bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–06–15
eight papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. eIF5A maintains intestinal epithelial homeostasis by sustaining intestinal stem cells.
  2. Dietary lipids, not ketone body metabolites, influence intestinal tumorigenesis in a ketogenic diet.
  3. To play Paneth or goblet: Shapeshifting secretory cells read the room.
  4. GCLM lactylation mediated by ACAT2 promotes ferroptosis resistance in KRASG12D-mutant cancer.
  5. Targeting Neutrophil Extracellular Traps to inhibit Colon Cancer Tumor Necrosis and Metastasis.
  6. Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer.
  7. CRABP2 promotes peritoneal metastasis in CRC through TGF-β/Smad-mediated EMT signaling and invadopodia formation.
  8. Exercise reduces the risk of colon cancer recurrence.
  1. Cell Regen. 2025 Jun 09. 14(1): 23
    eIF5A maintains intestinal epithelial homeostasis by sustaining intestinal stem cells.
    Leilei Li, Yanhui Xiao, Liansheng Liu, Qianying Zhang, Yong Zhang, Dahai Zhu, Ye-Guang Chen.
      Intestinal homeostasis is sustained by self-renewal of intestinal stem cells (ISCs), which continuously divide and produce proliferative transit-amplifying (TA) and then progenitor cells. Eukaryotic translation initiation factor 5A (eIF5A), a conserved translation factor, involves in a variety of cellular processes, yet its role in intestinal homeostasis remains unclear. Here, we demonstrate that eIF5A is indispensable for maintaining intestinal epithelial homeostasis. Conditional knockout of Eif5a in the adult mouse intestinal epithelium leads to stem cell loss, suppressed cell proliferation, and increased apoptosis within the crypts, concurrent with shortened gut length, reduced mouse body weight and rapid animal mortality. Consistently, Eif5a deletion in intestinal organoids also exhibits resembling cellular phenotypes. Mass spectrometry analysis reveals a significant downregulation of mitochondrial proteins, particularly those involved in mitochondrial translation, upon eIF5A depletion. Analysis of a published single-cell RNA sequencing dataset shows that mitochondrial translation-related genes, including Dars2, are highly expressed in ISC, TA and progenitor cells. Furthermore, eIF5A-deficient organoids exhibit impaired mitochondrial function, characterized by reduced ATP levels and increased reactive oxygen species (ROS). These findings highlight a critical role for eIF5A in sustaining intestinal epithelial homeostasis by regulating mitochondrial translation, providing a new insight into the molecular mechanism underlying intestinal stem cell renewal and tissue maintenance.
    Keywords:  Intestinal homeostasis; Intestinal stem cells; Mitochondrial translation; eIF5A
    DOI:  https://doi.org/10.1186/s13619-025-00243-z
  2. bioRxiv. 2025 Jun 07. pii: 2025.06.06.658169. [Epub ahead of print]
    Dietary lipids, not ketone body metabolites, influence intestinal tumorigenesis in a ketogenic diet.
    Jessica E S Shay, Fangtao Chi, Constantine N Tzouanas, Johanna Ten Hoeve, Kevin J Williams, Tolga Sever, Isabela Fuentes, Ömer H Yilmaz.
      Diet composition shapes tissue function and disease risk by modulating nutrient availability, metabolic state, and cellular dynamics. In the gastrointestinal tract, obesogenic high-fat diets enhance intestinal stem cell activity and tumorigenesis. However, the impact of ketogenic diets (KD), which contain even higher lipid content but induce ketogenesis, remains poorly understood. This is particularly relevant for patients with familial adenomatous polyposis (FAP), who face a high risk of small intestinal tumours. Here, we combine dietary, genetic, and metabolic manipulations in mouse models of spontaneous intestinal adenoma formation to dissect the role of systemic and epithelial ketogenesis in intestinal cancer. We show that KD accelerates tumour burden and shortens survival, independent of ketone body production. Through genetic manipulation of the ketogenic pathway, we modulate local and systemic ketone body production; however, neither inhibition nor augmentation of the ketogenic enzyme HMGCS2 nor disruption of ketolysis altered tumour progression. In contrast, inhibition of fatty acid oxidation did limit adenomatous formation. These findings reveal that dietary lipid content, through FAO rather than ketone body metabolism, influences intestinal tumorigenesis and highlight the need for nuanced consideration of dietary strategies for cancer prevention in genetically susceptible populations.
    DOI:  https://doi.org/10.1101/2025.06.06.658169
  3. Cell Stem Cell. 2025 Jun 05. pii: S1934-5909(25)00186-9. [Epub ahead of print]32(6): 861-863
    To play Paneth or goblet: Shapeshifting secretory cells read the room.
    Irene V Choi, Rachel K Zwick.
      The intestinal secretory lineage is thought to comprise four distinct cell types derived from one Atoh1+ progenitor, but the mechanisms that distinguish Paneth and goblet cells are unclear. Bhattacharya et al.1 argue that these cells are instead phenotypic manifestations of a common terminal Atoh1+ cell, actively shaped by niche-derived signals.
    DOI:  https://doi.org/10.1016/j.stem.2025.05.006
  4. Cell Rep. 2025 Jun 09. pii: S2211-1247(25)00545-5. [Epub ahead of print]44(6): 115774
    GCLM lactylation mediated by ACAT2 promotes ferroptosis resistance in KRASG12D-mutant cancer.
    Yubin Chen, Qian Yan, Shiye Ruan, Jinwei Cui, Zhenchong Li, Zhongyan Zhang, Jiayu Yang, Jike Fang, SiYang Liu, Shanzhou Huang, Baohua Hou, Chuanzhao Zhang.
      KRAS mutations drive tumorigenesis, but their role in ferroptosis regulation remains unclear. Here, we construct wild-type KRAS (KRASWT) and KRASG12D-mutant cancer cells and demonstrate that G12D-mutant cells exhibit increased viability and reduced ferroptosis upon RSL3 or erastin treatment. These cells show diminished lipid peroxidation and mitochondrial damage, indicating ferroptosis resistance. KRASG12D activates MEK/ERK signaling to phosphorylate LDHA, enhancing glycolysis and lactate production. Exogenous lactate supplementation similarly protects WT cells from ferroptosis. Mechanistically, G12D-mutation-derived lactate induces glutamate-cysteine ligase (GCL) modifier (GCLM) lactylation, a process catalyzed by acetyl-coenzyme A (CoA) acetyltransferase 2 (ACAT2). Inhibition of GCLM lactylation either through the mutation of the lactylation site or by knockdown of ACAT2 diminished the enzymatic activity of GCL and suppressed glutathione synthesis. Importantly, ACAT2 depletion overcomes ferroptosis resistance in KRASG12D-mutant tumors in vivo. Our findings reveal a KRASG12D-driven metabolic adaptation linking GCLM lactylation to ferroptosis resistance, proposing ACAT2 inhibition as a therapeutic strategy for KRAS-mutant cancers.
    Keywords:  CP: Cancer; CP: Metabolism; GCLM; KRAS mutation; ferroptosis; glutamate-cysteine ligase modifier; pancreatic cancer; protein lactylation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115774
  5. bioRxiv. 2025 Jun 06. pii: 2025.05.30.657122. [Epub ahead of print]
    Targeting Neutrophil Extracellular Traps to inhibit Colon Cancer Tumor Necrosis and Metastasis.
    E Gazzara, J M Adrover, A Lui, S Han, Z Aminzada, N Bhandari, N Sivetz, V S Shirue, B S Shergill, M B Curtis, S C George, A Cicala, A Rishi, C Chung, C Devoe, H Huang, M Weiss, E Lou, D A Tuveson, S Beyaz, P M K Westcott, M Egeblad, S Gholami.
      Necrosis, conventionally thought of as a passive consequence of aggressive tumor growth, is associated with poor prognosis in colorectal cancer (CRC). We recently discovered that necrosis can be caused by neutrophils and neutrophil extracellular traps (NETs) aggregates driving vascular occlusion within the tumor vasculature in models of breast cancer. Here, we evaluated the role of NETs in inducing necrosis and metastasis in CRC. We found that the numbers of neutrophils primed to form NETs were elevated in the circulation of patients with CRC as compared to controls. CD177 Low neutrophils were also elevated, and they showed reduced extravasation capacity with intact ability to form NETs. The extent of necrosis correlated with metastasis (stage IV disease), independent of tumor size, in our human cohort. In both human and murine CRC tumors, necrotic regions were characterized by neutrophil infiltration and NET accumulation, and NET aggregates were observed in the vasculature next to the necrotic regions. Single cell RNA sequencing and spatial transcriptomic analysis of human CRC and liver metastases revealed that necrotic tumors activate pathways associated with increased metastatic potential, including epithelial-to-mesenchymal-transition. Using a mouse model of DNA mismatch repair proficient CRC, we found neutrophil infiltration and NETs increased with tumor progression. Genetic or pharmacological inhibition of NET formation decreased necrosis and metastasis, and importantly enhanced chemotherapy efficacy. Altogether, our findings show that NET formation in human CRC is a key feature of tumor necrosis, that it is associated with metastasis, and further suggest that preventing NET formation may offer clinical benefits to CRC patients.
    DOI:  https://doi.org/10.1101/2025.05.30.657122
  6. Br J Cancer. 2025 Jun 06.
    Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer.
    Beatriz Rubio-Cuesta, Carlos Carretero-Puche, Patricia Llamas, Jacinto Sarmentero, Beatriz Gil-Calderon, Alberto Lens-Pardo, Beatriz Antón-Pascual, Eduardo Rubio-González, María Cámara-Jurado, Javier Salamanca, Daniel Rueda-Fernández, Marco Donatello Delcuratolo, Beatriz Soldevilla, Rocio Garcia-Carbonero.
       BACKGROUND: BRAFV600E mutations occur in ∼10% of colorectal cancer (CRC) patients, leading to poor prognosis. Although BRAF-targeted therapy is ineffective in CRC, adding EGFR inhibitors (EGFRi) improves efficacy, yet patient survival remains suboptimal. This study explores SRC as a key mediator of resistance to BRAF inhibitors (BRAFi) in preclinical BRAFV600E CRC models, and its potential as a therapeutic target.
    METHODS: We studied SRC using BRAF-mutated and wild-type CRC cell lines with CRISPR/Cas9 knockouts and lentiviral overexpression. We tested SRC, BRAF, EGFR, and JNK targeting drugs, assessing protein expression, cell viability, proliferation, migration, apoptosis, and cell cycle. CRC cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models were established for in vivo studies.
    RESULTS: SRC regulates proliferation, clonogenicity, migration and mediates BRAFi resistance in BRAFV600E CRC, regardless of microsatellite instability. Depletion or inhibition of SRC sensitized cells to BRAFi. Combined SRC and BRAF inhibition demonstrated a synergistic antitumor effect, reducing cell viability and inducing apoptosis and cell cycle arrest in cell lines and PDXs. The JNK/c-Jun pathway contributes to adaptive resistance, and its inhibition enhances the effects of dual SRC and BRAF inhibition.
    CONCLUSIONS: These findings identify new therapeutic targets for clinical trials, potentially improving outcomes for this high-risk CRC subgroup.
    DOI:  https://doi.org/10.1038/s41416-025-03058-6
  7. Cell Signal. 2025 Jun 10. pii: S0898-6568(25)00342-0. [Epub ahead of print]134 111927
    CRABP2 promotes peritoneal metastasis in CRC through TGF-β/Smad-mediated EMT signaling and invadopodia formation.
    Wende Hao, Xichen Dong, Zhenjun Wang, Tao Wen, Lijie Liu, Tao Gu, Huachong Ma.
      Peritoneal metastasis (PM) in colorectal cancer (CRC) is typically associated with a lower likelihood of successful conversion therapy and a poorer prognosis compared to metastases at other sites. Invadopodia, cancer-specific protrusive structures, play a vital role in the metastatic cascade by degrading the basement membrane and surrounding stroma. However, the exact mechanism of invadopodia regulation in PM of CRC still remains unclear. In the research, we have found that CRABP2 as a PM-associated differentially expressed gene (DEG) that promoted cell protrusion formation in CRC. CRABP2 was reported to be significantly overexpressed and correlated with poor prognostic features in CRC by integrated bioinformatics analysis and experiments, and CRABP2 also promoted CRC metastasis in vivo and vitro. Moreover, the enrichment analyses and verification assays indicated that CRABP2 may be involved in PM resulting from invadopodia formation and TGF-β/Smad-mediated epithelial-mesenchymal transition (EMT) signaling pathway in CRC. CRC patients in high-CRABP2 expression group were further suggested to have more genetic variants and better responses to several potential drugs and compounds. Finally, single-cell RNA sequencing (scRNA-seq) analysis revealed that CRABP2-associated epithelial cells exhibited enhanced communication with mesothelial cells via the CDH1 signaling pathway in CRC with PM. CRABP2 is a promising novel diagnostic and prognostic biomarker for CRC with PM, and its metastatic mechanisms indicate that CRABP2 may represent a vital therapeutic target that can be utilized for the clinical management of PM in CRC in the future.
    Keywords:  CRABP2; Colorectal cancer; Epithelial-mesenchymal transition; Invadopodia; Peritoneal metastasis
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111927
  8. Nat Med. 2025 Jun 09.
    Exercise reduces the risk of colon cancer recurrence.
    Karen O'Leary.
      
    Keywords:  Cancer; Clinical trials; Lifestyle modification
    DOI:  https://doi.org/10.1038/d41591-025-00038-4
This page is being maintained by Thomas Krichel. It was last updated on 2025‒06‒15 at 14:40.