bims-instec 2026-02-08 papers

bims-instec

Biomed News

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

Issue of 2026–02–08
twenty-two papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Dietary stearic acid accelerates intestinal tumorigenesis via fatty acid-binding protein 5 without promoting obesity.
Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer.
Plasticity as Resistance: KRAS Inhibition Reveals WNT Adaptation in Metastatic Colorectal Cancer.
BCL-xL as a therapeutic target in cetuximab-refractory colorectal cancer.
Shifting paradigms in tissue stem cell biology: Insights from the intestine.
Notch3 regulates pericyte phenotypic plasticity in colorectal cancer.
A syngeneic orthotopic mouse model of metastatic colorectal cancer.
Consensus Molecular Subtypes Inform HIPEC Agent Selection in Colorectal Cancer Peritoneal Metastases.
VGLL4 modulates Paneth cells and sustains intestinal homeostasis.
MYLK4 promotes colorectal cancer progression by regulating lipid metabolism reprogramming via targeting ferroptosis.
Palmitoylated STX11 suppresses AMPK to drive lipogenesis and colorectal cancer.
Unleashing Wnts: Wnt Ligands Fuel Cancer Spread.
Surrogate to predict overall survival in patients with BRAF V600E-mutant colorectal cancer treated with BRAF inhibitor combinations.
Carbonic Anhydrase-IX Is a Specific and Sensitive Theragnostic Target for Imaging and Radioimmunotherapy in Metastatic Colorectal Cancer.
Lactylation of SLC26A3 in the acidic tumor microenvironment promotes malignant progression of colorectal carcinoma.
Genetic attenuation of ALDH1A1 increases metastatic potential and aggressiveness in colorectal cancer.
Escherichia coli promotes colorectal cancer metastasis by maintaining enhancer-promoter loops through releasing neutrophil extracellular traps.
Colorectal cancer-derived FGF19 is a metabolically active serum biomarker that exerts enteroendocrine effects on mouse liver.
Toll signaling controls stem cell proliferation in intestinal regeneration and tumorigenesis.
Retreatment with oxaliplatin-based regimens in refractory metastatic colorectal cancer: characterization of high-response patients.
SLC46A1 deficiency-mediated folate restriction suppresses colorectal cancer progression through epigenetic-transcriptional reprogramming.
Cancer-associated fibroblasts (CAFs) derived from MFAP2 promote CRC proliferation and metastasis while suppressing CD8+ T cell-mediated antitumor immunity.

Cell Mol Gastroenterol Hepatol. 2026 Jan 28. pii: S2352-345X(26)00018-4. [Epub ahead of print] 101740

Dietary stearic acid accelerates intestinal tumorigenesis via fatty acid-binding protein 5 without promoting obesity.

Kazuaki Nakata, Seiga Komiyama, Keisuke Sekine, Motoyoshi Nagai, Takuma Okawa, Wakana Ohashi, Kenta Nakano, Tadashi Okamura, Takuma Kozono, Nobuyuki Takemura, Kazuhiko Yamada, Norihiro Kokudo, Taeko Dohi, Koji Hase, Yuki I Kawamura.

   BACKGROUND & AIMS: Dietary fat increases the risk of intestinal cancer, but the effect of the fatty acid composition on tumorigenesis is unclear. The aim of this study is to investigate the impact of diets with different fatty acids on carcinogenesis in the intestine.
METHODS: Mice were fed a linoleic acid (LA)-rich or stearic acid (SA)-rich high-fat diet (HFD) from the age of 4 weeks. The ApcMin/+ mice and an azoxymethane- and a dextran sulfate sodium-induced colorectal cancer (CRC) mouse model were used to examine the effects of different dietary fatty acids on CRC development. fatty acid-binding protein 5 (FABP5) knockout mice and SBFI-26, an inhibitor of FABP5, were used to assess its contribution.
RESULTS: We found that an SA-rich HFD more strongly accelerated tumorigenesis in murine CRC models than an LA-rich HFD, with fewer obesity phenotypes compared with LA-rich HFD-fed mice. Dietary SA more strongly promoted epithelial cell proliferation and Paneth cell differentiation than LA, whereas no differences in the numbers of leucine-rich repeat-containing G protein-coupled receptor 5+ and B lymphoma Mo-MLV insertion region 1 homolog+ intestinal stem cells were detected between the groups. In murine and human intestinal organoids, SA promoted crypt formation. We found that FABP5 was expressed in a small population of Ki67+ proliferative cells in crypts, and the number of Ki67+ FABP5+ cells was increased by SA-rich HFD feeding. FABP5 inhibition suppressed SA-induced epithelial cell proliferation, Paneth cell differentiation, and tumorigenesis.
CONCLUSIONS: Dietary SA can promote CRC via FABP5 without promoting obesity.

Keywords:  Dietary fatty acid; colorectal cancer; intestinal epithelial cell

DOI:  https://doi.org/10.1016/j.jcmgh.2026.101740
Neoplasia. 2026 Feb 05. pii: S1476-5586(26)00012-6. [Epub ahead of print]73 101283

Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer.

Mariah E Geisen, Josiane W Tessmann, Courtney O Kelson, Daheng He, Chi Wang, Abu Saleh Mosa Faisal, Ellen J Beswick, Yasmine Baca, Stephanie Rock, Jill M Kolesar, Yekaterina Y Zaytseva.

  The presence of BRAFV600E mutations is associated with poor prognosis in colorectal cancer (CRC). Although the FDA-approved combination of encorafenib and cetuximab provides clinical benefit in this population, only 22% of patients respond and most eventually develop resistance. This study investigated the mechanisms of resistance to PLX8394, a second-generation BRAF inhibitor. Using primary and established BRAFV600E CRC cells, we show that the development of resistance to PLX8394 results in cross-resistance of cells to encorafenib. Moreover, the acquired resistance is associated with increased proliferation, invasion, and upregulation of lipid metabolism, including increased expression of fatty acid synthase (FASN), a key enzyme of lipid synthesis. Yet, the combination of PLX8394 and FASN inhibitor TVB3664 has a synergistic effect on cell viability and colony formation in parental CRC cells, but not in PLX-resistant cells. Importantly, we demonstrate that addition of TVB3664 to the PLX8394 or encorafenib regimen significantly postpones development of resistance to BRAF-targeted therapy by inhibiting the cell cycle progression via a decrease in pRb (Ser780) and downregulation of E2F transcription factor and Cyclin D1 expression. Consistently, clinical data show that patients with BRAFV600E CRC who have high FASN expression in tumor tissues have higher expression of cell cycle-associated genes, including CDKs, E2F, CCDN1 (Cyclin D1), survivin, and MKI67. Collectively, these findings identify FASN-driven lipid metabolism as a critical mediator of resistance to BRAF-targeted therapy and suggest that incorporation of FASN inhibitors may enhance therapeutic efficacy and delay acquired resistance in BRAFV600E CRC.

Keywords:  BRAF(V600E); Colorectal cancer; Fatty acid synthase; PLX8394; TVB3664

DOI:  https://doi.org/10.1016/j.neo.2026.101283
Cancer Discov. 2026 Feb 06. 16(2): 201-203

Plasticity as Resistance: KRAS Inhibition Reveals WNT Adaptation in Metastatic Colorectal Cancer.

George Eng, Omer H Yilmaz.

Centonze and colleagues demonstrate that KRASG12D inhibition in metastatic colorectal cancer triggers rapid transcriptional reprogramming from a metastasis-associated EMP1+ state to a WNT-driven LGR5+ stem cell-like state, a plastic adaptation captured through real-time live cell imaging, revealing cell state conversion as a mechanism of therapeutic resistance that can be exploited through combinatorial targeting. See related article by Centonze et al., p. 320.

DOI: https://doi.org/10.1158/2159-8290.CD-25-2147
Cell Death Dis. 2026 Jan 31. 17(1): 187

BCL-xL as a therapeutic target in cetuximab-refractory colorectal cancer.

Stella Asmanidou, Julia Thiel, Thomas L Ekstrom, Julia Schueler, Eva Oswald, Patrick Metzger, Andreas C Blaumeiser, Melanie Boerries, Lisa-Marie Wiebl, Ronja Schiffler, Raluca Tamas, Frank Essmann, Meng Dong, Steven A Johnsen, Roland E Kontermann, Monilola A Olayioye.

Despite recent medical advances, colorectal cancer (CRC) remains the second-leading cause of cancer-related death worldwide. For patients with KRAS wild-type metastatic CRC, the monoclonal antibody cetuximab, which targets the epidermal growth factor receptor (EGFR), is an approved treatment option. However, therapeutic success is often limited by the emergence of drug-resistant cancer cell populations within a few months. Therefore, alternative strategies to effectively target cetuximab-refractory CRC are urgently needed. Here, we sought to identify second-line therapeutic strategies using a CRC cell line with acquired cetuximab resistance as a model. Transcriptomic profiling of the resistant cells identified the apoptosis pathway as a potential therapeutic target, which was supported by their increased susceptibility to BH3-mimetics targeting the anti-apoptotic proteins MCL-1 and BCL-xL under both 2D and 3D culture conditions. These findings were validated in organotypic CRC slice cultures generated from cetuximab-resistant patient-derived xenografts (PDXs). Multiplex immunofluorescence staining demonstrated that BCL-xL inhibition effectively triggered apoptosis in heterogeneous PDX tumor slice models, including models harboring oncogenic BRAF mutations. Our findings suggest that cetuximab-resistant CRC retains apoptotic competence, and that BCL-xL inhibition serves as a robust alternative therapeutic strategy that is largely independent of the tumor mutational profile.

DOI: https://doi.org/10.1038/s41419-026-08434-5
Cell. 2026 Feb 05. pii: S0092-8674(25)01438-2. [Epub ahead of print]189(3): 706-724

Shifting paradigms in tissue stem cell biology: Insights from the intestine.

Hans Clevers.

The small intestinal epithelium represents the most rapidly self-renewing adult mammalian tissue, with a turnover time of 1-2 weeks. It contains ∼12 easily recognizable cell types with a wide diversity of functions, including nutrient absorption, mucus production, antimicrobial defense, and the regulation of metabolism by incretins like Glp1. The simple and repetitive crypt-villus architecture allows for easily interpretable experimentation in transgenic mice in vivo, while the human stem cell hierarchy is experimentally accessible in epithelial organoids in vitro. This review aims to comprehensively describe the design, the cellular constituents, and the molecular regulation of crypt-villus epithelial self-renewal. More generally, it highlights deviations from commonly held views on tissue stem cell biology: gut stem cells divide continually and symmetrically. They can be expanded indefinitely in vitro, while the plasticity of daughter cells can recreate stem cells during regeneration.

DOI: https://doi.org/10.1016/j.cell.2025.12.025
Commun Biol. 2026 Jan 30.

Notch3 regulates pericyte phenotypic plasticity in colorectal cancer.

Niki Chalkidi, Athanasia Stavropoulou, Vasiliki-Zoi Arvaniti, Christina Paraskeva, Artemis Monogyiou, Maria Sakkou, Christoforos Nikolaou, Vasiliki Koliaraki.

Pericytes, essential components of the tumor microenvironment, undergo phenotypic alterations that influence cancer progression, yet the molecular mechanisms governing these changes remain poorly understood. Here, we investigate the role of Notch3 signaling in pericyte phenotype and functions in colorectal cancer (CRC). Using lineage tracing approaches, we show that murine tumor pericytes originate from normal tissue-resident pericytes, which proliferate inside tumors. In vivo genetic manipulation reveals that Notch3 pathway activation promotes pericyte proliferation, while suppressing contractile protein expression, and leads to increased endothelial cell proliferation and reduced blood vessel integrity. In contrast, Notch3 deletion leads to decreased endothelial proliferation, blood vessel normalization, and a significant reduction in tumorigenesis in an advanced orthotopic mouse model. Single-cell RNA sequencing analysis uncovers significant pericyte heterogeneity in both mouse colitis-associated cancer and human CRC. It specifically identifies distinct subpopulations characterized by differential Notch3 activity, which is enriched in a synthetic subset and absent in a contractile subset, further supporting our in vivo findings. Our results establish Notch3 as a key regulator of pericyte phenotypic plasticity in CRC and suggest that targeting this pathway could represent a promising strategy for improving therapeutic outcomes through vascular normalization.

DOI: https://doi.org/10.1038/s42003-026-09629-4
Methods Cell Biol. 2026 ;pii: S0091-679X(25)00132-3. [Epub ahead of print]201 23-38

A syngeneic orthotopic mouse model of metastatic colorectal cancer.

Virginie Feliu, Maha Ayyoub, Christel Devaud.

  Colorectal cancer (CRC) development is initiated in the colon-rectum sections of the gut, by the emergence of a primary tumor. CRC slowly progresses to a multiple locations metastatic disease, involving secondary tumors arising in various organs, such as the liver. Mouse models have been developed to investigate the immune response, locally generated in primary tumors. Classically, tumors are implanted under the skin, for practical reasons and simplicity of monitoring. However, the skin location does not necessarily recapitulate the tumor immune microenvironment (TME) that would normally be generated in the gut. The orthotopic CRC mouse model, that we describe hereafter, was generated to investigate the colon-local mechanisms driving the establishment and the polarization of primary tumors TME. In this chapter, we detail the procedures used to implant syngeneic colon tumor cells in the cecum of immunocompetent mice and to monitor the progression of visceral tumors in live mice. The same procedure can be implemented using other tumor cell lines and mouse genetic backgrounds.

Keywords:  Orthotopic model; colorectal cancer; tumor immunology

DOI:  https://doi.org/10.1016/bs.mcb.2025.05.004
Ann Surg Oncol. 2026 Feb 03.

Consensus Molecular Subtypes Inform HIPEC Agent Selection in Colorectal Cancer Peritoneal Metastases.

Princy Gupta, Elizabeth L Godfrey, Kurt S Schultz, Lu Qiao, Nicole Aguirre, Justin M Bader, Michael B Foote, John Paul Shen, Ardaman P Shergill, Michael Cecchini, Raghav Sundar, Jason M Sheltzer, Kiran K Turaga.

   BACKGROUND: Although hyperthermic intraperitoneal chemotherapy (HIPEC) added to cytoreductive surgery shows promise for colorectal cancer with peritoneal metastases (CRC-PM), effectiveness remains variable. Given the predominance of consensus molecular subtype 4 (CMS4) in CRC-PM and resistance to standard agents, we hypothesized CMS4 exhibits distinct drug sensitivities.
MATERIALS AND METHODS: Drug sensitivity data from the DepMap PRISM Repurposing Dataset for 34 CRC cell lines were classified into the 4 CMS subtypes. Five intraperitoneal agents were analyzed: mitomycin-C, oxaliplatin, irinotecan, 5-fluorouracil, and cisplatin. Differential drug response among CMS subtypes was assessed using log2 fold change (log2FC) in cell viability.
RESULTS: The 34 CRC cell lines were classified into 4 categories: CMS1 (29%), CMS2 (18%), CMS3 (26%), and CMS4 (26%). CMS4 cell lines demonstrated higher sensitivity than CMS2 lines to mitomycin-C (median log2FC = -2.35 versus -0.21, p = 0.019). CMS4 and CMS3 cell lines were significantly more sensitive to irinotecan than CMS1 and CMS2 cell lines (p = 0.004). Oxaliplatin, 5-fluorouracil, and cisplatin showed no differential sensitivity across subtypes. CMS4 cell lines demonstrated sensitivity (sensitivity threshold log2FC < -1.74) to mitomycin-C and irinotecan but showed lack of sensitivity to oxaliplatin, 5-fluorouracil, and cisplatin.
CONCLUSIONS: CMS4 exhibits distinct drug sensitivity patterns that could guide personalized HIPEC agent selection. This may explain the success of mitomycin-C and the limited efficacy of oxaliplatin in HIPEC trials. Future clinical trials should consider genomic subtyping and drug sensitivity testing to guide personalized HIPEC strategies for patients with CRC-PM.

Keywords:  Colorectal cancer; Consensus molecular subtypes; Hyperthermic intraperitoneal chemotherapy; Mitomycin-C; Oxaliplatin; Peritoneal metastases

DOI:  https://doi.org/10.1245/s10434-025-19057-z
EMBO Rep. 2026 Feb 02.

VGLL4 modulates Paneth cells and sustains intestinal homeostasis.

Haoen Zhang, Zuoyun Wang, Xiaodong Wang, Wentao Yu, Guoying Zhang, Haijiao Zhang, Yi Lu, Yang Sun, Tiantian Lu, Xiaoyu Li, Ruizeng Yang, Jiaqi Sun, Jinjin Xu, Shuo Huang, Xueyan Ma, Jiale Ren, Nan Tang, Zhonghua Cheng, Jing Yu, Fang Wei, Hu Zhou, Jinsong Li, Jun Qin, Yunyun Jin, Lei Zhang.

  Paneth cells are defensive cells in the intestinal tract, which secrete niche factors and antimicrobial peptides (AMPs) to maintain the small intestinal stem cell niche and immune homeostasis. Here, we show that Vestigial-like family member 4 (VGLL4) plays a pivotal role in maintaining small intestinal homeostasis and in regulating Paneth cells. VGLL4 expression is downregulated in response to irradiation and DSS-induced colitis. Consistently, public datasets of human colitis show reduced VGLL4 expression. Loss of VGLL4 in the intestinal epithelium decreases Paneth cell numbers and AMPs production, and triggers gut microbiota dysbiosis, impairing intestinal regenerative capacity. Mechanistically, VGLL4 forms a complex with TEAD4 and ATOH1, stimulating GFI1 expression and promoting Paneth cell differentiation. Furthermore, VGLL4 forms a complex with TEAD4 and TCF4 to induce defensin expression, thereby maintaining microbiota composition. Collectively, our findings uncover novel roles for VGLL4 in intestinal homeostasis.

Keywords:  ATOH1; GFI1; Intestinal Homeostasis; Paneth Cell; VGLL4

DOI:  https://doi.org/10.1038/s44319-026-00699-3
Neoplasia. 2026 Jan 29. pii: S1476-5586(25)00149-6. [Epub ahead of print]73 101270

MYLK4 promotes colorectal cancer progression by regulating lipid metabolism reprogramming via targeting ferroptosis.

Bishi Wang, Kongxiu Wu, Xin Liu, Yuhai Shen, Yanliang Li.

  The advancement of novel pharmaceuticals and targeted therapeutic approaches is considerably obstructed by the insufficient comprehension of the intricate pathophysiology of colorectal cancer (CRC). The therapeutic effectiveness of tyrosine kinase inhibitors (TKI)-based systemic treatment for advanced CRC is limited by medication resistance. Research has revealed that therapeutic strategies aimed at the myosin light chain kinase family member 4 (MYLK4) and its corresponding response element can suppress tumour proliferation and yield significant clinical advantages for cancer patients. This study reveals that MYLK4-mediated lipid metabolic reprogramming confers resistance to TKI-induced ferroptosis in CRC. MYLK4 directly interacts with tripartite motif containing 15 (TRIM15) in a way reliant on mouse double minute 2 homolog (MDM2), hence enhancing p53 ubiquitination and degradation. Significantly, p53 suppresses the transcription of stearoyl-CoA desaturase 1 (SCD1) through binding to its promoter. Elevated SCD1 levels correlate with increased MYLK4 levels, and their concurrent expression forecasts regorafenib resistance and poor prognosis in colorectal cancer. Regorafenib and SCD1 inhibitor (SCD1 inhibitor-3) co-treatment demonstrate promising anti-tumor efficacy in organoids and xenografted tumours derived from wild-type p53 colorectal cancer patients. Patients with colorectal cancer exhibiting elevated MYLK4 activity and wild-type p53 may derive clinical benefits from this combination therapy. These results suggest that MYLK4 may serve as a promising therapeutic target for the treatment of colorectal cancer.

Keywords:  Colorectal cancer; Ferroptosis; MYLK4; Regorafenib; TRIM15

DOI:  https://doi.org/10.1016/j.neo.2025.101270
Biochim Biophys Acta Mol Cell Biol Lipids. 2026 Jan 30. pii: S1388-1981(26)00016-8. [Epub ahead of print]1871(3): 159730

Palmitoylated STX11 suppresses AMPK to drive lipogenesis and colorectal cancer.

Bao Li, Zhongkang Yan, Wenyuan Dang, Jianxiong Han, Hongli Xue, Feifei Wang, Lili Wang, Xueqing Yang, Xingyuan Yang.

  Syntaxin 11(STX11), a SNARE family protein, regulates vesicular trafficking and cytokinesis, yet its functional role in colorectal cancer (CRC) pathogenesis remains poorly understood. Here, we identify STX11 as a critical regulator that potentiates CRC progression in vivo and in vitro. Mechanistically, STX11 modulates the AMPK signaling pathway in a palmitoylation-dependent manner, attenuating ACC phosphorylation to enhance its enzymatic activity and stimulate de novo lipogenesis. Genetic ablation of STX11 significantly impedes tumorigenesis in an AOM/DSS-induced CRC mouse model. Our findings establish STX11 as a critical regulator of lipid metabolism in CRC progression and nominate it as a promising therapeutic target.

Keywords:  AMP-activated protein kinase (AMPK); Acetyl-coA carboxylase (ACC); Colorectal cancer (CRC); Palmitoylation; Syntaxin11 (STX11)

DOI:  https://doi.org/10.1016/j.bbalip.2026.159730
J Cancer Biol. 2025 ;6(2): 91-107

Unleashing Wnts: Wnt Ligands Fuel Cancer Spread.

Kailey P Caroland, Jonathan B Trapani, Ethan Lee, Vivian L Weiss.

  Wnt signaling has long been implicated in cancer development, but recent studies have revealed new insights into how Wnt ligands themselves drive metastasis. Currently, research identifies Wnt1, Wnt2, Wnt2b, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt8a, Wnt9b, Wnt10a, Wnt10b, and Wnt16 as pro-metastatic Wnt ligands, while Wnt7a, Wnt7b, Wnt8b, Wnt9a, and Wnt11 exhibit conflicting pro- and anti-metastatic roles. These ligands arise from diverse sources in the tumor microenvironment and perform a wide range of roles in the metastatic cascade, including epithelial-to-mesenchymal transition, matrix metalloproteinase production, cell motility, angiogenesis, cell death resistance, and mesenchymal-to-epithelial transition. Their diverse and critical roles in metastasis make Wnt ligands attractive therapeutic targets.

Keywords:  EMT; Wnt; Wnt/β-catenin signaling; angiogenesis; cancer therapeutics; metastasis

DOI:  https://doi.org/10.46439/cancerbiology.6.079
ESMO Gastrointest Oncol. 2025 Sep;9 100225

Surrogate to predict overall survival in patients with BRAF V600E-mutant colorectal cancer treated with BRAF inhibitor combinations.

J Ros, V Navarro, G Villacampa, I Baraibar, F Salvà, M Rodriguez, C Vaghi, A Garcia, A Alcaraz, J Tabernero, E Élez, R Dienstmann.

   Background: The BRAF V600E mutation, found in up to 12% of patients with metastatic colorectal cancer, is associated with aggressive disease and poor response to standard chemotherapy. However, the advent of BRAF inhibitors has led to improved clinical outcomes and survival. While surrogate endpoints for predicting overall survival (OS) have been extensively studied in the overall colorectal cancer population treated with chemotherapy, their applicability in patients with BRAF V600E-mutant colorectal cancer receiving either BRAF inhibitor combinations or conventional chemotherapy remains unclear, and needs to be better elucidated. The aim of the study was to evaluate surrogate endpoints to predict OS in patients with BRAF V600E-mutant colorectal cancer treated with either BRAF inhibitor combinations or chemotherapy.
Materials and methods: A systematic review was carried out to identify clinical trials or real-world cohorts evaluating patients with BRAF-mutant colorectal cancer treated either with chemotherapy or BRAF inhibitor combinations. A control cohort of melanoma patients treated with BRAF inhibitors in a phase III randomized trial was included. Adjusted R 2 (R 2 adj) values were calculated to quantify the association between surrogate endpoints and median OS.
Results: Overall, a total of 5227 patients included in 29 cohorts were analyzed. Among patients with colorectal cancer treated with chemotherapy, overall response rate (ORR) and disease control rate (DCR) showed a high correlation with OS (R 2 adj > 0.90). Among patients treated with targeted therapy, progression-free survival (PFS) showed the highest correlation with OS (R 2 adj = 0.90). In the melanoma cohort, PFS was strongly associated with OS (R 2 adj = 0.92).
Conclusions: In BRAF-mutant colorectal cancer, standard surrogate endpoints for chemotherapy-based treatments accurately predict OS; however, when patients are treated with targeted therapies, both ORR and PFS have proven to be reliable predictors of survival.

Keywords:  BRAF inhibitor; BRAF mutation; colorectal cancer; surrogate markers; targeted therapy

DOI:  https://doi.org/10.1016/j.esmogo.2025.100225
Gastro Hep Adv. 2026 ;5(3): 100871

Carbonic Anhydrase-IX Is a Specific and Sensitive Theragnostic Target for Imaging and Radioimmunotherapy in Metastatic Colorectal Cancer.

Dijina Swaroop, Jai Smith, Jessica Van Zuykelom, Asif Noor, Robin A Wagner, Tamara Vu, Sarah Lee, Alexander G Heriot, Benjamin Loveday, Kelly Waldeck, Peter D Roselt, Benjamin Blyth, Paul S Donnelly, Frédéric Hollande.

   Background and Aims: Over 40% of colorectal cancer (CRC) patients develop metastatic disease. Their survival outlook is very low, highlighting the urgent need to improve the detection and therapeutic management of metastatic colorectal cancer (mCRC), particularly when metastases are not surgically resectable. Our study aimed to characterize the preclinical utility of targeting carbonic anhydrase IX (CA-IX) for metastasis imaging and for therapeutic purposes in patients with CRC liver metastases.
Methods: CA-IX expression was characterized in 46 liver metastasis samples using RNA sequencing and immunohistochemical staining. We labeled girentuximab, a clinical grade CA-IX antibody, with zirconium-89 ([89Zr]Zr) or lutetium-177 ([177Lu]Lu), and characterized its biodistribution in vivo. Using radiolabeled girentuximab in patient-derived liver metastasis organoids (PDOs) and xenograft models, we then characterized the preclinical utility of CA-IX imaging and therapeutic targeting in mCRC.
Results: CA-IX mRNA and/or protein expression was detected in 87% of CRC liver metastasis samples, with little to no expression in surrounding liver tissue. Both [89Zr]Zr- and [177Lu]Lu-girentuximab exhibited excellent biodistribution characteristics in mice xenografted with PDOs. Positron emission tomography imaging showed that [89Zr]Zr-girentuximab enabled specific and high-resolution detection of CA-IX-expressing lesions at subcutaneous and hepatic sites compared to [18F]F-fluoro deoxy-glucose. Finally, single-dose [177Lu]Lu-girentuximab treatment induced cytotoxicity in PDOs in vitro and strongly reduced tumor burden in 2 independent xenografted mouse models, with no signs of toxicity.
Conclusion: Our results demonstrate that CA-IX is a relevant target for a theragnostic strategy in mCRC, and provide the first demonstration in clinically-relevant models of metastasis that radiolabeled girentuximab can be used as a scouting agent to stratify and monitor mCRC patients and as a therapeutic alternative for patients with CA-IX-expressing tumors.

Keywords:  Bowel Cancer; Liver Metastases; Theragnostics

DOI:  https://doi.org/10.1016/j.gastha.2025.100871
Cell Death Dis. 2026 Jan 30. 17(1): 164

Lactylation of SLC26A3 in the acidic tumor microenvironment promotes malignant progression of colorectal carcinoma.

Chong Chen, Du Cai, Xuanhui Liu, Yifan Zheng, Xinxin Huang, Dongwen Chen, Jiawei Cai, Yiran Bie, Zhengran Zhou, Chuling Hu, Zhengyu Wei, Kuntai Cai, Ting Li, Shuzhen Luo, Dongbing Liu, Kui Wu, Zerong Cai, Feng Gao, Xiaojian Wu, Peishan Hu.

The acidic tumor microenvironment provides the energy that drives the development of malignant tumors. High concentrations of lactic acid and H+ are key features of the acidic tumor microenvironment, and lactylation has gradually been shown to play a significant role in tumor progression. The expression of solute carrier family 26 member 3 (SLC26A3) is closely related to the occurrence and development of colorectal cancer (CRC), but the specific molecular mechanisms remain unclear. We demonstrated that alterations in the acidic microenvironment and overexpression of SLC26A3 significantly inhibited CRC occurrence and progression in vivo. Our study indicates that SLC26A3 undergoes lactylation in the acidic tumor microenvironment, which decreases SLC26A3 stability and expression. SLC26A3 interacts with the RNA-binding proteins Hu antigen R (HuR) and CUG-binding protein 1 (CUGBP1). When SLC26A3 expression is reduced, its ability to bind to HuR/CUGBP1 is weakened. As a result, HuR and CUGBP1 more readily interact with a subset of oncogenic mRNAs, regulating their stability and influencing their expression, ultimately promoting malignant tumor progression. These findings highlight the role of SLC26A3 as a potential suppressor of CRC recurrence, drug resistance, and metastasis, providing new insights for improving the clinical treatment and prognosis of CRC.

DOI: https://doi.org/10.1038/s41419-026-08422-9
Mol Oncol. 2026 Feb 03.

Genetic attenuation of ALDH1A1 increases metastatic potential and aggressiveness in colorectal cancer.

Martina Poturnajova, Zuzana Kozovska, Ondrej Pos, Kristina Pavlov, Sachin Gulati, Peter Makovicky, Kristina Jakic, Monika Burikova, Eva Sedlackova, Barbora Svitkova, Silvia Tyciakova, Vojtech Bystry, Nicolas Blavet, Boris Tichy, Matej Hrnciar, Jaroslav Budis, Miroslav Tomas, Peter Dubovan, Georgina Kolnikova, Veronika Repaska, Nikoleta Mojzesova, Eva Zomborska, Daniel Pindak, Michal Mego, Tomas Szemes, Miroslava Matuskova.

  Colorectal cancer ranks third in global incidence and second in cancer mortality. Patient-derived models are irreplaceable for studying tumor biology. We established a human epithelial cell line from a rectal adenocarcinoma overexpressing cancer stem cell marker ALDH1A1, and we investigated the effect of ALDH1A1 knockout on tumor cell traits. The cell line and its CRISPR-Cas9 ALDH1A1 knockouts were characterized by genomic and cytogenetic methods (CNV, WES, RNAseq, karyotype), in vitro (proliferation, response to chemotherapy, migration, invasion, apoptosis), and in vivo methods. We identified the landscape of somatic mutations and copy number alterations in the original tumor and the derived cell line. Genetic attenuation of ALDH1A1 was characterized by an increase in migratory potential and extensive metastatic ability, accompanied by reduced growth of subcutaneous xenografts and alterations in gene expression associated with inhibited proliferation and promoted invasion and metastasis, ultimately resulting in dysregulation of the Wnt signaling pathway. Increased metastatic potential was also confirmed in HT-29 cells after ALDH1A1 genetic attenuation. CRISPR-Cas9-mediated editing led to functional, cellular, and molecular changes confirming the role of ALDH1A1 in colorectal cancer carcinogenesis.

Keywords:  CRISPR‐Cas9; aldehyde dehydrogenase; colorectal cancer; metastasis

DOI:  https://doi.org/10.1002/1878-0261.70215
Nat Commun. 2026 Feb 03.

Escherichia coli promotes colorectal cancer metastasis by maintaining enhancer-promoter loops through releasing neutrophil extracellular traps.

Banglun Pan, Yuxin Yao, Zhu Zhang, Dongjie Ye, Hao Wu, Xinyu Zhang, Xiaoqian Wang, Nanhong Tang.

The involvement of intestinal microbiota in the process of neutrophil-mediated colorectal cancer liver metastasis (CRCLM) is not yet fully understood. Here, we show that Escherichia coli (E. coli) is prevalent in CRC tissues with LM using 2bRAD-M-Seq and is linked to the release of neutrophil extracellular traps (NETs). Utilizing multi-omics and molecular techniques, we establish that E. coli recruits RIPK2, which promotes the binding of HNRNPK to the Atf3/Relb promoters in neutrophils, thereby enhancing their transcription. This process results in the upregulation of Ncf4, which triggers p-MLKL-mediated NET formation. NETs, in turn, increase the expression of TRPC1 and NFATC3 in CRC cells, promoting the calcium-dependent assembly of the STAT3/S100A8/9 heterotrimer. This trimer stabilizes STAT3-enhancer-promoter loops (EPLs), thereby reinforcing the Tns1 transcription and facilitating CRCLM. Our findings elucidate the mechanism by which E. coli-induced NETs promote CRCLM through epigenetic modifications, offering an insight into the role of EPLs in immune regulation and tumor progression.

DOI: https://doi.org/10.1038/s41467-026-69005-y
Mol Oncol. 2026 Feb 03.

Colorectal cancer-derived FGF19 is a metabolically active serum biomarker that exerts enteroendocrine effects on mouse liver.

Jordan M Beardsley, Michael W Rohr, Joseph A Goode, Sai Preethi Nakkina, Jignesh G Parikh, Deborah A Altomare.

  Despite having excellent prognosis when detected early, colorectal cancer (CRC) remains a leading cause of cancer-related deaths globally. Screening remains an important contributor to CRC survival, but the cost and invasiveness of traditional imaging methodologies can hinder patient compliance. A blood-based approach would be more convenient and accessible, but reliable serum markers are lacking. In this study, the peptide enteroendocrine hormone Fibroblast Growth Factor 19 (FGF19) was identified as an attractive marker for CRC through a meta-transcriptomic analysis. While its pro-tumor effects are documented, FGF19's utility as a blood serum marker for CRC is not well defined. Studies presented here show that FGF19 is constitutively expressed and secreted in 3 of 5 CRC cell lines, and secreted levels increase with seeding density. A subcutaneous CRC cell line-derived xenograft model revealed that FGF19 is detectable in serum of mice injected with FGF19-positive, but not negative, CRC cells at levels corresponding to tumor volume. Enteroendocrine effects of tumor-derived FGF19, including suppression of bile acid synthesis, are evident in liver samples via RNA sequencing and validated by RT-PCR. Notably, the hepatic response to CRC-secreted FGF19 has not been explored prior to this study even though FGF19 is a key regulator of hepatic cholesterol metabolism and bile acid homeostasis. Collectively, these findings support the clinical utility of FGF19 as a putative serum marker for CRC and provide important evidence that CRC-derived FGF19 can modulate liver physiology consistent with the enteroendocrine function of FGF19.

Keywords:  colon cancer; enterohepatic signaling; fibroblast growth factor‐19; meta‐analysis; serum marker

DOI:  https://doi.org/10.1002/1878-0261.70212
EMBO Rep. 2026 Feb 03.

Toll signaling controls stem cell proliferation in intestinal regeneration and tumorigenesis.

Guofan Peng, Shichao Yang, Yuexia Zhang, Yu Zhao, Xiaoyun Huang, Shengen Yi, Lei Gu, Ganqian Zhu, Kewei Zheng, Huijun Zhou, Kang Han, Jun Zhou.

  The Drosophila Toll/NF-κB pathway has been extensively studied for its roles in innate immunity and embryonic development. Nevertheless, the regulatory mechanisms underlying Spz/Toll signaling in non-immune contexts remain poorly understood. Here, we demonstrate a critical role for Toll in regulating intestinal stem cell activity through direct transcriptional control of PI3K and Akt in an insulin-independent manner. Time-series transcriptomic analysis of intestinal damage and repair responses reveals that the stress-responsive factor Jumu regulates Spz expression to activate Toll signaling. Disruption of the Jumu/Spz/Toll cascade or PI3K/Akt signaling impairs intestinal regeneration and suppresses tumor growth, and epistasis analysis confirms that PI3K/Akt functions downstream of Toll. Our findings elucidate an autocrine Spz/Toll-mediated mechanism that drives stem cell function via the PI3K/Akt pathway during tissue homeostasis and uncover a critical non-immune role of Toll signaling in both physiological and pathological contexts.

Keywords:   Drosophila ; Akt/PI3K Signaling; Intestinal Stem Cell; Toll/TLRs Signaling; Tumorigenesis

DOI:  https://doi.org/10.1038/s44319-026-00693-9
ESMO Gastrointest Oncol. 2025 Sep;9 100230

Retreatment with oxaliplatin-based regimens in refractory metastatic colorectal cancer: characterization of high-response patients.

F Salvà, G Catani, N Saoudi, I Baraibar, J Ros, M Rodriguez, C Salvà de Torres, A Alcaraz, A Garcia, R Comas, F Ruiz-Pace, A Rezqallah, R Dienstmann, J Tabernero, E Elez.

   Background: Oxaliplatin, a key agent used for managing metastatic colorectal cancer (mCRC), is often discontinued due to cumulative toxicity. Its reintroduction in later treatment lines remains a common clinical practice, despite the absence of robust prospective trials supporting this therapeutic strategy. This study aimed to evaluate the efficacy of oxaliplatin rechallenge in refractory mCRC and to identify patient characteristics predictive of improved outcomes with this approach.
Patients and methods: We retrospectively analyzed patients treated with oxaliplatin in the third- or fourth-line setting at Vall d'Hebron Hospital between 2015 and 2021. Outcomes included overall response rate (ORR), disease control rate (DCR), and median progression-free survival (PFS). Patients achieving median PFS >6 months were classified as best-responders. Factors affecting PFS were analyzed with a Cox regression model. Amplicon-seq analysis of 61 genes was carried out using Illumina technology.
Results: Of 735 patients receiving third- or fourth-line treatment, 102 (14%) received oxaliplatin retreatment (69% in third line; 31% in fourth line). Median PFS was 4.0 months (95% CI 3.29-5.03 months), with an ORR of 12% and DCR of 39%. Twenty-eight patients (27%) were best-responders. Predictors of efficacy included response to first-line oxaliplatin, planned oxaliplatin discontinuation, and an oxaliplatin-free interval of at least 22.0 months. No significant associations were identified between molecular alterations and prognostic subgroups.
Conclusions: Oxaliplatin-based reintroduction therapy is a viable strategy in mCRC, particularly for patients with a favorable prior response and prolonged oxaliplatin-free intervals. However, identifying more precise biomarkers is essential to improve patient selection and maximize treatment efficacy.

Keywords:  metastatic colorectal cancer (mCRC); oxaliplatin; rechallenge; refractory; reintroduce

DOI:  https://doi.org/10.1016/j.esmogo.2025.100230
Cell Death Dis. 2026 Jan 31. 17(1): 189

SLC46A1 deficiency-mediated folate restriction suppresses colorectal cancer progression through epigenetic-transcriptional reprogramming.

Yelu Zhou, Yanxing Liu, Yi Liu, Chang Che, Yihan Zhao, Jianing Yu, Xinhang Li, Ang Li, Shuyi Chen, Haojia Wang, Mingzhen Zhou, Dan Liu, Wenfang He, Zhuo Wang, Hua Han, Xin Wang, Yuanyuan Lu, Kaichun Wu, Xiaodi Zhao.

The association between folate metabolism abnormalities and the development of colorectal cancer (CRC) remains controversial. Here, we report that the folate exerts a tumor-suppressive role in CRC; however, the manifestation of this effect is restricted by the expression level of folate transporter SLC46A1 in CRC cells. Multi-cohort profiling revealed significant downregulation of SLC46A1 in CRC tissues compared to adjacent normal tissues, where low expression independently predicted poor overall survival. Functional studies demonstrated that SLC46A1-mediated folate uptake suppressed tumor proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, SLC46A1 deficiency restricted intracellular folate availability and impaired cellular methylation potential, as evidenced by a reduced SAM/SAH ratio, leading to DNA hypomethylation at specific sites such as the FOS proto-oncogene promoter. This epigenetic reprogramming triggers transcriptional activation of key oncogenic effectors CCND1, BCL2, and PLAU involved in CRC progression. Clinically, we found a significant inverse correlation between SLC46A1 expression and folate levels in tumor interstitial fluids of CRC, suggesting impaired folate uptake in low SLC46A1 tumors. Multi-color immunofluorescence across two cohorts further demonstrated conserved inverse associations between SLC46A1 and FOS expression in primary tumors and metastatic lesions. This study elucidates the molecular mechanism by which folate inhibits CRC progression through the "SLC46A1-epigenetic-transcriptional regulation" axis, providing mechanistic insights into folate deficiency-driven CRC progression and biomarkers for precision CRC intervention. This study elucidates the tumor-suppressive role of the folate transporter SLC46A1 in CRC. In normal cells, SLC46A1 facilitates folate uptake, supporting one-carbon metabolism and maintaining genomic stability. In CRC, however, SLC46A1 downregulation induces intracellular folate deficiency, triggering locus-specific DNA hypomethylation at the FOS promoter, which activates oncogenic transcription of key downstream effectors (CCND1, BCL2, PLAU), driving tumor progression. The graphical abstract illustrates the differential impact of SLC46A1 on folate metabolism and gene expression in normal versus tumor cells, highlighting its potential as a therapeutic target in CRC.

DOI: https://doi.org/10.1038/s41419-026-08423-8
Cell Death Dis. 2026 Jan 30. 17(1): 159

Cancer-associated fibroblasts (CAFs) derived from MFAP2 promote CRC proliferation and metastasis while suppressing CD8+ T cell-mediated antitumor immunity.

Xu Zhang, Yuxiang Fei, Chunqi Xie, Tao Li, Ben Niu, Zihao Yang, Mengwei Song, Fanjun Meng, Hongting Diao, Jing Ji, Qianming Du, Chao Liu.

Colorectal cancer (CRC) ranks among the most prevalent malignancies of the digestive system, with the intricate tumor immune microenvironment (TIME) emerging as a key determinant of poor prognosis. Cancer-associated fibroblasts (CAFs), a central constituent of the tumor microenvironment, critically influence tumorigenesis and progression by orchestrating immunosuppression through cytokine secretion and other mechanisms. This study investigates the multifaceted interplay between CAFs and the immune system to identify novel therapeutic targets and improve prognostic outcomes for CRC patients. Through comprehensive analyses of clinical samples and public database data, we identified elevated MFAP2 expression in both CRC tissues and fibroblasts. Mechanistically, we established that CAFs-derived MFAP2 interacts with integrin β8 (ITGB8) on cancer cell surfaces, activating the integrin-FAK-ERK1/2 signaling cascade to drive CRC progression. Furthermore, ERK1/2 phosphorylates and activates the transcription factor ETS2, which upregulates the expression of CYP27A1, an enzyme that modulates lipid metabolism and suppresses CD8+ T cell function via liver X receptor beta (LXRβ) signaling. These findings elucidate a novel MFAP2-ITGB8-FAK-ERK1/2-ETS2-CYP27A1-LXRβ signaling axis, significantly activated by CAFs-derived MFAP2 in both in vitro and in vivo models, contributing to immune exhaustion and tumor progression. This axis offers significant therapeutic and prognostic potential for CRC, providing critical insights into CAF-mediated immune modulation and paving the way for targeted immunotherapeutic strategies.

DOI: https://doi.org/10.1038/s41419-026-08413-w