bims-instec 2026-02-15 papers

bims-instec

Biomed News

on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration

Issue of 2026–02–15
eighteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Epigenetic Gatekeeping of Intestinal Stem Cell Transformation.
Engineered intestinal crypt geometry uncovers YAP1-dependent fetal-to-adult transition.
The Role of Fibroblast-Epithelial Cross-Talk on the Distribution of Distinct Fibroblast Phenotypes in the Intestinal Crypt.
FASN Inhibition Enhances the Efficacy of Chemotherapy in Colorectal Cancer by Inhibiting the DNA Damage Response.
Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis.
Elovl6 inhibits colorectal cancer progression through stearic acid-mediated mitochondrial fusion and metabolic reprogramming.
Colorectal Cancer Organoid Model Reveals the Mechanisms of Irinotecan Resistance at Single-Cell Resolution.
Colorectal cancer stem cells in the tumor microenvironmental niche: Mechanistic insights and emerging therapies.
Metabolic permissiveness: how tissue context shapes cancer.
Subcellular Redistribution of Endomembrane GPR15 Promotes NAD+-Mediated Metabolic Reprogramming and Boosts 5-FU Chemosensitivity in Colorectal Cancer.
Targeting HIF-2α in Colorectal Cancer Reveals a Cholesterol Biosynthesis-Dependent Ferroptotic Vulnerability.
Compartmentalized branched-chain amino acid metabolism orchestrates colorectal cancer dissemination via an UMP-vimentin axis.
SPP1⁺ macrophage-FADS1⁺ tumor cell crosstalk via the PDGFB-PDGFRB axis drives liver metastasis in colorectal cancer.
Metabolic modeling and functional genomics reveal taxa and host gene interactions in colorectal cancer.
Metabolic stress conditions dictate MAPKAPK2-dependent efficiency of MEK1/2 inhibition in colorectal carcinoma.
CT26.MtC3, a new preclinical model to investigate immune resistance in metastatic colorectal cancer.
Preoperative exercise induces anti-tumor Kupffer cells to prevent surgical stress-promoted colorectal cancer liver metastasis.
Key genes and pathway differences between serrated polyps and conventional adenomas: insights from multi-omics.

bioRxiv. 2026 Feb 03. pii: 2026.01.31.702974. [Epub ahead of print]

Epigenetic Gatekeeping of Intestinal Stem Cell Transformation.

Alireza Lorzadeh, Sweta Sharma, Geroge Ye, Sabrina Rabaya, Yun Jee Kang, Ramesh A Shivdasani, Unmesh Jadhav.

Widespread cell plasticity recognized in fetal intestinal epithelium is preserved in limited fashion in Wnt-responsive adult stem cells and contributes to tumor initiation, progression, and relapse. 1, 2, 3 It is unclear which epigenetic features maintain stem-cell properties, restrict adult expression of fetal genes 4 , and are attenuated in tumors, allowing non-stem cells to replenish targeted tumor stem cells 5 . Here we show that reversible stemness in normal adult intestinal crypt cells hinges on a dynamic balance between activating H3K27ac and repressive H3K27me3 marks. Cells that leave the Wnt-rich stem-cell niche normally acquire H3K27me3 at thousands of stemness-associated enhancers. Constitutive tumorigenic Wnt activity transforms Apc ‒/‒ intestinal stem cells by gradual erosion of H3K27me3 at select enhancers and extends stem-like properties beyond usual anatomic confines; continued depletion of H3K27me3 reactivates enhancers that control growth and expression of a wider swath of fetal genes than appreciated previously. Subsequent focal DNA demethylation at expanded superenhancer domains is associated with tumor growth. Human colorectal cancers also carry evidence of this epigenetic rewiring. Accelerated H3K27me3 loss in mice hastens, and its preservation delays, activation of stemness-related enhancers, superenhancers, and tumor progression. During transformation, H3K27me3 loss at enhancers erases a crucial distinction between stem and non-stem populations, endowing the latter with stemness and providing an explanation for tumor resistance to cancer stem cell targeting. Thus, H3K27me3 at Wnt-responsive enhancers is an intrinsic barrier to intestinal tumorigenesis and aberrant reactivation of hundreds of fetal genes.

DOI: https://doi.org/10.64898/2026.01.31.702974
Cell Stem Cell. 2026 Feb 12. pii: S1934-5909(26)00029-9. [Epub ahead of print]

Engineered intestinal crypt geometry uncovers YAP1-dependent fetal-to-adult transition.

Martti Maimets, Mikhail Nikolaev, Cecilia Lövkvist, Fabien Bertillot, Hjalte List Larsen, Raul Bardini Bressan, Antonios Georgantzoglou, Nikolce Gjorevski, Eirini Filidou, Maureen Zøylner, Stine Lind Hansen, Astrid M Baattrup, Isidora Banjac, Jordi Guiu, Sara A Wickström, Matthias P Lutolf, Kim B Jensen.

  During morphogenesis, the intestine undergoes significant structural remodeling, transitioning from a simple tube of immature epithelium into a complex crypt-villus architecture housing mature cell types. However, the relationship between these structural changes and epithelial maturation has remained enigmatic. Using engineered scaffolds that replicate crypt-like geometries, we establish a robust platform for guiding the morphogenesis and differentiation of fetal intestinal cells into mature engineered tissues that mimic their in vivo counterparts. Mechanistically, tissue maturation is driven by cell crowding, leading to reduced YAP1 activation. Modulating YAP signaling in both engineered tissues and the developing mouse intestine alters epithelial lineage specification. These findings uncover a geometry-dependent mechanism that links tissue architecture to cell fate transitions. Our work provides a platform for modeling aspects of intestinal development and offers insights for refining stem cell differentiation protocols and regenerative strategies for intestinal disorders.

Keywords:  bioengineering; intestine; maturation; state transitions; stem cells

DOI:  https://doi.org/10.1016/j.stem.2026.01.006
Bull Math Biol. 2026 Feb 09. 88(3): 36

The Role of Fibroblast-Epithelial Cross-Talk on the Distribution of Distinct Fibroblast Phenotypes in the Intestinal Crypt.

George Atkinson, Simon Leedham, Helen M Byrne.

  Intestinal crypts are test tube-like structures lined with an epithelial monolayer. Under homeostasis, mitotic forces drive epithelial cells to migrate up the crypt, from the stem cell niche. As the cells migrate up the crypt, they differentiate into specialised cells. This process is regulated by morphogen gradients established by distinct populations of subepithelial fibroblasts, and recent studies suggest fibroblasts and epithelial cells have co-evolved to maintain crypt structure and function via complementary morphogen expression. We present a mathematical model of fibroblast-epithelial cross-talk, in which fibroblast and epithelial phenotypes emerge from morphogen binding to cell surface receptors. The model predicts the formation of distinct zones of mutually supporting phenotypes at different crypt heights. These findings support the idea that fibroblast and epithelial cell phenotypes are an emergent property of the crypt microenvironment. We use the model to investigate how mutations in the fibroblasts may disrupt these phenotypic zones. Our results suggest that such mutations may lead to uncontrolled epithelial cell growth and, as such, indicate how dysfunctional fibroblasts may contribute to the emergence of colorectal cancer.

Keywords:  BMP; BMPi; Cross-talk; Epithelial cells; Fibroblasts; Hedgehog; Intestinal crypts; Phenotype; WNT

DOI:  https://doi.org/10.1007/s11538-025-01588-x
Cancer Res. 2026 Feb 09.

FASN Inhibition Enhances the Efficacy of Chemotherapy in Colorectal Cancer by Inhibiting the DNA Damage Response.

Moumita Banerjee, Yekaterina Y Zaytseva, Ellen M Reusch, Dana L Napier, Sumati Hasani, Piotr Rychahou, Tadahide Izumi, Dennis A Cheek, Jing Li, Robert M Flight, Hunter N B Moseley, Heidi L Weiss, William McCulloch, B Mark Evers, Tianyan Gao.

Altered lipid metabolism is a potential targetable metabolic vulnerability in colorectal cancer (CRC). Fatty acid synthase (FASN), the rate limiting enzyme of de novo lipogenesis, is an important regulator of CRC progression, but the FASN inhibitor TVB-2640 showed only modest efficacy in reducing tumor burden in pre-clinical studies, suggesting combination strategies might be required to prolong patient survival. Here, by using samples from a window trial of TVB-2640 treatment in CRC patients, we found that FASN inhibition induced DNA damage but impaired the DNA damage response (DDR). In colon cancer cell lines and patient-derived organoids, FASN inhibition potentiated chemotherapy-induced double-strand DNA breaks (DSBs) and apoptotic cell death by altering histone acetylation levels. In addition, FASN inhibitor treatment blocked DDR by decreasing ATM expression and CHK2 phosphorylation. Mechanistically, FASN inhibition attenuated activation of the DDR pathway by attenuating BRCA1 and ATM recruitment to -H2AX foci in an acetylation-dependent manner. Moreover, FASN inhibition mediated DNA repair deficiency induced synthetic lethality with PARP inhibition in CRC cells. Importantly, combining FASN inhibition with the chemotherapeutic drug irinotecan synergistically decreased xenograft tumor growth and delayed tumor relapse, which was potentiated by the PARP inhibitor olaparib as maintenance treatment. Taken together, this study describes a therapeutic strategy in which FASN inhibitors can be utilized to delay tumor recurrence after chemotherapy, which is a major challenge in patients with CRC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-1917
Nat Cell Biol. 2026 Feb 11.

Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis.

Anna Bång-Rudenstam, Myriam Cerezo-Magaña, Marton Horvath, Hugo Talbot, Emma Gustafsson, Stevanus Jonathan, Chaitali Chakraborty, Itzel Nissen, Kelin Gonçalves de Oliveira, Axel Boukredine, Sarah Beyer, Julio Enriquez Perez, Maria C Johansson, Lena Kjellén, Emil Tykesson, Anders Malmström, Toin H van Kuppevelt, Karin Forsberg-Nilsson, Jeffrey D Esko, Silvia Remeseiro, Johan Bengzon, Valeria Governa, Mattias Belting.

Aggressive tumours are defined by microenvironmental stress adaptation and metabolic reprogramming. Within this niche, lipid droplet accumulation has emerged as a key strategy to buffer toxic lipids and suppress ferroptosis. Lipid droplet formation can occur via de novo lipogenesis or extracellular lipid-scavenging. However, how tumour cells coordinate these processes remains poorly understood. Here we identify a chondroitin sulfate (CS)-enriched glycocalyx as a hallmark of the acidic microenvironment in glioblastoma and central nervous system metastases. This CS-rich glycocalyx encapsulates tumour cells, limits lipid particle uptake and protects against lipid-induced ferroptosis. Mechanistically, we demonstrate that converging hypoxia-inducible factor and transforming growth factor beta signalling induces a glycan switch on syndecan-1-replacing heparan sulfate with CS-thereby impairing its lipid-scavenging function. Dual inhibition of CS biosynthesis and diacylglycerol O-acyltransferase-1, a critical enzyme in lipid droplet formation, triggers catastrophic lipid peroxidation and ferroptotic cell death. These findings define glycan remodelling as a core determinant of metabolic plasticity, positioning the dynamic glycocalyx as a master regulator of nutrient access, ferroptotic sensitivity and therapeutic vulnerability in cancer.

DOI: https://doi.org/10.1038/s41556-026-01879-y
Sci Adv. 2026 Feb 13. 12(7): eadz2892

Elovl6 inhibits colorectal cancer progression through stearic acid-mediated mitochondrial fusion and metabolic reprogramming.

Zhiqian Bi, Xiaoyao Chang, Shengyun Zhu, Shuilian Fu, Yuzhe Zhang, Tingting Wang, Feng Wang, Hongqin Zhuang, Zi-Chun Hua.

Lipid metabolic reprogramming is a hallmark of colorectal cancer (CRC), yet the precise molecular mechanisms underlying lipid-mediated oncogenesis and the specific lipid metabolic enzymes involved remain largely elusive. Here, we identify elongation of very-long-chain fatty acid protein 6 (Elovl6) as a critical regulator in CRC progression. Clinical data reveal significant down-regulation of Elovl6 in colon cancer tissues, with low expression levels correlating with unfavorable patient prognosis. We demonstrate that Elovl6 exerts potent tumor-suppressive effects, significantly inhibiting cellular proliferation in vitro and attenuating tumor growth in vivo. Mechanistically, it maintains intestinal microbial homeostasis by preventing the expansion of opportunistic pathogens while simultaneously orchestrating metabolic reprogramming through modulation of phospholipid biosynthesis pathways. Notably, we find that stearic acid, a key Elovl6-derived metabolite, promotes mitochondrial fusion by stabilizing mitofusin 1 protein. These findings not only position Elovl6 as a promising therapeutic target but also suggest that dietary supplementation with stearic acid could represent a viable strategy for CRC prevention and treatment.

DOI: https://doi.org/10.1126/sciadv.adz2892
Cancer Med. 2026 Feb;15(2): e71550

Colorectal Cancer Organoid Model Reveals the Mechanisms of Irinotecan Resistance at Single-Cell Resolution.

Yi Pan, Lin Chen, Yuqing Hu, Jie Chang, Xifeng Xu, ShuoChen Xu, YiWen Li, Jinlin Du, JianPing Wang, Wenxia Xu.

   OBJECTIVE: Irinotecan, a standard therapeutic agent for metastatic colorectal cancer (mCRC), often faces significant limitations due to drug resistance, with treatment failure observed in approximately 30%-50% of patients, leading to poor clinical outcomes. This study aims to systematically elucidate the molecular mechanisms underlying irinotecan resistance in colorectal cancer (CRC) by constructing patient-derived organoid (PDO) models combined with single-cell transcriptomics technology.
METHODS: PDO models were successfully established from irinotecan-resistant and sensitive CRC patients. Single-cell RNA sequencing (scRNA-seq) was performed on the organoids, analyzing the transcriptomic heterogeneity of 12,360 high-quality cells. Gene Set Variation Analysis (GSVA), transcriptional regulatory networks, and cell communication networks were employed to dissect the resistance mechanisms.
RESULTS: Drug sensitivity assays demonstrated that the IC50 value of irinotecan in CRC5 was significantly higher than that in CRC11, which was entirely consistent with their respective clinical phenotypes. Single-cell sequencing identified CRC5-specific drug-resistant cell clusters, Cluster 1 and Cluster 6. Cluster 1 (MARCKSL1+) was characterized by the activation of the Wnt signaling pathway and extracellular matrix (ECM) remodeling, which collectively contributed to the maintenance of stem cell-like properties, while Cluster 6 (AKR1C3+) exhibited significant enrichment in lipid metabolism and the Notch signaling pathway.
CONCLUSION: This study integrates PDO models with single-cell transcriptomics technology to reveal key cell subpopulations and molecular mechanisms underlying irinotecan resistance. The core mechanisms driving resistance involve the activation of Wnt signaling and the synergistic effect of lipid metabolism-Notch pathways. Cluster 1 and Cluster 6 are identified as potential therapeutic targets, providing a theoretical basis for developing combination therapies targeting cancer stem cells or the metabolic microenvironment.

Keywords:  irinotecan resistance; lipid metabolism; notch signaling; patient‐derived colorectal cancer organoids; single‐cell RNA sequencing

DOI:  https://doi.org/10.1002/cam4.71550
Biochim Biophys Acta Rev Cancer. 2026 Feb 10. pii: S0304-419X(26)00031-4. [Epub ahead of print] 189559

Colorectal cancer stem cells in the tumor microenvironmental niche: Mechanistic insights and emerging therapies.

Sandhiya Viswanathan, Madhuja Raha, Sudeshna Mishra, Srinivas Patnaik.

  Colorectal cancer (CRC) is a highly heterogenous disease, wherein a specific population of cancer stem cells (CSCs) are crucial in tumor initiation, therapeutic resistance, metastasis and disease progression. The tumor microenvironment (TME) plays a key role in the development of CRC stem cells (CCSCs) by sending signals and allowing cells to interact with each other, which helps to stem cells stay viable and regenerate. The ongoing interaction between CCSCs and diverse components of TME promotes treatment resistance and tumor recurrence. Recent advancements permitted the fabrication of three-dimensional (3D) tumor models using CCSCs. These models better replicate the in vivo TME and provide useful ways in personalized drug discovery and tumor biology. Therapy resistance in CCSCs is still an important concern in CRC therapy, because cells remain active, have good DNA repair systems, and interact with other cells in the TME. Targeted treatment techniques are being formulated to interrupt in various pathways, including DNA/RNA-based methods that inhibit oncogenic drivers or restore tumor suppressors in CCSCs. TME-targeted immunotherapies, including immune checkpoint inhibitors, T-cell-based treatments, and cytokine modulation, are shown potential in counteracting immune evasion by CCSCs. Numerous clinical trials are examining the effectiveness of inhibitors targeting CCSC-related pathways in metastatic CRC. This review comprehensively explores the evolution and role of CCSC within the TME, the development of 3D TME models from patient derived stem cells, mechanism of resistance and targeted immunotherapeutic strategies aimed at eradicating CSCSs to improve clinical outcomes in CRC.

Keywords:  Clinical research; Colon cancer; Stem cells; Targeted therapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2026.189559
Genes Dev. 2026 Feb 09.

Metabolic permissiveness: how tissue context shapes cancer.

Chrysanthi Moschandrea, Christian Frezza.

  An emerging paradox in cancer metabolism is that identical oncogenic mutations produce profoundly different metabolic phenotypes depending on tissue context, with many mutations exhibiting striking tissue-restricted distributions. Here we introduce metabolic permissiveness as the inherent capacity of a tissue to tolerate, adapt to, or exploit metabolic disruptions, providing a unifying framework for explaining this selectivity. We examine tissue-specific metabolic rewiring driven by canonical oncogenes (MYC and KRAS), tumor suppressors (p53, PTEN, and LKB1), and tricarboxylic acid (TCA) cycle enzymes (FH, SDH, and IDH), demonstrating that baseline metabolic architecture, nutrient microenvironment, redox buffering, and compensatory pathways determine whether mutations confer a selective advantage or metabolic crisis. We further discuss how the tumor microenvironment shapes metabolic adaptation and therapeutic vulnerability. This framework reveals shared principles of tissue-specific metabolic vulnerability in cancer and provides a mechanistic basis for precision metabolic therapies.

Keywords:  cancer; metabolism; permissiveness

DOI:  https://doi.org/10.1101/gad.353516.125
Cancer Res. 2026 Feb 09.

Subcellular Redistribution of Endomembrane GPR15 Promotes NAD+-Mediated Metabolic Reprogramming and Boosts 5-FU Chemosensitivity in Colorectal Cancer.

Zhiying Yue, Wentao Dai, Zhuoran Cao, Bin Hu, Ziyuan Wang, Xinrun Ma, Da Qin, Taiyu Zhang, Qingqing Sang, Jing Mei, Tianci Yu, Yong Zhou, Zai Luo, Junming Xu, Zengjin Yuan, Yuan-Yuan Li, Jinyan Zhang, Chen Huang, Zhengfeng Yang.

G protein-coupled receptors (GPCRs) are increasingly recognized for their organelle-specific functions in cancer. A better understanding of the mechanisms governing their dynamic subcellular distribution and functional coordination is essential for developing spatially targeted therapies that exploit the subcellular signaling networks of GPCRs. Here, we found that Golgi-localized GPR15 underwent spatiotemporal trafficking to enhance 5-fluorouracil (5-FU) chemosensitivity in colorectal cancer. Dependent on Gαq, GPR15 associated with and restrained PARP4 enzymatic activity in the Golgi apparatus to drive cytosolic NAD⁺ accumulation. MGST1 interacted with and navigated GPR15 redistribution to mitochondria to increase mitochondrial NAD+ abundance, which fueled central carbon metabolism and activated downstream metabolic networks to prime tumors for 5-FU cytotoxicity. Treatment with the PARP inhibitor rucaparib showed potent synergy with 5-FU and demonstrated robust tumor suppression in patient-derived organoids and xenograft models through NAD⁺-mediated metabolic perturbation. This work establishes spatially encoded GPCR signaling as a druggable axis to potentiate chemotherapy efficacy, redefining intracellular receptor trafficking as an important regulator of metabolic plasticity in cancer therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2586
bioRxiv. 2026 Feb 05. pii: 2025.09.08.674939. [Epub ahead of print]

Targeting HIF-2α in Colorectal Cancer Reveals a Cholesterol Biosynthesis-Dependent Ferroptotic Vulnerability.

Prarthana J Dalal, Rashi Singhal, Boyan Hu, Drew Stark, Nicholas Rossiter, Chesta Jain, Peter Sajjakulnukit, Costas A Lyssiotis, Yatrik M Shah.

Colorectal carcinoma (CRC) remains a major cause of cancer-related mortality, with rising incidence in individuals under 55, highlighting the need for novel therapeutic strategies. Hypoxia-inducible factor 2 alpha (HIF-2α) has been genetically validated as a critical driver of colorectal tumorigenesis, with intestinal epithelium-specific deletion in mice markedly reducing tumor formation. While selective HIF-2α inhibitors such as PT2385 are FDA-approved for renal cell carcinoma, pharmacologic HIF-2α inhibition has not been explored in CRC. Here, we demonstrate that HIF-2α inhibition alone fails to suppress CRC growth in vitro under normoxic or hypoxic conditions and in xenograft models in vivo. To identify vulnerabilities induced by HIF-2α blockade, we performed an unbiased CRISPR metabolic screen, revealing cholesterol biosynthesis as a critical dependency. Targeting this pathway with clinically approved statins (atorvastatin, pitavastatin, simvastatin) synergized with PT2385 to suppress CRC cell growth, reduce colony formation, and enhance cell death. Mechanistic studies show that combined HIF-2α and HMG-CoA reductase inhibition promotes ferroptosis, characterized by increased lipid peroxidation and depletion of antioxidant metabolites. These effects are fully reversed by the ferroptosis inhibitor liproxstatin-1. Genetic knockdown of HIF-2α or HMG-CoA reductase recapitulated the enhanced sensitivity to combination therapy. In vivo, co-administration of PT2385 and atorvastatin significantly reduced tumor growth and increased ferroptotic cell death in xenografts, confirming the mechanistic link. Collectively, these findings uncover a metabolic vulnerability of CRC to dual HIF-2α and cholesterol biosynthesis inhibition, supporting a clinically actionable strategy that leverages safe, FDA-approved statins to potentiate HIF-2α-targeted therapy.

DOI: https://doi.org/10.1101/2025.09.08.674939
Cell Metab. 2026 Feb 06. pii: S1550-4131(26)00007-0. [Epub ahead of print]

Compartmentalized branched-chain amino acid metabolism orchestrates colorectal cancer dissemination via an UMP-vimentin axis.

Fenfen Ji, Pingmei Huang, Qiming Zhou, Lok Hin Ko, Qinyao Wei, Charis Cheuk-Lok Chan, Danyu Chen, Huarong Chen, Wei Kang, Alvin Ho-Kwan Cheung, Cillian H Cheng, Jianming Shen, Yasi Pan, Ying Jiao, Lin Zhu, Tat Wai Chik, Peisi Xie, Xiao Liang, Onno Kranenburg, Zongwei Cai, Jun Yu, Chi Chun Wong.

  The role of metabolic compartmentalization in cancer metastasis is unexplored. Here, we identified that compartmentalized branched-chain amino acid (BCAA) metabolism modulates colorectal cancer (CRC) metastasis. Cytosolic BCAA transaminase (BCAT1) promotes epithelial-to-mesenchymal transition (EMT) and cancer spread of CRC cells, whereas the mitochondrial isoform (BCAT2) exerted opposite effects. The location of BCAT is critical, as mitochondria-targeted BCAT1 and cytosolic BCAT2 demonstrated opposite functions in EMT and cell migration, compared with their wild-type counterparts. Mechanistically, cytosolic BCAT promotes nitrogen flux from BCAA to glutamate, aspartate, and uridine monophosphate (UMP), whereas mitochondrial BCAT activity diverts nitrogen flux via glutamate dehydrogenase (GDH) to give NH3. UMP binds to vimentin and protects it against ubiquitination-proteasome degradation. Dietary BCAA restriction or blockade of UMP biosynthesis impaired cancer spread of BCAT1-high CRC, and BCAT1-to-BCAT2 expression ratio is an independent prognostic factor in CRC and pan-cancer cohorts, highlighting translational relevance of BCAA metabolic compartmentalization in cancer metastasis.

Keywords:  BCAA; BCAT1; BCAT2; UMP; branched-chain amino acids; colorectal cancer; dietary restriction; metabolic compartmentalization; metastasis; uridine monophosphate

DOI:  https://doi.org/10.1016/j.cmet.2026.01.007
Transl Oncol. 2026 Feb 07. pii: S1936-5233(26)00033-1. [Epub ahead of print]66 102696

SPP1⁺ macrophage-FADS1⁺ tumor cell crosstalk via the PDGFB-PDGFRB axis drives liver metastasis in colorectal cancer.

Pingfan Zhao, Fuyong Pei, Yanmin Liu, Yinan Jiang, Xiaochang Fang, Lin Shu, Xin Hu, Feiyang Chen, Maohui Feng, Xuanfei Li.

  Liver metastasis is the predominant cause of mortality among individuals diagnosed with colorectal cancer (CRC). However, the mechanisms underlying the tumor-microenvironment interactions that promote this process remain poorly defined. Here, we developed an integrative multiomics framework to dissect the cellular and molecular determinants of colorectal cancer liver metastasis (CRLM). By analyzing 1,156 metastasis-associated genes, we identified three molecular subtypes with distinct prognostic and immunometabolic features: C1 with mixed phenotypes and favorable survival, C2 with metabolic activation and immune suppression, and C3 with immune activation and signaling dysregulation, which had the poorest outcomes. Mechanistically, we discovered that SPP1⁺ macrophages secrete PDGFB, which activates PDGFRB signaling in FADS1⁺ tumor cells to trigger epithelial-mesenchymal transition (EMT) and promote liver metastasis. This macrophage-tumor crosstalk was validated by single-cell transcriptomics, genetic perturbation, and coculture experiments. Collectively, our findings define a macrophage-derived PDGFB-PDGFRB axis that drives CRC liver metastasis and highlight a potential therapeutic target for overcoming metastatic progression and immune resistance.

Keywords:  CRLM; Gene interaction network; Network-based subtypes; Single-cell analysis; Spatial transcriptomics

DOI:  https://doi.org/10.1016/j.tranon.2026.102696
bioRxiv. 2026 Jan 28. pii: 2026.01.26.700635. [Epub ahead of print]

Metabolic modeling and functional genomics reveal taxa and host gene interactions in colorectal cancer.

Katja Della Libera, Elizabeth M Adamowicz, Amanda Muehlbauer, Sambhawa Priya, Adnan Alazizi, Francesca Luca, Ran Blekhman.

Colorectal cancer (CRC) is associated with changes in the microbial communities in the tumor microenvironment. Although metabolic reprogramming is an important feature of host cells in CRC, little is known about metabolic changes in the tumor-associated microbiota and how these microbial metabolic alterations can contribute to disease. Here, we investigated metabolic host-microbiome interactions in CRC using complementary computational and experimental approaches. Using patient-specific in silico metabolic models across three independent datasets, we discovered that Fusobacterium , a cancer-promoting taxon, consistently grows faster in tumor-associated versus normal tissue-associated microbiomes. This finding prompted us to investigate whether host metabolic changes drive these microbial growth advantages. By integrating our metabolic predictions with host transcriptomics data, we identified correlations between tumor gene expression and the growth of CRC-associated taxa (including Porphyromonadaceae , Blautia , and Streptococcus ), as well as associations between host genes and microbial metabolism of dietary components (including choline, amino acids, and starch). To test whether these correlations reflect causal relationships, we simulated spent medium experiments in silico , demonstrating that Blautia preferentially grows on metabolites produced by tumor versus normal host cells. We further validated the direct impact of microbes on host metabolism using an in vitro system, where colon cancer cells exposed to human microbiomes showed gene expression changes in response to specific taxa including Bilophila , Anaerotruncus , and Escherichia . Together, these findings reveal a metabolic dialogue between host and microbiome in CRC, where tumor metabolic reprogramming creates a favorable environment for pathogenic microbes, which in turn may reinforce tumorigenic processes through metabolic crosstalk.

DOI: https://doi.org/10.64898/2026.01.26.700635
Proc Natl Acad Sci U S A. 2026 Feb 17. 123(7): e2505331123

Metabolic stress conditions dictate MAPKAPK2-dependent efficiency of MEK1/2 inhibition in colorectal carcinoma.

Niti Kumari, Xu Chen, Amber M Baldwin, Kristin I Clemons, Mohammad El-Harakeh, Lilian E Calisto, Balawant Kumar, Qiaoqiao Zhang, Jiang Min, Bin Xiao, Amar B Singh, Bin Wang, Brian J North.

  The kinase MAPKAPK2 regulates cell survival, proliferation, and death, and is upregulated in colorectal carcinoma (CRC) where it is associated with tumor growth and progression. However, how it regulates tumor progression in conjunction with other signaling pathways, such as MEK/ERK, remains elusive. Solid tumors are often subjected to metabolic stress, notably glucose deprivation. Here, we demonstrate that MAPKAPK2 protein levels in CRC regulate cell fate decision during stress conditions, such as glucose deprivation and therapeutic treatment. While MAPKAPK2 expression is a limiting factor for CRC growth in vitro, depleting MAPKAPK2 or inhibiting its activity pharmacologically provides a survival advantage to CRC cells under glucose limiting conditions. Subjecting CRC cells to low glucose resulted in an ERK1/2-mediated decline in MAPKAPK2 to promote survival. Additionally, cells with reduced MAPKAPK2 activity were less sensitive to trametinib under glucose limiting conditions. Utilizing transcriptomic profiling, we found that glucose deprivation and MAPKAPK2 depletion activate pathways associated with survival during metabolic stress. This relationship was also observed in CRC patients (TCGA), where tumors with low MAPKAPK2 expression had higher ERK1/2 activation and upregulated stress-induced pathways, leading to poor survival. Finally, MAPKAPK2 modulated growth of CRC organoids, subcutaneous tumors, and patient-derived xenografts (PDX), and reduced MAPKAPK2 levels decreased efficacy of trametinib, in vitro and in vivo. Overall, this study identifies an interrelationship between MEK/ERK and p38/MAPKAPK2 signaling pathways during glucose deprivation to support cell survival and features MAPKAPK2 loss as a possible mechanism leading to reduced efficacy of trametinib-based anticancer therapy and poor patient outcomes in CRC.

Keywords:  ERK; MAPKAPK2; colorectal cancer; glucose; trametinib

DOI:  https://doi.org/10.1073/pnas.2505331123
Cancer Cell Int. 2026 Feb 09.

CT26.MtC3, a new preclinical model to investigate immune resistance in metastatic colorectal cancer.

Célia Bienassis, Jordan Da Silva, Nora Fournil, Yolanda Prezado, Frédérique Megnin-Chanet, Sébastien Paris.



Keywords:  CEACAM-1a; CT26.WT; Metastasis; Mouse model; Radiotherapy; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12935-026-04200-x
Cell Rep Med. 2026 Feb 09. pii: S2666-3791(26)00006-6. [Epub ahead of print] 102589

Preoperative exercise induces anti-tumor Kupffer cells to prevent surgical stress-promoted colorectal cancer liver metastasis.

Yunwei Zhang, Yiyu Zhang, Chengli Shen, Jiye Li, Han Wang, Ahmad Hamad, Chunyan Cao, Mohamad El Moheb, Yu Wang, Yujia Xia, Kaelyn C Cummins, Joal Beane, Aslam Ejaz, Hai Huang, Allan Tsung, Hongji Zhang.

  Colorectal cancer mortality is primarily driven by hepatic metastasis, with 50-60% of patients relapsing following liver metastasis resection due to micro-metastases or tumor cell dissemination. Surgery-induced immunologic disturbances contribute to liver recurrence. Exercise modulates immune responses, yet its role in surgical stress-promoted liver metastasis remains unclear. We demonstrate that 4 weeks of preoperative exercise (PEx) limits tumor growth in a murine model of surgical stress-promoted liver metastasis by shifting Kupffer cells toward an anti-tumor phenotype. PEx promotes Kupffer cell cytotoxic cytokines release and enhances CD8+ T cells recruitment and activation via the CXCL9-CXCR3 axis. Elevated CXCL9 levels are observed in murine and patient sera post exercise, with Kupffer cells identified as the primary source. Furthermore, exercise-induced butyrate accumulation in Kupffer cells inhibits histone deacetylase 3 activity, promoting CXCL9 expression. These findings suggest that PEx may serve as a non-invasive strategy to reduce recurrence and provide potential targets for exercise-mimetic therapies.

Keywords:  preoperative exercise, colorectal liver metastasis, surgical stress, hepatic immune microenvironment, Kupffer cells, CD8+ T cells, butyrate, histone deacetylase 3, CXCL9, CXCR3

DOI:  https://doi.org/10.1016/j.xcrm.2026.102589
Transl Cancer Res. 2026 Jan 31. 15(1): 35

Key genes and pathway differences between serrated polyps and conventional adenomas: insights from multi-omics.

Youtao Zhou, Cuiyan Yang, Yuan Gao, Sihua Ye, Hongdan Zhou, Zikai Lin, Yuewu Fu, Xinci Ning, Chuanfeng Ke.

   Background: As two major colorectal cancer (CRC) pathways, serrated polyps (SP) and traditional adenomas show distinct cellular and molecular features, yet the key cell types and causal genes driving their malignant progression remain unknown. This study aimed to investigate the pivotal cellular groups and genes in the cancerous transformation of SP and traditional adenomas using multi-omics approach.
Methods: scPagwas (pathway-based polygenic regression method) was used to integrate CRC genome-wide association study (GWAS) data with single-cell sequencing in intestinal polyps, identifying cell groups and genes associated with phenotypic traits. Transcriptome-wide association studies (TWAS) analysis and fine-mapping, based on summary-level expression quantitative trait loci (eQTLs), were utilized to further screen for CRC-associated risk genes. Cell communication and gene set enrichment analysis (GSEA) determined receptor differences and pathway expression variations between SP and traditional adenomas. Mendelian randomization (MR) and phenome-wide association study analyses were used to investigate the connections between crucial genes and specific phenotypes.
Results: Serrated-specific cells (SSC) were identified as the epithelial population most strongly associated with CRC genetic risk, whereas adenoma-specific cells (ASC) showed no significant enrichment. Integrating TWAS, fine-mapping, and SMR analyses, we identified six robust risk genes-MIR4435-2HG, SMAD9, PITPNC1, LIMCH1, POU2AF2, and HES6. SSC and ASC displayed distinct transcriptional programs, with pathway analysis highlighting differences in TGF-β signaling and oxidative phosphorylation. Notably, MIR4435-2HG and SMAD9 emerged as particularly important genes, as they were consistently identified across scPagwas, TWAS and fine-mapping analyses, exhibited strong and contrasting specificity for SSC cells and ASC cells respectively, and demonstrated clear pathway relevance to serrated and conventional adenoma biology.
Conclusions: This multi-omics analysis reveals that the development of sessile serrated adenomas and conventional adenomas (CA) is associated with distinct epithelial origins, with serrated lesions linked to SSC cells and CA linked to ASC cells. These lesion-specific molecular features provide a mechanistic basis for improving preoperative detection and for developing adjunct molecular tools for high-risk polyp assessment.

Keywords:  Serrated polyps (SP); conventional adenomas (CA); gene effects; key genes; multi-omics

DOI:  https://doi.org/10.21037/tcr-2025-2138