 2 (EZH2) serving a pivotal role in these processes. However, the mechanisms by which it drives tumor proliferation and therapeutic resistance through autophagy regulation remain unclear. Here, we demonstrated that EZH2 expression is elevated in CRC tissues and cell lines, correlating with chemoresistance and diagnostic potential (Area Under the Curve, AUC = 0.968). EZH2 knockdown markedly reduced CRC cell proliferation, while its overexpression promoted tumor growth and increased resistance to irinotecan. Mechanistically, EZH2 suppressed autophagy in CRC cells, a process linked to chemosensitivity, by directly regulating LC3bI/II expression. Notably, EZH2 enhanced the Neuropilin-1 (NRP1) level by binding to the NRP1 promoter, thereby promoting tumor proliferation and irinotecan resistance through autophagy inhibition. NRP1 depletion partially reversed these effects, underscoring the crucial role of the EZH2-NRP1 axis in CRC. Our findings highlight that targeting the EZH2-NRP1 interaction could represent a novel therapeutic approach to overcoming chemoresistance in CRC.
    Keywords:  Autophagy; Chemoresistance; Colorectal cancer; EZH2; NRP1; autophagy; chemotherapy resistance; colorectal cancer; neuropilins
    DOI:  https://doi.org/10.1042/BCJ20240607
  8. Cell Death Dis. 2025 May 02. 16(1): 355
    NAG-1/GDF15 as a tumor suppressor in colorectal cancer: inhibition of β-catenin and NF-κB pathways via interaction with EpCAM.
    Jaehak Lee, Ilju Kim, Junsun Ryu, Thomas Eling, Seung Joon Baek.
      NAG-1/GDF15, a tumor suppressor, is synthesized as a pro-form in colorectal cancer (CRC) cells and undergoes cleavage to generate its mature form. While the biological function of pro-NAG-1/GDF15 remains unclear, our study reveals its crucial role in suppressing oncogenic signaling. We demonstrate that pro-NAG-1/GDF15 is predominantly retained within cells, whereas its mature form is secreted into the media. The expression of NAG-1/GDF15, or uncleavable R193A mutant, inhibits β-catenin and NF-κB signaling, key pathways in CRC progression. Mechanistically, the pro-NAG-1/GDF15 interacts with EpCAM, preventing its cleavage and nuclear translocation, thereby reducing β-catenin and NF-κB activity. This inhibition correlates with decreased expression of oncogenic targets such as cyclin D1 and c-myc. In vivo, NAG-1/GDF15 expression significantly reduces tumor growth in cancer xenograft models, accompanied by decreased proliferation and increased apoptosis. Furthermore, analysis of public datasets suggests that high NAG-1/GDF15 expression is associated with improved CRC patient survival. These findings highlight NAG-1/GDF15 via the formation of pro-NAG-1/GDF15 as a promising therapeutic target for cancer, with potential applications in modulating tumorigenic signaling pathways.
    DOI:  https://doi.org/10.1038/s41419-025-07695-w
  9. Nat Commun. 2025 Apr 26. 16(1): 3932
    Glucose-6-phosphate-dehydrogenase on old peroxisomes maintains self-renewal of epithelial stem cells after asymmetric cell division.
    Hien Bui, Simon Andersson, Agustin Sola-Carvajal, Tommaso De Marchi, Eliisa Vähäkangas, Minna Holopainen, Andrew H House, Bohdana M Rovenko, Johanna I Englund, Maria Kasper, Emilia Kuuluvainen, Reijo Käkelä, Ville Hietakangas, Emma Niméus, Pekka Katajisto.
      Selective inheritance of sub-cellular components has emerged as a mechanism guiding stem cell fate after asymmetric cell divisions. Peroxisomes play a crucial role in multiple metabolic processes such as fatty acid metabolism and reactive oxygen species detoxification, but the apportioning of peroxisomes during stem cell division remains understudied. Here, we develop a mouse model and labeling technique to follow the dynamics of distinct peroxisome age-classes, and find that old peroxisomes are inherited by the daughter cell retaining full stem cell potency in mammary and epidermal stem cell divisions. Old peroxisomes carry Glucose-6-phosphate-dehydrogenase, whose specific location on the peroxisomal membrane promotes stem cell function by facilitating peroxisomal ether lipid synthesis. Our study demonstrates age-selective apportioning of peroxisomes in vivo, and unveils how functional heterogeneity of peroxisomes is utilized by asymmetrically dividing cells to metabolically divert the fate of the two daughter cells.
    DOI:  https://doi.org/10.1038/s41467-025-58752-z
  10. Clin Cancer Res. 2025 Apr 29.
    Spatial heterogeneity, stromal phenotypes, and therapeutic vulnerabilities in colorectal cancer peritoneal metastasis.
    Johnny Chin-Ann Ong, Joseph J Zhao, Ying Liu, Supriya Srivastava, Daryl K A Chia, Ying En Quek, Xiaonan Fan, Haoran Ma, Kie Kyon Huang, Taotao Sheng, Qiu Xuan Tan, Gillian Ng, Joey W S Tan, Jia-Ying Joey Lee, Lit-Hsin Loo, Li Yen Chong, Xue Wen Ong, Su Ting Tay, Takeshi Hagihara, Angie Tan, Craig Ryan Cecil Joseph, Melissa C C Teo, Josephine Hendrikson, Clara Y L Chong, Wanyu Guo, Claramae S Chia, Jolene S M Wong, Chin Jin Seo, Mingzhe Cai, Yvonne Tay, Kevin M S Sim, Ryan Y K Tay, Robert Walsh, Marcello Guaglio, Federica Morano, Ming Teh, Huey Yew Jeffrey Lum, Tony K H Lim, Louis Vermeulen, Maarten F Bijlsma, Kristiaan Lenos, Samuel J Klempner, Joe P S Yeong, Wei Peng Yong, Filippo Pietrantonio, Patrick Tan, Raghav Sundar.
       PURPOSE: Peritoneal metastases (PM) in colorectal cancer (CRC) portend a poor prognosis. We sought to elucidate molecular features differentiating primary tumors (PTs) from PMs and actionable targets facilitating transcoelomic dissemination and progression.
    EXPERIMENTAL DESIGN: We performed multi-omic profiling of 227 samples from 136 patients, including 56 primary tumor (PT) and 120 synchronous PMs comprising 34 matched PT-PM pairs. Whole exome, and bulk RNA-seq analysis was conducted to identify underlying genomic aberrations and transcriptomic differences between primary and peritoneal lesions. We spatially characterized the microenvironment of tumor-stroma compartments and studied the roles of stromal phenotypes in promulgating tumorigenesis.
    RESULTS: Whole exome sequencing found genomic alterations and clonality patterns between PTs and PMs remain broadly similar. Transcriptomic profiles however, suggest a transition as tumors reach the peritoneum towards a more mesenchymal tumor profile and fibrotic tumor microenvironment. Applying spatial profiling, we identify a fibro-collagenous and immune-infiltrated stromal phenotype (stromal cluster [SC] 2) characterized by increased cancer-associated fibroblasts, memory B cells, M2 macrophages and T-cell exhaustion. These findings were orthogonally validated by multiplex immunohistochemistry. Patients with SC2 stroma had poorer survival and were characterized by high SERPINE-1 (PAI-1) expression. PM in patients with SC2 stroma were associated with enriched oncogenic pathways such as TGF-β. PAI-1 inhibition of CRC PM cell-lines with a novel biologic demonstrated reduced IL2-STAT5 and TGF-β pathways and cell death.
    CONCLUSIONS: Our findings unveil distinctive and actionable molecular signatures, offering deeper insights into the intricate crosstalk between tumor cells and stromal microenvironments enabling PM in CRC.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-3780
  11. Pathol Res Pract. 2025 Apr 28. pii: S0344-0338(25)00186-4. [Epub ahead of print]270 155994
    From blockage to biology: Unveiling the role of extracellular matrix dynamics in obstructive colorectal cancer pathogenesis.
    Jun Wang, Mian Chen, Guanxin Wei, Falong Zou, Junnan Gu, Yinghao Cao, Shenghe Deng, Kailin Cai.
      Colorectal cancer obstruction is a common problem with distinct symptomatic clues on CT/MR images even under incomplete conditions. The choice of management in the emergency setting has a significant effect on the prognosis of obstructive and nonobstructive colorectal cancer patients. Previous studies have demonstrated that obstruction in colorectal cancer is associated with significantly poorer outcomes, alongside distinct alterations in the composition of the extracellular matrix. Based on accumulating evidence, it is hypothesized that ECM remodeling plays a pivotal role in the development of colorectal cancer obstruction. This review explores the pathological features of obstructive colorectal cancer, emphasizing extracellular matrix remodeling as a central process. Key mechanisms include tumor-stromal cell interactions, tumor cell aggregation and migration mediated by the peripheral nervous system, vascular and lymphatic remodeling within the tumor microenvironment, and microbiota-mediated regulation of cancer progression. These findings demonstrate that further remodeling of the extracellular matrix may be a molecular biological feature of obstructive colorectal cancer with poor prognosis.
    Keywords:  Extracellular matrix remodeling; Matrix stiffness; Obstructive colorectal cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.prp.2025.155994
  12. iScience. 2025 May 16. 28(5): 112364
    Hepatic iNKT cells facilitate colorectal cancer metastasis by inducing a fibrotic niche in the liver.
    Marc Nater, Michael Brügger, Virginia Cecconi, Paulo Pereira, Geo Forni, Hakan Köksal, Despoina Dimakou, Michael Herbst, Anna Laura Calvanese, Giulia Lucchiari, Christoph Schneider, Tomas Valenta, Maries van den Broek.
      The liver is an important metastatic organ that contains many innate immune cells, yet little is known about their role in anti-metastatic defense. We investigated how invariant natural killer T (iNKT) cells influence colorectal cancer-derived liver metastasis using different models in immunocompetent mice. We found that hepatic iNKT cells promote metastasis by creating a supportive niche for disseminated cancer cells. Mechanistically, iNKT cells respond to disseminating cancer cells by producing the fibrogenic cytokines interleukin-4 (IL-4) and IL-13 in a T cell receptor-independent manner. Selective abrogation of IL-4 and IL-13 sensing in hepatic stellate cells prevented their transdifferentiation into extracellular matrix-producing myofibroblasts, which hindered metastatic outgrowth of disseminated cancer cells. This study highlights a novel tumor-promoting axis driven by iNKT cells in the initial stages of metastasis.
    Keywords:  Biological sciences; Immune response; Immunology; Microenvironment; Natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2025.112364
  13. Clin Colon Rectal Surg. 2025 May;38(3): 171-172
    Colon Cancer: The Young, the Old, and the Ugly.
    Beatrice Dionigi.
      
    DOI:  https://doi.org/10.1055/s-0044-1787882
  14. Am J Pathol. 2025 Apr 30. pii: S0002-9440(25)00151-8. [Epub ahead of print]
    PI3K Signaling Enhances Intestinal Crypt Epithelial Cell Recovery after Radiation.
    Evan B Lynch, Neeraj Kapur, Tatiana Goretsky, Emily M Bradford, Hemendra Vekaria, Sarayu Bhogoju, Syed A Hassan, Emily Pauw, Margarita G Avdiushko, Goo Lee, Tianyan Gao, Patrick G Sullivan, Terrence A Barrett.
      Intestinal stem cell (ISC) signaling maintains the balance of self-renewal and differentiation. The role of PI3K signaling in ISC responses to radiation was interrogated using Villin-Cre pik3r1lox/lox (p85ΔIEC) mice and p85α-deficient human enteroids (shp85α). Lethal whole-body irradiation in mice was performed to monitor PI3K-mediated survival responses. Rectal biopsies from patients with radiation proctitis were examined by IHC for the PI3K/Akt- and Wnt-target survivin. The intestinal epithelial cells (IECs) from p85ΔIEC mice showed increased protein levels of p-PTEN, p-AktSer473, survivin, cyclinD1 and ρ-β-cateninSer552 as well as increased mRNA for ISC/PC. In situ hybridization showed that enhanced PI3K signaling reduced Lgr5+ cells but expansion of Axin2+ cells. The shp85α enteroids showed increased mRNA expression of Wnt-targets and transcription factor ASCL2, needed for dedifferentiation-mediated restoration of ablated ISCs. The p85α-deficient enteroids showed reduced HES1 mRNA and increases in secretory (ATOH1/MATH1) signaling determinants GFI1 and SPDEF, indicative of reduced NOTCH signaling. Seahorse analyses and p-p38 staining in IECΔp85 mice indicated that enhanced PI3K signaling led to increased IEC mitochondrial respiration and ROS generation. Expression of survivin correlated with the radiation injury in patients. The current data indicate that PI3K signaling increases mitochondrial ROS generation and ISC activation that improves IEC recovery from radiation-induced injury. The results suggest that increasing PI3K signaling and induced mitochondrial respiration may improve mucosal healing from radiation injury in patients.
    Keywords:  IECs; Mitochondria; PI3K; ROS; Radiation; Stem Cell; p85α
    DOI:  https://doi.org/10.1016/j.ajpath.2025.04.010
  15. J Pharm Biomed Anal. 2025 Apr 23. pii: S0731-7085(25)00253-5. [Epub ahead of print]263 116912
    Untargeted LC-MS/MS- based metabolomics profiling of colorectal cancer cell lines reveals potential hypoxia-associated biomarkers.
    Refat M Nimer, Sara Arjah, Marya Obeidat, Saied A Jaradat, Ruba A Zenati, Yasser Bustanji, Mohammad H Semreen, Lina A Dahabiyeh.
      Colorectal cancer (CRC), a common cancer of the large intestine, is influenced by metabolic reprogramming due to hypoxia. Novel biomarkers may be identified through metabolomics. While many CRC studies have reported metabolomic profiling, the metabolic profile of CRC in the context of oxygen content has yet to be elucidated. Comprehending the metabolic alterations in cancer cells transitioning from normoxia (NMX) to hypoxia (HPX) and anoxia (ANX) is essential for the formulation of drugs that target particular metabolic pathways. Our study aimed to find metabolic changes in the HCT-116 CRC cell line under ANX, HPX, and NMX conditions, as well as to investigate novel biomarkers for CRC utilizing liquid chromatography-mass spectrometry (LC-MS/MS) based metabolomics approaches. Our findings showed significant changes in 77 metabolites in HCT-116 CRC cells across ANX, HPX, and NMX conditions, with 34 metabolites significantly disrupted in HPX compared to NMX, and 64 metabolites significantly changed in HPX compared to ANX. Significant differences included glutathione, gamma-glutamylcysteine, glycerophosphocholine, adenosine monophosphate, 5'-methylthioadenosine, guanosine 5'-diphosphate, threonic acid, and L-acetylcarnitine. Comprehending the metabolic changes in HPX, ANX, and NMX may uncover new pathways that could be targeted for potential treatments.
    Keywords:  Biomarkers; Colorectal cancer; Hypoxia; LC-MS/MS; Metabolomics
    DOI:  https://doi.org/10.1016/j.jpba.2025.116912
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