bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–10–05
eighteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Crotonate enhances intestinal regeneration after injury via HBO1-mediated H3K14 crotonylation.
  2. Lmo3-expressing peri-isthmus progenitor cells sustain renewal and repair of the mammalian intestinal telocyte niche.
  3. Distinct roles of branched-chain amino acids in the intestinal epithelium: Valine is essential for intestinal stem cell maintenance.
  4. Metabolic plasticity drives specific mechanisms of chemotherapy and targeted therapy resistance in metastatic colorectal cancer.
  5. Ferritinophagy Loss Drives Mitochondrial Iron Import and Colorectal Tumorigenesis.
  6. Dietary cysteine enhances intestinal stemness via CD8+ T cell-derived IL-22.
  7. Mast cells interact directly with colorectal cancer cells to promote epithelial-to-mesenchymal transition.
  8. Proteomic landscape of colorectal cancer liver metastasis.
  9. Reduced intestinal GLP-1 + cell numbers are associated with an inflammation-related epithelial metabolic signature.
  10. Spatially resolving cancer: from cell states to therapy.
  11. Pvf1-Pvr-mediated crosstalk between trachea and gut guides intestinal stem cell migration to promote gut regeneration.
  12. Microbial lipid shifts in a multi-stage simulated gut.
  13. Cytoplasmic TRIM24 promotes colorectal cancer cell proliferation by activating Wnt/β-catenin signaling.
  14. Alternatively Spliced Citrate Synthase Supports Colorectal Cancer.
  15. CRISPR/Cas9 screenings reveal the role of STX1A and CDK1 in Cathepsin G entering and killing colorectal cancer cells.
  16. Dissecting the impact of transcription factor dose on cell reprogramming heterogeneity using scTF-seq.
  17. Deacetylation of ACLY Mediates RNA M6A-Modification of NOXA and Promotes Chemoresistance of Colorectal Cancer.
  18. Exosomal FGG promotes colorectal cancer liver metastases through inducing angiogenic pre-metastatic niche formation.
  1. Nat Commun. 2025 Oct 02. 16(1): 8800
    Crotonate enhances intestinal regeneration after injury via HBO1-mediated H3K14 crotonylation.
    Yanhui Xiao, Shicheng Yu, Mengxian Zhang, Nanshan Zhong, Shan Hua, Zhi Fang, Zhe Zhang, Huidong Liu, Ronghui Tan, Yuan Liu, Ye-Guang Chen.
      The intestinal epithelium undergoes rapid turnover driven by Lgr5+ intestinal stem cells at the crypt base, and can recover upon damage. Histone crotonylation plays a critical role in chromatin regulation and gene expression. However, the role of histone crotonylation, specifically H3K14 crotonylation (H3K14cr) in the intestine remains poorly understood. Here we demonstrate that both crotonate and H3K14cr levels are increased in the regenerating crypts. Treatment with sodium crotonate significantly alleviates dextran sulfate sodium induced colitis, an effect largely dependent on HBO1-mediated H3K14cr. Notably, HBO1 deficiency severely dampens regeneration, correlating with reduced H3K14ac and H3K14cr levels, decreased chromatin accessibility at transcriptional start sites, and impaired expression of stem and fetal genes. Single-cell RNA sequencing analysis reveals that HBO1 is expressed in stem cells and regenerative cells during recovery after irradiation, further supporting the critical role of HBO1 in intestinal regeneration. Together, our findings uncover a mechanism by which crotonate, HBO1, and H3K14cr contribute to epithelial regeneration and suggest that crotonate may represent a promising therapeutic agent for the treatment of gastrointestinal diseases.
    DOI:  https://doi.org/10.1038/s41467-025-63869-2
  2. Dev Cell. 2025 Sep 26. pii: S1534-5807(25)00564-7. [Epub ahead of print]
    Lmo3-expressing peri-isthmus progenitor cells sustain renewal and repair of the mammalian intestinal telocyte niche.
    Daxin Jiang, Guoli Zhu, Yongchao Zhang, Jiawen Wang, Nannan Qian, Zhen Jin, Qingyu Sun, Haimeng Yu, Kebei Tang, Tao Cai, Fengchao Wang, Rongwen Xi.
      Intestinal telocytes that reside immediately beneath the intestinal epithelium exert niche-supporting roles for intestinal stem cells and their progenies. They are heterogeneous cells compartmentalized along the crypt-villus axis, but the mechanisms governing the maintenance of this telocyte population remain unclear. Here, we identify a distinct population of subepithelial mesenchymal cells in the developing mouse embryo, marked by LIM Domain Only 3 (Lmo3), as the cellular origin of post-natal intestinal telocytes. The Lmo3+ cells emerge prior to villus formation at embryonic day 13.5, and after birth, they progressively acquire a spatial confinement to the intestinal isthmus region, where they persist as long-lived, slow-cycling cells, supplying both peri-villus and peri-crypt telocytes. Further, we show that Lmo3+ cells respond rapidly to tissue damage, becoming activated to promote repair of the telocyte niche. Therefore, a quiescent and damage-responsive progenitor cell population marked by Lmo3 maintains the intestinal telocyte niche.
    Keywords:  BMP; FOXL1; LMO3; cell differentiation; intestinal telocyte; irradiation damage; mesenchymal cell niche; stem cell self-renewal; telocyte progenitor cell; villus formation
    DOI:  https://doi.org/10.1016/j.devcel.2025.09.004
  3. Biochem Biophys Res Commun. 2025 Sep 27. pii: S0006-291X(25)01440-8. [Epub ahead of print]786 152724
    Distinct roles of branched-chain amino acids in the intestinal epithelium: Valine is essential for intestinal stem cell maintenance.
    Ayumi Kozai, Yurika Tajima, Yuri Azuma, Yuri Hatanaka, Kinuko Uno, Miho Sasaki, Yuki Saito-Matsuzawa, Ken Iwatsuki, Makoto Shimizu, Yoshiko Sugita-Konishi, Katsuhiro Miyajima, Miki Tadaishi, Kazuo Kobayashi-Hattori.
      Intestinal stem cells (ISCs) are essential for epithelial regeneration and maintaining intestinal homeostasis. Although ISCs react quickly to nutritional changes, the effects of specific nutrients are not fully clear. Previously, using mouse intestinal organoids (enteroids), we demonstrated that a lack of valine (Val) may reduce their proliferation. Thus, we investigated how branched-chain amino acids (BCAAs), Val, leucine (Leu), and isoleucine (Ile), affect ISC functions. Val deprivation uniquely lowered enteroid formation, reduced the number of leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5)-positive cells, decreased proliferation, and increased apoptosis in ISCs. Additionally, mice on a Val-deficient diet for three weeks had shallower crypts, fewer proliferating intestinal epithelial cells, and less ex vivo enteroid formation. While removing Val or Leu did not alter ISC differentiation, Ile deprivation increased the number of enteroendocrine cells. These findings show that individual BCAAs have different effects on ISCs, with Val being crucial for ISC maintenance.
    Keywords:  Branched-chain amino acids; Enteroids; Intestine; Stem cells; Valine
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152724
  4. Explor Target Antitumor Ther. 2025 ;6 1002337
    Metabolic plasticity drives specific mechanisms of chemotherapy and targeted therapy resistance in metastatic colorectal cancer.
    Mariam Rojas, Malena Manzi, Sergio Madurga, Fernando Enrique García Velásquez, Maira Alejandra Romero, Silvia Marín, Marta Cascante, Joan Maurel.
      Microsatellite-stable metastatic colorectal cancer (MSS mCRC) is currently treated with chemotherapy and targeted agents based on RAS and BRAF mutational status. Although these therapies offer initial benefit, most patients rapidly develop resistance, with fewer than 20% remaining progression-free at two years. This review aims to synthesize emerging evidence on the metabolic mechanisms driving treatment resistance in MSS mCRC, with a particular focus on the immune-metabolic signature (IMMETCOLS) classification. We conducted a comprehensive review of preclinical models, transcriptomic datasets, and clinical trial results addressing metabolic adaptations to chemotherapy and targeted therapies in MSS mCRC. The IMMETCOLS framework defines three metabolic subtypes-IMC1, IMC2, and IMC3-each associated with distinct resistance mechanisms. IMC1 exhibits glycolysis and transforming growth factor-β (TGF-β)-dependent signaling enriched in inflammatory fibroblasts, conferring resistance to chemotherapy. IMC2 relies on oxidative phosphorylation and glutamine metabolism, supporting antioxidant defenses and resistance to both cytotoxic agents and anti-EGFR therapies. IMC3 demonstrates lactate-fueled respiration and pentose phosphate pathway activation, contributing to redox balance, DNA repair, and resistance to targeted therapies such as anti-BRAF or KRAS inhibitors. All subtypes display metabolic plasticity under therapeutic pressure. Emerging clinical data support tailoring targeted therapy combinations based on IMMETCOLS subtype, particularly in BRAF- and HER2-positive populations. Understanding subtype-specific metabolic rewiring in MSS mCRC offers novel opportunities to overcome drug resistance. Targeting the metabolic vulnerabilities defined by the IMMETCOLS signature may improve response durability and inform precision treatment strategies.
    Keywords:  IMMETCOLS; chemotherapy resistance; colorectal cancer; metabolic subtypes; targeted therapy
    DOI:  https://doi.org/10.37349/etat.2025.1002337
  5. Res Sq. 2025 Sep 23. pii: rs.3.rs-7483419. [Epub ahead of print]
    Ferritinophagy Loss Drives Mitochondrial Iron Import and Colorectal Tumorigenesis.
    Xiang Xue, Hyeoncheol Kim, Luke Villareal, Naiara Santana-Codina, Christian Cabanlong, Lavanya Goodla, Eric Prossnitz, David Martin, Joseph Mancias.
      Iron is an essential cofactor for mitochondrial metabolism, yet the regulatory networks linking cellular iron homeostasis to colorectal cancer (CRC) progression remain incompletely understood. Here, we identify nuclear receptor coactivator 4 (NCOA4), a ferritinophagy receptor, as a context-dependent tumor suppressor that coordinates cytosolic and mitochondrial iron handling in CRC. Analysis of human tumors and colon-specific Ncoa4 knockout mice revealed that NCOA4 loss drives tumorigenesis by inducing transferrin receptor-mediated iron uptake and mitochondrial calcium uniporter (MCU)-dependent mitochondrial iron import. This dual iron overload elevates mitochondrial reactive oxygen species, activates STAT3 signaling, and enhances tumor cell proliferation. NCOA4 overexpression reverses these effects, reducing MCU expression and tumor growth. Pharmacological inhibition of MCU, STAT3, or mitochondrial iron transport mitigated tumorigenesis in NCOA4-deficient models. Our findings define an NCOA4-MCU-STAT3 metabolic signaling axis that couples iron metabolism to oncogenic progression and reveal mitochondrial iron handling as a therapeutic vulnerability in CRC.
    DOI:  https://doi.org/10.21203/rs.3.rs-7483419/v1
  6. Nature. 2025 Oct 01.
    Dietary cysteine enhances intestinal stemness via CD8+ T cell-derived IL-22.
    Fangtao Chi, Qiming Zhang, Jessica E S Shay, Shixun Han, Johanna Ten Hoeve, Yin Yuan, Zhenning Yang, Heaji Shin, Samuel Block, Sumeet Solanki, Yatrik M Shah, Matthew G Vander Heiden, Judith Agudo, Ömer H Yilmaz.
      A fundamental question in physiology is understanding how tissues adapt and alter their cellular composition in response to dietary cues1-8. The mammalian small intestine is maintained by rapidly renewing LGR5+ intestinal stem cells (ISCs) that respond to macronutrient changes such as fasting regimens and obesogenic diets, yet how specific amino acids control ISC function during homeostasis and injury remains unclear. Here we demonstrate that dietary cysteine, a semi-essential amino acid, enhances ISC-mediated intestinal regeneration following injury. Cysteine contributes to coenzyme A (CoA) biosynthesis in intestinal epithelial cells, which promotes expansion of intraepithelial CD8αβ+ T cells and their production of interleukin-22 (IL-22). This enhanced IL-22 signalling directly augments ISC reparative capacity after injury. The mechanistic involvement of the pathway in driving the effects of cysteine is demonstrated by several findings: CoA supplementation recapitulates cysteine effects, epithelial-specific loss of the cystine transporter SLC7A11 blocks the response, and mice with CD8αβ+ T cells lacking IL-22 or a depletion of CD8αβ+ T cells fail to show enhanced regeneration despite cysteine treatment. These findings highlight how coupled cysteine metabolism between ISCs and CD8+ T cells augments intestinal stemness, providing a dietary approach that exploits ISC and immune cell crosstalk for ameliorating intestinal damage.
    DOI:  https://doi.org/10.1038/s41586-025-09589-5
  7. Oncogene. 2025 Oct 02.
    Mast cells interact directly with colorectal cancer cells to promote epithelial-to-mesenchymal transition.
    Rosie Lanzloth, Nicole L Harris, Anthony M Cannon, Mark H Kaplan, Heather M O'Hagan.
      Mast cells (MCs), a type of granulocytic immune cell, can be both pro- and anti-tumorigenic in colorectal cancer (CRC). We hypothesized that these contrasting findings may be in part due to differential interactions of MCs with CRC subtypes. BRAF mutant CRC uniquely contains intestinal secretory cell types. In this study, we demonstrated that MCs are enriched in BRAF mutant CRC, likely because they are recruited by factors released from cancer secretory cells. To investigate the functional consequences of MC-CRC cell interactions, we performed direct coculture experiments. We demonstrated that MCs promote epithelial-to-mesenchymal transition (EMT) in CRC cells in a calcium- and contact-dependent fashion. Furthermore, inhibiting LFA-1 and ICAM1 integrin binding reduced the coculture-induced EMT-related marker expression in CRC cells. The MC-CRC cell interaction facilitates the transfer of biological materials, including mRNA molecules, from MCs to CRC cells. This study is the first to report a contact-dependent, pro-tumorigenic role of MCs in CRC, as well as the transfer of molecules encoded by MCs to CRC cells. These findings enhance our comprehension of cell-cell communication between immune and cancer cells. Furthermore, this work suggests that targeting MC-CRC interactions, particularly through modulating integrin pathways, could offer new therapeutic strategies for aggressive CRC subtypes.
    DOI:  https://doi.org/10.1038/s41388-025-03589-5
  8. Transl Oncol. 2025 Sep 29. pii: S1936-5233(25)00289-X. [Epub ahead of print]62 102558
    Proteomic landscape of colorectal cancer liver metastasis.
    Ju Wu, Linlin Liu, Yaoyuan Chang, Xiaoyu Duan, Xi Chen, He Li, Zheng Wang, Lianyi Guo, Jiajun Yin.
       BACKGROUND: Colorectal cancer metastasis, especially liver metastasis, is characterized by significant intricate diversity and remains a major contributor to patient mortality. Despite its clinical importance, the precise molecular mechanisms driving metastasis remain poorly understood.
    METHODS: To investigate the molecular drivers of metastasis heterogeneity, we performed a comprehensive proteomic analysis of non-metastatic (NM) colorectal cancer tissues, as well as metachronous (MM) and synchronous (SM) metastatic tissues.
    RESULTS: Our analysis revealed distinct biological features associated with colorectal cancer liver metastasis. Notably, we identified P53-mediated hyperproliferation as a common initiating factor in the occurrence of CRC. Additionally, metabolic dysregulation emerged as a key hallmark of CRC liver metastasis. Importantly, MM tumors exhibited suppressed ferroptosis and activation of the TGF-β signaling pathway, while SM tumors displayed inhibited anoikis and activation of the WNT signaling pathway, accompanied by activated angiogenesis. Most strikingly, CEACAM6 was identified as the only protein exhibiting a stepwise decrease in expression from NM to MM and further to SM, underscoring its unique role in metastatic progression.
    CONCLUSIONS: These findings provide new insights into the molecular complexities underpinning colorectal cancer liver metastasis. Our identification of CEACAM6 as a differential marker highlights its potential as a diagnosis marker and therapeutic target, offering new avenues for the treatment of metastatic CRC.
    Keywords:  Biomarkers; Colorectal cancer; Liver metastasis; Proteomics analysis; Therapeutic targets
    DOI:  https://doi.org/10.1016/j.tranon.2025.102558
  9. bioRxiv. 2025 Sep 23. pii: 2025.03.05.641577. [Epub ahead of print]
    Reduced intestinal GLP-1 + cell numbers are associated with an inflammation-related epithelial metabolic signature.
    Elisabeth Urbauer, Doriane Aguanno, Katharina Kuellmer, Amira Metwaly, Nadine Waldschmitt, Mohamed Ahmed, Sevana Khaloian, Gabriele Hörmannsperger, Julien Planchais, Tobias Fromme, R Balfour Sartor, Harry Sokol, Dirk Haller, Eva Rath.
       Background & Aims: Enteroendocrine cells (EECs) are known for their role in digestion and metabolism, yet their role in intestinal inflammation remains unclear. In inflammatory bowel diseases (IBD), a contribution of EECs to pathogenesis is indicated by autoantibodies affecting EEC function and general disease symptoms like insulin resistance and altered intestinal motility. Particularly, the L cell-derived hormone glucagon-like peptide 1 (GLP-1), suggested to orchestrate metabolic-inflammatory responses may influence inflammatory pathways in the intestine.
    Methods: We quantified numbers of GLP-1 + cells in 4 different mouse models of intestinal inflammation and performed transcriptional analyses of colonic epithelial cells from inflamed interleukin (IL)10-deficient mice. Using a publicly available single-cell RNA sequencing dataset including mucosal biopsies from Crohn's disease (CD) patients, we confirmed findings from the murine models. A model of mitochondrial dysfunction (ClpP ΔIEC mice) as well as murine and human intestinal organoids were used to study molecular mechanisms.
    Results: Numbers of GLP-1 expressing cells are consistently reduced at the site of active disease in mouse models and CD patients. Despite this reduction, L cells from inflamed IL-10-deficient mice remained functional regarding GLP-1 secretion. Transcriptional analyses of intestinal epithelial cells indicate altered differentiation correlating with an inflammatory metabolic fingerprint. Reduced GLP-1 + cells in ClpP ΔIEC mice and inhibition of respiration in organoid cultures supports a causative role for metabolism in steering differentiation.
    Conclusion: Reduction of GLP-1 + cells represents a general feature of ileal and colonic inflammation in mice and human. Given the numerous properties of GLP-1, this reduction likely affects inflammatory processes in the mucosa and disease-related symptoms on multiple levels, and therefore, should be considered a therapeutic target in IBD.
    Data Transparency: All data generated or analyzed during this study are included in this published article. Additional datasets, including raw data, are available from the corresponding author upon reasonable request.
    Synopsis: This study examines GLP-1 + cells in intestinal inflammation, showing consistent reductions in inflamed areas. Findings from mouse models and human data reveal an inflammatory metabolic profile linked to altered epithelial differentiation. GLP-1, involved in endocrine-immune crosstalk, may impact mucosal inflammation and symptoms, making it a therapeutic target.
    DOI:  https://doi.org/10.1101/2025.03.05.641577
  10. Trends Cancer. 2025 Oct 02. pii: S2405-8033(25)00230-4. [Epub ahead of print]
    Spatially resolving cancer: from cell states to therapy.
    Guangsheng Pei, Yang Liu, Linghua Wang.
      Recent advances in spatial multi-omics technologies and analytical methods are transforming our understanding of how cancer cells and their microenvironments interact to drive critical processes such as lineage plasticity, immune evasion, and therapeutic resistance. By linking cancer cell states, lineage plasticity, clonal dynamics, oncogenic pathways, and cellular interactions to their spatial context, these innovations provide deep biological insights and reveal clinically relevant molecular programs and spatial biomarkers. This review highlights key breakthroughs in spatial profiling and computational approaches, including integration with computational pathology, multimodal data, and machine learning to uncover important biological insights. We discuss challenges in spatial multimodal data integration and emerging clinical applications, and we propose a roadmap to accelerate clinical translation and advance precision oncology through spatially resolved, actionable, molecular insights.
    Keywords:  cancer cell state; computational pathology; machine learning; multimodal data integration; spatial multi-omics; spatial profiling
    DOI:  https://doi.org/10.1016/j.trecan.2025.09.002
  11. Nat Commun. 2025 Sep 29. 16(1): 8597
    Pvf1-Pvr-mediated crosstalk between trachea and gut guides intestinal stem cell migration to promote gut regeneration.
    D J Mackay, A John, C F Christensen, E Connolly, R Loudhaief, A B Tanari, M Rauzi, J Colombani, D S Andersen.
      In adult tissues, stem cells (SCs) reside in specialized niches, where they remain relatively stationary state until activated by injury. While migration is essential for regeneration, mechanisms guiding SCs towards injury sites remain poorly understood due to challenges in tracking them in vivo. Here, we present an experimental framework to monitor intestinal SC (ISC) movement in real time during early gut regeneration. We identify the Drosophila PDGF-VEGF-related receptor, Pvr, as a critical regulator of this process, with ISC-specific Pvr depletion strongly impairing migration and regeneration. The ligand, Pvf1, produced by gut-associated trachea after damage, serves as a guidance cue directing ISCs towards injury sites. Our work highlights a critical role of gut-trachea crosstalk in guiding ISC migration during regeneration. As neovascularization of injury sites is a key feature of tissue repair in both flies and mammals, these findings could have broader implications for regenerative processes across diverse adult tissues.
    DOI:  https://doi.org/10.1038/s41467-025-63704-8
  12. bioRxiv. 2025 Sep 26. pii: 2025.09.25.678496. [Epub ahead of print]
    Microbial lipid shifts in a multi-stage simulated gut.
    Ifrat Tamanna, Katja Salonen, Helena Mannochio-Russo, Matilda Kråkström, Paulo Wender P Gomes, Vincent Charron Lamoureux, Ipsita Mohanty, Sofia D Forssten, Arthur C Ouwehand, Tuulia Hyötyläinen, Alex M Dickens, Pieter C Dorrestein, Matej Orešič, Santosh Lamichhane.
      Food residues that bypass human digestion are further digested by gut microbes, leading to the production of diverse metabolites, including lipids. To investigate how lipids are affected during this transition, we used a colon simulator with four distinct vessels that mimics the proximal to distal part of the human colon. We observed dynamic shifts in a diverse array of microbially derived lipid molecules in the simulated intestinal chyme, including bile acids and N -acyl amides with short and odd-chain lipids. Histamine-linked N -acyl lipids increased from the proximal to the distal colon vessels (pH 5.5 - 7.0), whereas putrescine-linked, initially abundant in the media, decreased across the colon vessels. We uncovered dynamic associations between in vitro-derived short-chain N -acyl lipids and major lipid species such as cholesterol esters, phosphatidylethanolamines, ceramides, and sphingomyelins. To determine the broader relevance of these findings, we applied a reverse metabolomics approach and examined lipid profiles in human small intestine and fecal samples from public datasets. This validated the colon simulator as a model for studying diet-derived and microbially transformed metabolites with relevance to human and animal health and could perhaps be used as a strategy to discover microbial metabolites.
    DOI:  https://doi.org/10.1101/2025.09.25.678496
  13. Nat Commun. 2025 Sep 29. 16(1): 8598
    Cytoplasmic TRIM24 promotes colorectal cancer cell proliferation by activating Wnt/β-catenin signaling.
    Ya Wang, Yuanbing Yao, Zehong Liu, Shichao Long, Feng Yi, Qing Fang, Dongbo Wu, Qing Zhu, Hongyan Zai, Shuai Xiao, Fengyi Wan, Kai Fu.
      Aberrant activation of Wnt/β-catenin signaling is proposed as a major molecular mechanism underlying the occurrence and progression of colorectal cancer (CRC). However, the precise mechanisms controlling the accumulation of β-catenin protein in CRC cells remain incompletely understood. Here, we show that TRIM24 is elevated in CRC tissues and partially distributed in the cytoplasm. TRIM24 is phosphorylated at serine 1042 by Aurora kinase B (AURKB), which promotes its cytoplasmic distribution. Subsequently, TRIM24 activates Wnt/β-catenin signaling by facilitating AKT activation through interaction with and ubiquitination of its negative regulator von Hippel-Lindau (VHL), resulting in β-catenin accumulation and enhanced proliferation of CRC cells. Moreover, chemical inhibition of AURKB suppresses tumor growth in subcutaneous mouse model and exhibits particular effectiveness against tumors derived from CRC cells characterized by prominent cytoplasmic TRIM24 distribution. Together, these findings reveal a critical role of TRIM24 in CRC cell proliferation, particularly through activating Wnt/β-catenin signaling.
    DOI:  https://doi.org/10.1038/s41467-025-63685-8
  14. Cancer Res. 2025 Oct 01. OF1-OF3
    Alternatively Spliced Citrate Synthase Supports Colorectal Cancer.
    Désirée Schatton, Christian Frezza.
      Metabolic changes are a major hallmark of cancer with the mitochondrial tricarboxylic acid (TCA) cycle playing a central role in this process. Remodeling of the TCA cycle occurs in cancer cells to sustain the increased anabolic and energetic demands required to grow, proliferate, and metastasize. Alternative splicing (AS) is increasingly recognized as a key regulator of cancer metabolism, yet its specific impact on TCA cycle enzymes remains unclear. In this issue of Cancer Research, Cheung and colleagues describe a novel splicing isoform of citrate synthase (CS), termed CS-ΔEx4, which is highly expressed in colorectal cancer. This CS-ΔEx4 isoform forms heterocomplexes with full-length CS, enhancing CS activity and promoting the metabolic reprogramming characteristic of malignancy. Overexpression of CS-ΔEx4 increases mitochondrial respiration and drives glycolytic carbon flux toward TCA intermediates, resulting in elevated levels of the metabolite 2-hydroxyglutarate. Mechanistically, this increase in 2-hydroxyglutarate, facilitated by increased activity of phosphoglycerate dehydrogenase, leads to epigenetic alterations that support oncogenic gene expression and tumor progression. Suppression of CS-ΔEx4 or pharmacologic inhibition of its activity reverts these metabolic and epigenetic changes, reducing cancer cell survival and metastatic potential. These findings establish a direct link between AS of a core metabolic enzyme and the emergence of cancer hallmarks, suggesting that targeting AS-derived variants like CS-ΔEx4 may represent a promising therapeutic strategy for colorectal cancer and potentially other malignancies in which such isoforms are expressed. See related article by Cheung et al., p. XX.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3356
  15. bioRxiv. 2025 Sep 26. pii: 2025.09.24.678097. [Epub ahead of print]
    CRISPR/Cas9 screenings reveal the role of STX1A and CDK1 in Cathepsin G entering and killing colorectal cancer cells.
    Yuxiang Wang, Valery Rozen, Trang Dinh, He Li, Yamu Li, Zhenghe Wang.
      Neutrophils are the major populations of white blood cells and have been reported to facilitate cancer metastasis. Meanwhile, emerging evidence has recently suggested the anti-cancer role of neutrophils. Our previous study revealed that CB-839 and 5-FU-treated colorectal cancer (CRC) tumors recruited neutrophils and induced neutrophil extracellular traps (NETs). Cathepsin G (CTSG), which is released during NET formation, enters CRC cells through the receptor for advanced glycation end products (RAGE) and cleaves 14-3-3ε to promote apoptosis. However, the detailed mechanism underlying CTSG's anti-tumor function remains less studied. In this study, we report that CTSG enters CRC cells through RAGE-mediated endocytosis. Knocking out RAGE or inhibiting endocytosis blocks CTSG from entering CRC cells and attenuates CTSG-induced apoptosis. Furthermore, the clathrin coat assembly complex and SNARE proteins were enriched in an arrayed CRISPR/Cas9 screening targeting human membrane trafficking genes. Knocking out SNARE protein STX1A prevents the spread of CTSG in CRC cells and the induction of cleaved PARP. A pooled genome-wide CRISPR/Cas9 screening further identifies the role of CDK1 in the NET-induced killing of CRC cells. Inhibiting CDK1 protected CRC cells from killing by CTSG. Our study reveals novel mechanisms by which CTSG enters and kills CRC cells.
    DOI:  https://doi.org/10.1101/2025.09.24.678097
  16. Nat Genet. 2025 Oct 03.
    Dissecting the impact of transcription factor dose on cell reprogramming heterogeneity using scTF-seq.
    Wangjie Liu, Wouter Saelens, Pernille Rainer, Marjan Biočanin, Vincent Gardeux, Antoni Jakub Gralak, Guido van Mierlo, Angelika Gebhart, Julie Russeil, Tingdang Liu, Wanze Chen, Bart Deplancke.
      Reprogramming often yields heterogeneous cell fates, yet the underlying mechanisms remain poorly understood. To address this, we developed single-cell transcription factor sequencing (scTF-seq), a single-cell technique that induces barcoded, doxycycline-inducible TF overexpression and quantifies TF dose-dependent transcriptomic changes. Applied to mouse embryonic multipotent stromal cells, scTF-seq generated a gain-of-function atlas for 384 mouse TFs, identifying key regulators of lineage specification, cell cycle control and their interplay. Leveraging single-cell resolution, we uncovered how TF dose shapes reprogramming heterogeneity, revealing both dose-dependent and stochastic cell state transitions. We classified TFs into low-capacity and high-capacity groups, with the latter further subdivided by dose sensitivity. Combinatorial scTF-seq demonstrated that TF interactions can shift from synergistic to antagonistic depending on the relative dose. Altogether, scTF-seq enables the dissection of TF function, dose and cell fate control, providing a high-resolution framework to understand and predict reprogramming outcomes, advancing gene regulation research and the design of cell engineering strategies.
    DOI:  https://doi.org/10.1038/s41588-025-02343-7
  17. Adv Sci (Weinh). 2025 Oct 02. e03323
    Deacetylation of ACLY Mediates RNA M6A-Modification of NOXA and Promotes Chemoresistance of Colorectal Cancer.
    Jun Wen, Mengqin Shen, Haitao Zhao, Liu Liu, Qian Hua, Xiaoping Zhao, Jianjun Liu, Haizhong Feng, Gang Huang.
      Chemoresistance is a major challenge for colorectal cancer (CRC) therapy and is a leading cause of cancer mortality, yet the underlying molecular mechanism remains unclear. ATP citrate lyase (ACLY), a rate-limiting enzyme of de novo lipid synthesis, plays an important role in tumor progression and chemotherapy. Here, It is demonstrated that deacetylation of ACLY is critical for chemoresistance in CRC. Through proteomic screening acetylated proteins in chemoresistant patient-derived cells, It is identified that ACLY is deacetylated at K978 site, which induces the relocation of ACLY to the nucleus and promotes its binding to RNA-binding protein 15 (RBM15). This facilitates N6-methyladenosine (m6A) methylation of NOXA (also known as PMAIP1, phorbol-12-myristate-13-acetate-induced protein 1) and decreases the stability of NOXA mRNA, resulting in chemoresistance. With the selective inhibitor Santacruzamate A, targeting the deacetylase histone deacetylase 2 (HDAC2) to inhibit the acetylation may enhance the sensitivity of chemoresistance. These findings provide new insights into the mechanism of ACLY deacetylation promoting chemoresistance and suggest a potential therapeutic strategy to mitigate the chemoresistant effects.
    Keywords:  ACLY; acetylation; chemoresistance; colorectal cancer; m6A
    DOI:  https://doi.org/10.1002/advs.202503323
  18. Arch Biochem Biophys. 2025 Sep 25. pii: S0003-9861(25)00339-X. [Epub ahead of print]774 110625
    Exosomal FGG promotes colorectal cancer liver metastases through inducing angiogenic pre-metastatic niche formation.
    Lingling Yang, Lifang Chen, Xin Chen, Haiqiang Huang, Hui Zhu, Liangtao Zeng, Jun Huang, Hao Ding.
      Angiogenesis is a defining feature of a pre-metastatic niche and is essential for primary colorectal cancer (CRC) tumor metastasis. Epithelial-mesenchymal transition (EMT) also serves as a critical driver of CRC tumor metastatic progression. Here, we hypothesized that exosomes from CRC cells promoted liver metastasis by remodeling tumor microenvironment. To verify this hypothesis, exosomes from CRC cells were isolated and identified, and the effects of these exosomes on human umbilical vein endothelial cells (HUVECs) were investigated. Exosomes from CRC cells promoted vascularization, permeability and migration of HUVECs. Mechanistically, exosomes derived from CRC cells delivered Fibrinogen gamma (FGG) to exert their effects on HUVECs. Furthermore, FGG downregulated the levels of VE-cadherin and E-cadherin in CRC cells, while upregulating N-cadherin and vimentin levels, thereby enhancing endothelial permeability and promoting EMT. In vivo experiments demonstrated that FGG downregulated VE-cadherin in CRC tissues and upregulated CD31 in liver tissues, ultimately leading to an increased number of metastatic liver nodules in a mouse model of CRC liver metastasis. In conclusion, FGG facilitates CRC liver metastasis by regulating key angiogenic, adhesion and mesenchymal markers via exosome-mediated mechanisms, resulting enhanced angiogenesis, vascular permeability, and EMT induction. These findings offer new insights into the mechanisms and treatment strategies of CRC liver metastasis.
    Keywords:  Colorectal cancer; Fibrinogen gamma; Liver metastasis; Pre-metastatic niche; VE-Cadherin
    DOI:  https://doi.org/10.1016/j.abb.2025.110625
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