bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–10–12
sixteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Adiponectin Regulated by Indole-3-Acetic Acid in Paneth Cells Controls Renewal and Differentiation of Gut Stem Cells.
  2. Reduced intestinal GLP-1+ cell numbers are associated with an inflammation-related epithelial metabolic signature.
  3. Stromal cells in normal colon and colon cancers: importance of thyroid hormone signaling.
  4. Cancer-associated fibroblasts expressing FSTL3 promote vasculogenic mimicry formation and drive colon cancer malignancy.
  5. Hijacked brain-gut polysynaptic pathway promotes colorectal cancer growth.
  6. ETV1 is a key regulator of enteroendocrine PYY production.
  7. Acidosis orchestrates adaptations of energy metabolism in tumors.
  8. YEATS4 reads histone crotonylation to promote fatty acid metabolism and cancer cell stemness.
  9. Senescence-coupled differentiation selectively eliminates cancer-prone stem cells.
  10. SMAD4 mutation drives gut microbiome shifts toward tumor progression in colorectal cancer.
  11. Current and emerging concepts for systemic treatment of metastatic colorectal cancer.
  12. Decoding ferroptosis for cancer therapy.
  13. Atg16l1 and Xbp1 cooperatively protect from transcription-associated mutagenesis and small intestinal carcinogenesis.
  14. The integration of single-cell and metabolomics reveals the increase of oxidative phosphorylation during the liver metastasis of colorectal cancer.
  15. A Notch signal pathway related gene signature predicts overall survival in colorectal cancer.
  16. Inflammation and mutational burden differentially associated with nivolumab or ipilimumab combination efficacy in colorectal cancer.
  1. FASEB J. 2025 Oct 15. 39(19): e71101
    Adiponectin Regulated by Indole-3-Acetic Acid in Paneth Cells Controls Renewal and Differentiation of Gut Stem Cells.
    Hang Liu, Xiaomin Su, Juanjuan Wang, Mengli Jin, Yuan Zhang, Rongcun Yang.
      The intestinal epithelium is tightly regulated by intestinal stem cells (ISCs), but the precise mechanisms governing their differentiation remain incompletely understood. We here demonstrate that adiponectin secreted by Paneth cells (PCs) suppresses ISC renewal and differentiation via adiponectin receptor 1 (adipoR1). Genetic ablation of adiponectin in gut epithelial cells (adipfl/fl-Villi-Cre mice) enhanced crypt cell renewal and differentiation. Single-cell RNA sequencing (scRNA-seq) revealed a significant increase in the enrichment of ISCs and transit-amplifying (TA) cells in adipfl/fl-Villi-Cre mice compared to control adipfl/fl mice. Furthermore, adipfl/fl/-Villi-Cre mice exhibited accelerated regeneration of intestinal epithelial cells following irradiation or dextran sulfate sodium (DSS)-induced injury. Intestinal organoids derived from adipfl/fl-Villi-Cre mice also displayed markedly faster growth than those from adipfl/fl mice. Consistent with these findings, adipoR1 knockout (KO) mice exhibited elongated crypt structures, further supporting adiponectin's inhibitory role in ISC proliferation. Notably, gut microbiota-derived indole-3-acetic acid (IAA) downregulated adiponectin expression, thereby promoting ISC renewal and proliferation. This was corroborated by in vitro organoid cultures, where IAA treatment accelerated development. Thus, our findings reveal that adiponectin modulated by microbial IAA serves as a critical regulator of ISC dynamics, ensuring epithelial homeostasis.
    Keywords:  Paneth cells; adiponectin; gut epithelial cells; indole‐3‐acetic acid; intestinal stem cells
    DOI:  https://doi.org/10.1096/fj.202501229RR
  2. Cell Mol Gastroenterol Hepatol. 2025 Oct 03. pii: S2352-345X(25)00197-3. [Epub ahead of print] 101656
    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 (ClpPΔIEC 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 ClpPΔIEC 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.
    Keywords:  Enteroendocrine cells; Glucagon-like peptide 1; L cells; inflammatory bowel disease
    DOI:  https://doi.org/10.1016/j.jcmgh.2025.101656
  3. Cell Death Dis. 2025 Oct 06. 16(1): 699
    Stromal cells in normal colon and colon cancers: importance of thyroid hormone signaling.
    Mathieu Reslinger, Michelina Plateroti.
      Thyroid hormones (THs, namely T3 and T4) regulate intestinal development and homeostasis via thyroid hormone nuclear receptors (TRs), which are T3-modulated transcription factors. Previous work has highlighted the importance of THs and the TRα1 receptor in intestinal stem cell biology and tumor formation, through actions on WNT, NOTCH, and BMP signaling pathways, which mediate epithelial-stromal cell interactions. Recent findings underscore the critical role of stromal cells in maintaining homeostasis and interacting with colonic stem cells. Stromal cells, especially cancer-associated fibroblasts (CAFs), are also essential in colorectal cancer (CRC). While the TH/TR signaling on gut epithelia-stromal interactions is well characterized in amphibians during the TH-dependent metamorphosis process, its function in the normal mammalian colon is still poorly defined, and in CRCs, it remains underexplored. In addition, it is worth underlining that TRα1 mutations in patients are responsible for Resistance to Thyroid Hormone-α (RTH-α) syndrome. This syndrome is a complex pathology that recapitulates typical traits of hypothyroidism, including gut malfunction. Up to now, very little is known about the cellular alterations in the gut of RTH-α patients. This review summarizes recent studies on the roles of T3 and TRα1 in colon physiopathology, with an emphasis on epithelial/stromal or tumor/stromal interactions via cell-cell signaling.
    DOI:  https://doi.org/10.1038/s41419-025-08005-0
  4. Cell Death Dis. 2025 Oct 06. 16(1): 706
    Cancer-associated fibroblasts expressing FSTL3 promote vasculogenic mimicry formation and drive colon cancer malignancy.
    Leqian Ying, Yini Zhu, Lu Zhang, Min Ji, Meidan Wang, Lei Dong, Zhengcheng Yun, Yanping Chen, Jingyi Zhou, Chunchun Huang, Shengwei Zhang, Xuhong Yang, Hui Yang, Guichun Huang, Shukui Qin, Jinbing Xie, Lin Liu.
      Anti-angiogenic therapies are commonly employed in colon cancer management, yet many patients eventually develop resistance and experience disease progression. Vasculogenic mimicry (VM)-the formation of tumor-derived vessel-like networks-has been recognized as one mechanism contributing to this resistance, although the underlying details remain incompletely understood. Here, by integrating bioinformatic analyses of publicly available datasets and validating the results in patient samples (n = 157), we identified follistatin-like 3 (FSTL3) as a critical factor predominantly expressed in colon cancer-associated fibroblasts (CCAFs), with its expression strongly correlating with increased VM formation, intratumoral blood vessels, and poor prognosis. Single-cell RNA sequencing of tumors from VM and non-VM patients revealed that hypoxia drives FSTL3 expression in CCAFs, leading to extracellular matrix remodeling and enhancing cancer cell endothelial-like plasticity. Mechanistically, FSTL3 binds to transferrin receptor (TfR1), an iron-uptake receptor on cancer cells, thereby activating the TfR1/AKT/mTOR pathway and elevating VE-Cadherin to support endothelial-like transformation, VM, and metastatic progression. Notably, FSTL3-targeting antibodies (aFSTL3) effectively inhibited VM and angiogenesis in both in vitro and in vivo models, while the combination of aFSTL3 with bevacizumab produced synergistic suppression of neovascular-like structures and distant metastases. These findings demonstrate a pivotal role for FSTL3+ CCAFs in facilitating VM through TfR1-mediated signaling and offer a promising dual-target approach to overcome anti-angiogenic therapy resistance in colon cancer.
    DOI:  https://doi.org/10.1038/s41419-025-08009-w
  5. Nat Cancer. 2025 Oct 07.
    Hijacked brain-gut polysynaptic pathway promotes colorectal cancer growth.
      
    DOI:  https://doi.org/10.1038/s43018-025-01050-w
  6. Dis Model Mech. 2025 Oct 06. pii: dmm.052610. [Epub ahead of print]
    ETV1 is a key regulator of enteroendocrine PYY production.
    Astrid M Baattrup, Marianne Terndrup Pedersen, Stine L Hansen, Martti Maimets, Fiona Gribble, Frank Reimann, Kim B Jensen.
      Background The intestine constitutes the largest endocrine organ and is a rich source of hormones that regulate metabolism. Enteroendocrine cells (EECs) can be subtyped based on their secretion of specific hormones with L-cells being characterised by expression of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). Collectively, these hormones play important roles in appetite regulation, however, it is not known, how they are regulated transcriptionally. The ETS Variant Transcription Factor 1 (ETV1) is expressed by L-cells, but its function remains unknown. Methods We examined Etv1 expression in single-cell-RNA-sequencing (scRNA-seq) datasets from the mouse small intestine and from organoid cultures. To assess the functional role of ETV1 in EECs, ETV1 loss-of-function and overexpression experiments were performed in murine small intestinal organoids. Gene expression was subsequently assessed with qPCR and scRNA-seq. Results We confirmed that Etv1 is enriched in the L-cell lineage both in vivo and in organoid cultures. Furthermore, we find that mutations of ETV1 in organoids led to a decrease in Pyy expression levels with no effect on Gcg levels or on overall cell composition and organoid morphology. Moreover, overexpression of ETV1 led to a modest but specific increase in Pyy levels. Conclusions We identify ETV1 as a regulator of Pyy expression illustrating for the first time how specific hormone levels in the L-cell lineage are transcriptionally regulated.
    Keywords:  ETV1; Enteroendocrine cells; GLP-1; Intestinal organoids; L-cells; PYY
    DOI:  https://doi.org/10.1242/dmm.052610
  7. Science. 2025 Oct 09. 390(6769): eadp7603
    Acidosis orchestrates adaptations of energy metabolism in tumors.
    Sven Groessl, Robert Kalis, Marteinn T Snaebjornsson, Leon Wambach, Jakob Haider, Florian Andersch, Almut Schulze, Wilhelm Palm, Johannes Zuber.
      Malignant tumors are characterized by diverse metabolic stresses, including nutrient shortages, hypoxia, and buildup of metabolic by-products. To understand how cancer cells adapt to such challenges, we conducted sequential CRISPR screens to identify genes that affect cellular fitness under specific metabolic stress conditions in cell culture and to then probe their relevance in pancreatic tumors. Comparative analyses of hundreds of fitness genes revealed that cancer metabolism in vivo was shaped by bioenergetic adaptations to tumor acidosis. Mechanistically, acidosis suppressed cytoplasmic activity of extracellular signal-regulated kinase (ERK), thereby preventing oncogene-induced mitochondrial fragmentation and promoting fused mitochondria. The resulting boost in mitochondrial respiration supported cancer cell adaptations to various metabolic stresses. Thus, acidosis is an environmental factor that alters energy metabolism to promote stress resilience in cancer.
    DOI:  https://doi.org/10.1126/science.adp7603
  8. Cell Rep. 2025 Oct 07. pii: S2211-1247(25)01171-4. [Epub ahead of print]44(10): 116400
    YEATS4 reads histone crotonylation to promote fatty acid metabolism and cancer cell stemness.
    Zijun Peng, Huajing Yu, Yizhou Wang, Dan Zhao, Hangwei Fa, Leyi Qin, Yilei Ma, Mengyang Geng, Yuqing Wu, Ge Wu, Xin Wu, Chengying Zhang, Yue Wang, Jianying Liu, Haitao Li, Zhimin Lu, Yongfeng Shang, Jing Liang.
      How histone lysine crotonylation (Kcr) is read and interpreted remains to be elucidated. We report here that YEATS4, a potential breast cancer driver identified recently by two independent genome-wide association studies, is a reader of H3K14cr. Integrative metabolomic, epigenomic, and transcriptomic analyses reveal that H3K14cr reading by YEATS4 is associated with a shift of cellular metabolic profile and transcription activation of a cohort of genes, including CD36, CPT1A, and ACOX1, that are critically involved in the uptake and metabolism of fatty acids. High expression of YEATS4 fortifies fatty acid metabolism, enhances self-renewal and growth of ALDH+ breast cancer stem cells, and is correlated with poor prognosis of breast cancer patients, especially the ER+ subtype. Our work uncovers YEATS4 as an "amplifier" in the feedforward circuit of histone crotonylation and lipid metabolism underlying the stemness and cell proliferation, supporting the pursuit of YEATS4 as a potential target for breast cancer intervention.
    Keywords:  CP: Cancer; CP: Molecular biology; YEATS4; breast cancer stemness; fatty acid metabolism; histone crotonylation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116400
  9. Nat Cell Biol. 2025 Oct 07.
    Senescence-coupled differentiation selectively eliminates cancer-prone stem cells.
      
    DOI:  https://doi.org/10.1038/s41556-025-01783-x
  10. Discov Oncol. 2025 Oct 09. 16(1): 1841
    SMAD4 mutation drives gut microbiome shifts toward tumor progression in colorectal cancer.
    Travis J Gates, Dechen Wangmo, Kyra M Boorsma Bergerud, Bridget M Keel, Christopher Staley, Subbaya Subramanian.
       BACKGROUND: Colorectal cancer (CRC) progression is driven by a series of sequential mutations in key driver genes; however, the factors underlying tumor progression and metastasis remain poorly understood. Mutations in TP53 and SMAD4, in particular, are associated with CRC progression. Although gut microbiome dysbiosis is implicated in CRC initiation and progression, the interactions between the microbiome and specific CRC driver mutations, especially those promoting metastasis, are not well defined.
    METHODS: In this study, we utilized triple mutant (Apc, Kras, Tp53; AKP) and quadruple mutant (Apc, Kras, Tp53, Smad4; AKPS) organoid-based orthotopic mouse models of CRC to investigate the impact of the SMAD4 mutation on microbiome composition.
    RESULTS: Our results reveal significant differences in metastatic potential and microbial community dynamics between the two tumor models. AKPS tumors exhibited metastasis to the lymph nodes, liver, and lungs, while AKP tumors remained confined to the colon. Longitudinal microbiome analysis showed shifts in microbial composition within each tumor model. Both AKP and AKPS models demonstrated enrichment of Faecalibaculum and a decrease in Dubosiella over time; however, additional shifts were noted with distinct taxa associated with late-stage tumors in each group. Notably, the AKPS model exhibited higher relative abundances of pro-inflammatory taxa, including Turicibacter, Romboutsia, and Akkermansia, suggesting that the SMAD4 mutation promotes a more immunosuppressive and pro-metastatic microbiome profile.
    CONCLUSIONS: These findings emphasize  the significance of SMAD4 mutation and microbiome modulation, revealing the interaction between host genetics and gut microbiota in driving colorectal cancer aggressiveness and suggesting potential microbial targets.
    Keywords:  Colorectal cancer; Driver gene mutations; Gut microbiome; Metastasis; SMAD4
    DOI:  https://doi.org/10.1007/s12672-025-02580-6
  11. Gut. 2025 Oct 05. pii: gutjnl-2025-335412. [Epub ahead of print]
    Current and emerging concepts for systemic treatment of metastatic colorectal cancer.
    Christoph Steup, Kilian Kennel, Markus F Neurath, Stefan Fichtner-Feigl, Florian Greten.
      Colorectal cancer (CRC) is one of the most common malignant cancers and its incidence is steadily rising particularly in young patients. While screening measures and the widespread availability of surgical treatment have led to an impressive improvement of prognosis within the overall CRC population, patients with metastatic CRC still face 5-year survival rates of around 10-25%. Despite continuous development of new systemic treatment strategies that include cytotoxic chemotherapy and targeted therapy, most patients with metastatic CRC eventually progress. However, a small proportion of patients with mismatch repair-deficient or microsatellite unstable CRC responds exceptionally well to treatment with immune checkpoint inhibitors, thereby proving that CRC is in principle amenable to immunotherapy and showing that long-term disease stabilisation can be achieved even in metastasised stages. However, the reasons for the lack of response to immunotherapy in the vast majority of CRC cases remain to be elucidated. Yet, recent evidence suggests that the tumour stroma, which includes non-immune cells in the colorectal tumour microenvironment, mediates immunosuppressive mechanisms that prevent effective immunotherapy. These findings open new avenues for the development of advanced immunotherapies for CRC. In this review, we summarise major developments in the systemic therapy of CRC within the last couple of decades, provide an overview of emerging and soon-to-be implemented therapeutic strategies and present concepts from clinical and preclinical research to manipulate tumour cells and the tumour stroma to sensitise microsatellite stable colorectal tumours to immunotherapy.
    Keywords:  COLORECTAL CANCER
    DOI:  https://doi.org/10.1136/gutjnl-2025-335412
  12. Nat Rev Cancer. 2025 Oct 10.
    Decoding ferroptosis for cancer therapy.
    Adam Wahida, Marcus Conrad.
      Resisting cell death is a pivotal hallmark of cancer and one of several increasingly actionable functional capabilities acquired by cancer cells to sustain their malignant state. Since the early 2000s, the discovery of multiple regulated cell death programmes has intensified interest in targeting these maladaptive traits that cancer cells employ to resist cellular demise. Among these, ferroptosis - the lethal outcome of iron-dependent (phospho)lipid peroxidation - stands apart from other regulated cell death mechanisms, as it is persistently suppressed while lacking an activating signal. In cancer research, ferroptosis has garnered considerable attention, with growing evidence suggesting that its deregulation intersects with other hallmarks of malignancy, thus positioning it as a pleiotropic target. However, in the absence of approved ferroptosis-based drugs and despite substantial advances in understanding the metabolic manoeuvres of cancer cells to evade ferroptosis, its heralded translational value remains somewhat speculative at this stage. This Review reconciles the biochemical foundation of ferroptosis, the evidence supporting its role in cancer biology and the potential strategies for rationalizing targeted therapies to induce ferroptosis-prone states in malignancies. Building on this foundation, we explore contentious issues surrounding ferroptosis, including its implications for immunogenicity and redox imbalances in cancer. Finally, we address critical considerations such as therapeutic windows and biomarkers of ferroptosis, which are prerequisites for successful translation into clinical oncology.
    DOI:  https://doi.org/10.1038/s41568-025-00864-1
  13. Oncogene. 2025 Oct 07.
    Atg16l1 and Xbp1 cooperatively protect from transcription-associated mutagenesis and small intestinal carcinogenesis.
    Nassim Kakavand, Hang Xiang, Georg Laue, Taous Mekdoud, Lina Welz, Miguel Gomes Silva, Joana P Bernardes, Go Ito, Silke van den Bossche, Julia Kugler, Florian Tran, Alexander Ossysek, Simon Imm, Finn Hinrichsen, Moritz Jesinghaus, Arthur Kaser, Richard Blumberg, Timon E Adolph, Stefan Schreiber, Markus Tschurtschenthaler, Philip Rosenstiel, Konrad Aden.
      Atg16l1 plays a critical role in autophagy, and Xbp1 is part of the endoplasmic reticulum (ER) homeostasis. Both, Atg16l1 and Xbp1 are known risk genes for inflammatory bowel disease (IBD). Previous studies have shown that dysfunctional Atg16l1 and Xbp1 are epithelial-derived drivers of small intestinal inflammation. Despite a clear link between Crohn's disease and small intestinal adenocarcinoma, the molecular impact of autophagy and ER stress in this malignant transformation is not known. Using a model of impaired ribonucleotide excision repair (RER), a key homeostatic repair mechanism in highly proliferative cells, we investigated the impact of Atg16l1 on epithelial DNA damage responses and small intestinal carcinogenesis with and without functional ER homeostasis. We used conditional mouse models for deficient RER (Rnaseh2bΔIEC), bearing a co-deletion of disrupted autophagy (Atg16l1/Rnaseh2bΔIEC) or ER stress resolution (Xbp1/Rnaseh2bΔIEC), and triple-conditional knock-out mice for both, Xbp1 and Atg16l1 (Atg16l1/Xbp1/Rnaseh2bΔIEC). We assessed the degree of DNA damage and the incidence of small intestinal carcinoma. We report that defective epithelial RER induces autophagy, and that dysfunctional autophagy increases RER-induced DNA damage and causes the loss of RER-induced proliferative arrest but no spontaneous carcinogenesis in the gut. We demonstrate that dysfunctional Atg16l1 drastically increases the incidence of spontaneous intestinal adenocarcinomas in mice with defective epithelial RER and impaired ER homeostasis. We provide experimental evidence that the same epithelial mechanisms suppressing gut inflammation also critically protect from small intestinal carcinogenesis. Our findings set a molecular framework for the increased risk of intestinal carcinogenesis in patients with IBD, which links perturbations of ER homeostasis and autophagy defects with accumulating DNA damage. In a model of transcription-associated mutagenesis, deficiency of the IBD risk gene Atg16l1 does not induce small intestinal cancer. In contrast, double deficiency of Xbp1 and Atg16l1 drives spontaneous tumor formation highlighting a cooperative role of Xbp1 and Atg16l1 in tumor suppression.
    DOI:  https://doi.org/10.1038/s41388-025-03591-x
  14. Cancer Metab. 2025 Oct 09. 13(1): 41
    The integration of single-cell and metabolomics reveals the increase of oxidative phosphorylation during the liver metastasis of colorectal cancer.
    Tianyu Liu, Sizheng Sun, Yicheng Huang, Yiming E, Wenyuan Li, Fanggui Xu, Zhengxia Liu, Xiagang Luo, Chen Lu, Chunzhao Yu.
       BACKGROUND: Colorectal cancer (CRC) is among the most prevalent malignant tumors, with liver metastasis as the leading cause of mortality. Although metabolic reprogramming is known to play a crucial role in tumor metastasis, our understanding of this process during colorectal cancer liver metastasis (CRLM) remains limited.
    METHODS: A stepwise mouse model of CRC liver metastasis was developed, and metabolomic profiling was performed to verify model stability and identify metabolic changes. Single-cell RNA sequencing (scRNA-seq) was used to assess oxidative phosphorylation (OXPHOS) activity within the metastatic tumor microenvironment (TME). Additionally, spatial transcriptomics (ST) was conducted to elucidate the spatial distribution of metabolic phenotypes within metastatic sites. Finally, in vivo experiments were conducted by administering TGFβ inhibitor (LY2157299) or OXPHOS inhibitor (IACS-010759) to evaluate the potential for liver metastasis, and in vitro, the functions of HCT116 and SW620 cells were assessed through Transwell assays and oxygen consumption rate (OCR) measurements.
    RESULTS: Metabolomic profiling revealed heightened tricarboxylic acid (TCA) cycle activity in liver metastases. ScRNA-seq analysis showed increased OXPHOS in metastatic cells, including a highly malignant cell subtype characterized by augmented OXPHOS. Further analysis identified a significant upregulation of OXPHOS associated with TGFβ pathway activation. ST localized this OXPHOS -enriched subtype within metastatic tissue. Both in vivo and in vitro experiments demonstrate that inhibition of TGFβ signaling reduces OXPHOS activity, thereby attenuating the progression of colorectal cancer liver metastasis.
    CONCLUSIONS: This study identifies OXPHOS upregulation as a key metabolic alteration during CRC liver metastasis, which could be induced by TGFβ signaling pathway. These findings contribute to a refined understanding of CRC metabolic adaptation in liver metastases and may inform therapeutic strategies targeting OXPHOS in advanced CRC.
    Keywords:  Colorectal cancer; Liver metastasis; Oxidative phosphorylation; TGFβ
    DOI:  https://doi.org/10.1186/s40170-025-00408-z
  15. BMC Gastroenterol. 2025 Oct 08. 25(1): 704
    A Notch signal pathway related gene signature predicts overall survival in colorectal cancer.
    Mingyou Dong, Zhihao Ding, Xinyi Liang, Meng Gao, Mengqi Fan, Xueying Peng, Lusheng Liao, Xiaodong Zhang.
      
    Keywords:  Cell phenotype; Colorectal cancer; Gene signature; Notch pathway; Overall survival
    DOI:  https://doi.org/10.1186/s12876-025-04292-1
  16. Nat Commun. 2025 Oct 06. 16(1): 8868
    Inflammation and mutational burden differentially associated with nivolumab or ipilimumab combination efficacy in colorectal cancer.
    Ming Lei, Michael J Overman, Jin Yao, Thierry André, Sara Lonardi, Heinz-Josef Lenz, Massimo Aglietta, Fabio Gelsomino, Ray McDermott, Ka Yeung Mark Wong, Michael A Morse, Eric Van Cutsem, Alain Hendlisz, Dana B Cardin, Bart Neyns, Andrew Hill, Anuradha Krishnamurthy, Franklin Chen, Samith Kochuparambil, Robert R Jenq, Sandzhar Abdullaev, Beilei He, Ruslan Novosiadly, Scott Kopetz.
      Nivolumab alone and in combination with ipilimumab demonstrated durable clinical benefit in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer in the phase 2 CheckMate 142 study. Here, we report exploratory biomarker analyses from CheckMate 142 evaluating associations between various tissue biomarkers and the efficacy of nivolumab monotherapy and nivolumab plus ipilimumab combination in these patients. Higher expression of inflammation-related gene expression signatures is associated with improved response per investigator assessment and survival benefit with nivolumab monotherapy. In contrast, higher tumor mutational burden, tumor indel burden, and degrees of microsatellite instability are associated with improved response per investigator assessment and survival benefit with nivolumab plus ipilimumab. While interpretation is limited by the exploratory nature of these analyses, they suggest that tumor antigenicity rather than baseline tumor inflammation might be important for the combinatorial efficacy. Validation of these findings in larger, randomized studies is necessary.
    DOI:  https://doi.org/10.1038/s41467-025-63960-8
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