bims-instec 2025-09-28 papers

bims-instec

Biomed News

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

Issue of 2025–09–28
eighteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Mechanosensitive calcium channels and integrins coordinate the reprogramming of colorectal cancer cells into a fetal-like state.
Isolation and Co-culture of Paneth Cells and Intestinal Stem Cells.
Stearoyl-CoA Desaturases regulate stem and progenitor cell metabolism and function in response to nutrient abundance.
The Colonic Crypt: Cellular Dynamics and Signaling Pathways in Homeostasis and Cancer.
Extracellular Vesicle-Packaged miR-99a Reprograms Fibroblasts to Create an Inflammatory Niche that Drives Colorectal Cancer Metastasis.
The molecular and functional landscape of resistance to FOLFIRI chemotherapy in metastatic colorectal cancer.
The immune microenvironment of colorectal cancer.
Cancer-associated fibroblast secreted DKK1 promotes the immunosuppressive tumor microenvironment and colorectal cancer resistance to chemotherapy.
Identification, functional insights and therapeutic targeting of EMT tumour states.
Patient-specific pharmacogenomics demonstrates xCT as predictive therapeutic target in colon cancer with possible implications in tumor connectivity.
Patient-derived organoids predict treatment response in metastatic colorectal cancer.
Human gut evolution: insights from stem cell models and single-cell genomics.
TYK2 Promotes Immunosurveillance of Colorectal Cancer Liver Metastasis.
Artery formation in the intestinal wall and mesentery by intestine-derived Esm1+ endothelial cells.
Inhibiting arginine metabolism via ALDH2/ARG2 axis blockade potentiates immune checkpoint inhibitors in colorectal cancer.
Gut epithelium modifies enteric behaviors during nutritional adversity via distinct peptidergic signaling axes.
UCL-MetIsoLib: A Public High-Resolution Tandem Mass Spectrometry Library for HILIC-Based Isomer-Resolved Profiling of Glycolysis, Central Carbon Metabolism, and Beyond in Urine, Plasma, Tissues, Cells, and Patient-Derived Organoids.
TRIM21 promotes colorectal cancer development through regulating DNA replication by TCF3/MCM2/5 axis.

Cell Rep. 2025 Sep 22. pii: S2211-1247(25)01079-4. [Epub ahead of print]44(10): 116308

Mechanosensitive calcium channels and integrins coordinate the reprogramming of colorectal cancer cells into a fetal-like state.

Mirjam C van der Net, Marjolein J Vliem, Lars J S Kemp, Carlos Perez-Gonzalez, Tariq S Haddad, Esther A Strating, Ana Krotenberg-Garcia, Ronja M Houtekamer, Willem-Jan Pannekoek, Karen B van den Anker, Susan Zwakenberg, Jooske L Monster, Suzanne E M van der Horst, Hugo J G Snippert, Antoine A Khalil, Jacco van Rheenen, Saskia J E Suijkerbuijk, Onno Kranenburg, Femke Simmer, Iris D Nagtegaal, Danijela Matic Vignjevic, Martijn Gloerich.

  Colorectal cancer (CRC) cells exhibit high plasticity and transition between different cellular states during the development of metastasis. Lgr5-expressing cancer stem cells fuel the growth of the primary tumor and metastasis, yet disseminated tumor cells arriving at the metastatic site and seeding liver metastases are devoid of Lgr5 expression. Using CRC organoid models, we demonstrate that mechanical interactions with collagen I, a main constituent of the interstitial matrix, instruct the reprogramming of CRC cells. Collagen I-induced pulling forces are sensed by integrins and mechanosensitive calcium channels, which together direct the transition of CRC cells into a cellular state with transcriptional similarities to fetal intestinal cells. CRC cells infiltrating the interstitial stroma show upregulation of this fetal-like transcriptional program, which correlates with the ability of Lgr5-negative cells to initiate metastasis formation. Our findings indicate that mechanical interactions with collagen I regulate cell fate transitions associated with the metastatic cascade of CRC.

Keywords:  CP: Cancer; CP: Cell biology; Lgr5; TRPV4; YAP1; cancer stem cell; colorectal cancer; fetal-like state; integrins; mechanosensitive calcium channels; mechanotransduction

DOI:  https://doi.org/10.1016/j.celrep.2025.116308
Bio Protoc. 2025 Sep 20. 15(18): e5449

Isolation and Co-culture of Paneth Cells and Intestinal Stem Cells.

Ryosuke Isotani, Masaki Igarashi, Masaomi Miura, Toshimasa Yamauchi.

  Crypts at the base of intestinal villi contain intestinal stem cells (ISCs) and Paneth cells, the latter of which work as niche cells for ISCs. When isolated and cultured in the presence of specific growth factors, crypts give rise to self-renewing 3D structures called organoids that are highly similar to the crypt-villus structure of the small intestine. However, the organoid culture from whole crypts does not allow investigators to determine the contribution of their individual components, namely ISCs and Paneth cells, to organoid formation efficiency. Here, we describe the method to isolate Paneth cells and ISCs by flow cytometry and co-culture them to form organoids. This approach allows the determination of the contribution of Paneth cells or ISCs to organoid formation and provides a novel tool to analyze the function of Paneth cells, the main component of the intestinal stem cell niche. Key features • This protocol introduces the method for isolating Paneth cells and Lgr5+ ISCs by flow cytometry and co-culturing them. • This protocol allows analyzing the effect of genetic or biochemical modifications of Paneth or Lgr5+ ISCs on organoid formation. • This protocol provides a new platform to analyze Paneth cell function.

Keywords:  Co-culture; Crypt; Intestinal stem cells; Organoid; Paneth cells

DOI:  https://doi.org/10.21769/BioProtoc.5449
bioRxiv. 2025 Sep 20. pii: 2025.09.17.676943. [Epub ahead of print]

Stearoyl-CoA Desaturases regulate stem and progenitor cell metabolism and function in response to nutrient abundance.

Kübra B Akkaya-Colak, Andrea R Keller, Maria H Festing, Khushboo Gupta, James Sledziona, Ayobami Adeniyi, Omar West, Patrick Stevens, Maciej Pietrzak, Sue E Knoblaugh, Helaina Walesewicz, Dominique A Baldwin, Judith A Simcox, James Ntambi, Steven K Clinton, Maria M Mihaylova.

Dietary components and metabolites play a critical role in regulating intestinal stem and progenitor cell function and proliferation. Here we show that Stearoyl-CoA Desaturases (SCDs), which regulate intracellular saturated to monounsaturated fatty acids ratios, are induced in response to nutrient abundance, especially in the distal intestine, and regulate intestinal homeostasis. Genetic or pharmacological inhibition of SCDs altered lipid metabolism, increased ER stress, and reduced proliferative intestinal stem and progenitor cells in intestinal organoids. These effects were largely mitigated by oleic acid supplementation. Intestinal epithelium-specific deletion of Scd1 and Scd2 led to metabolic rewiring, leading to expansion of progenitor cell populations. DSS-induced epithelial damage revealed a dependence on SCD enzymes during regeneration, accelerating epithelial damage and inflammation in intestines lacking epithelial Scd1 and Scd2 . These findings underscore key metabolic pathways and dependencies that enable intestinal stem and progenitor cells to adapt to nutrient fluctuations and support epithelial tissue regeneration following injury.

DOI: https://doi.org/10.1101/2025.09.17.676943
Cells. 2025 Sep 11. pii: 1428. [Epub ahead of print]14(18):

The Colonic Crypt: Cellular Dynamics and Signaling Pathways in Homeostasis and Cancer.

Anh L Nguyen, Molly A Lausten, Bruce M Boman.

  The goal of this review is to expand our understanding of how the cellular organization of the normal colonic crypt is maintained and elucidate how this intricate architecture is disrupted during tumorigenesis. Additionally, it will focus on implications for new therapeutic strategies targeting Epithelial-Mesenchymal Transition (EMT). The colonic crypt is a highly structured epithelial unit that functions in maintaining homeostasis through a complex physiological function of diverse cell types: SCs, transit-amplifying (TA) progenitors, goblet cells, absorptive colonocytes, Paneth-like cells, M cells, tuft cells, and enteroendocrine cells. These cellular subpopulations are spatially organized and regulated by multiple crucial signaling pathways, including WNT, Notch, Bone Morphogenetic Protein (BMP), and Fibroblast Growth Factor (FGF). Specifically, we discuss how these regulatory networks control the precise locations and functions of crypt cell types that are necessary to achieve cellular organization and homeostasis in the normal colon crypt. In addition, we detail how the crypt's hierarchical structure is profoundly perturbed in colorectal cancer (CRC) development. Tumorigenesis appears to be driven by LGR5+ cancer stem cells (CSCs) and the hyperproliferation of TA cells as colonocytes undergo metabolic reprogramming. Goblet cells lose their secretory phenotype, while REG4+ Paneth-like cells foster SC niches. Tumor microenvironment is also disrupted by upregulation of M cells and by tumor-immune crosstalk that is promoted by tuft cell expansion. Moreover, the presence of enteroendocrine cells in CRC has been implicated in treatment resistance due to its contribution to tumor heterogeneity. These cellular changes are caused by the disruption of homeostasis signaling whereby: overactivation of WNT/β-catenin promotes stemness, dysregulation of Notch inhibits differentiation, suppression of BMP promotes hyperproliferation, and imbalance of FGF/WNT/BMP/NOTCH enhances cellular plasticity and invasion. Further discussion of emerging therapies targeting epithelial markers and regulatory factors, emphasizing current development in novel, precision-based approaches in CRC treatment is also included.

Keywords:  M cells; Paneth-like cells; colonic crypt; colorectal cancer; enteroendocrine cells; epithelial–mesenchymal transition; goblet cells; signaling pathways; stem cells; tuft cells

DOI:  https://doi.org/10.3390/cells14181428
Cancer Res. 2025 Sep 24.

Extracellular Vesicle-Packaged miR-99a Reprograms Fibroblasts to Create an Inflammatory Niche that Drives Colorectal Cancer Metastasis.

Mingzhen Zhou, Hao Liu, Juan Hui, Qing Chen, Yihan Zhao, Haojia Wang, Wanning Liu, Yibo Bian, Songtao Ji, Boda Wang, Yangsong He, Ge Miao, Yi Liu, Yongzhan Nie, Hua Han, Stephan Emmrich, Xin Wang, Yuanyuan Lu, Xiaodi Zhao.

Inflammation and epithelial-to-mesenchymal transition (EMT) are hallmarks of cancer progression. A better understanding of the mechanisms driving these processes could help uncover strategies to treat and prevent metastasis. Here, we found that extracellular vesicle (EV)-mediated crosstalk between colorectal cancer (CRC) cells and fibroblasts facilitates inflammation and promotes metastasis. Fibroblasts were highly activated in primary tumors from CRC patients with metastatic disease, and EVs secreted from highly metastatic CRC cells promoted fibroblast activation. Mechanistically, EV-packaged miR-99a-5p (EV-miR-99a) specifically targeted NLRP2 mRNA in fibroblasts and activated the pro-inflammatory NF-κB signaling pathway, thereby converting normal fibroblasts into cancer-associated fibroblasts (CAFs). EV-miR-99a-activated CAFs enhanced the migratory capacity of CRC cells by secreting CCL7, which potently induced EMT by increasing the expression of multiple E-cadherin repressors via the CCR5-mTOR-p70S6K pathway. Expression of miR-99a in CRC cells was upregulated by TGF-β1 secreted from CAFs in an NF-κB-dependent manner, forming an miR-99a/TGF-β1 regulatory circuit. The communication between CRC cells and fibroblasts engendered a proinflammatory niche that facilitated metastasis, which could be abolished by treatment with the p70S6K inhibitor LY2584702. Clinically, EV-miR-99a levels in the plasma correlated with the metastatic status of CRC patients. Together, these findings highlight the metastasis-promoting function of an inflammatory fibroblast niche induced by cancer cell-derived EVs and provide potential targets for the prediction and management of CRC metastasis.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0663
Cancer Discov. 2025 Sep 22.

The molecular and functional landscape of resistance to FOLFIRI chemotherapy in metastatic colorectal cancer.

Marco Avolio, Simonetta M Leto, Francesco Sassi, Barbara Lupo, Elena Grassi, Irene Catalano, Eugenia R Zanella, Valentina Vurchio, Francesca Cottino, Petros K Tsantoulis, Luca Lazzari, Paolo Luraghi, Martina Ferri, Francesco Galimi, Enrico Berrino, Sara E Bellomo, Marco Viviani, Alberto Sogari, Gianluca Mauri, Federica Tosi, Federica Cruciani, Andrea Sartore-Bianchi, Salvatore Siena, Felice Borghi, Valter Torri, Elena Élez, Josep Tabernero, Maria Nieva, Clara Montagut, Noelia Tarazona, Andres Cervantes, Sabine Tejpar, Alberto Bardelli, Caterina Marchiò, Silvia Marsoni, Andrea Bertotti, Livio Trusolino.

The combination of 5-fluorouracil and irinotecan (FOLFIRI) remains a standard-of-care treatment for metastatic colorectal cancer (mCRC), yet benefits only about half of patients. Using patient-derived xenografts (PDXs), we investigated the biological underpinnings of this heterogeneous response. FOLFIRI-resistant models showed transcriptional upregulation of innate immunity and mitochondrial metabolism genes, together with reduced expression of the DNA polymerase POLD1. Sensitive counterparts exhibited a BRCAness-like phenotype with genomic scars of homologous recombination (HR) deficiency, not caused by genetic or epigenetic loss of HR genes but by low abundance of the RAD51 recombinase. In tumoroids, forced RAD51 overexpression attenuated HR deficiency-related scars and chemotherapy-induced damage, while HR inhibition through ATM blockade enhanced drug sensitivity. The predictive relevance of key response determinants was validated in clinical samples. This work illuminates functional, non-genetic facets of BRCAness in mCRC and introduces actionable biomarkers and targets, offering prospects to improve clinical decision-making and broaden therapeutic options for chemorefractory patients.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0556
Nat Rev Cancer. 2025 Sep 22.

The immune microenvironment of colorectal cancer.

Kilian B Kennel, Florian R Greten.

Colorectal cancer (CRC) progression depends on the close interaction of tumour cells and the tumour microenvironment (TME). Although the TME contributes to poor therapy responses and immune evasion, immune cells within the TME can be therapeutically leveraged, as exemplified by immune checkpoint blockade (ICB). Unfortunately, only a small subset of patients with CRC benefit from ICB therapy; those with immune-activated, microsatellite unstable CRC respond, whereas the predominant group of patients with CRC, those with microsatellite-stable tumours, do not. Although challenging, modulating the TME of CRC to convert these lowly immunogenic and immunosuppressed tumours into immune-activated tumours holds tremendous therapeutic potential. In this Review we provide an overview of the cellular and molecular components of immunity in the TME of CRCs at various stages of disease as well as the mechanisms of immunosuppression and immune evasion. We further describe how systemic and local therapies for CRC impact the tumour and systemic immune microenvironments, and how immunity could serve as a therapeutic and prognostic biomarker. Lastly, we highlight novel immunotherapeutic strategies and approaches that modulate the TME of CRCs to make them amenable to immunotherapy.

DOI: https://doi.org/10.1038/s41568-025-00872-1
Cancer Lett. 2025 Sep 24. pii: S0304-3835(25)00632-9. [Epub ahead of print] 218060

Cancer-associated fibroblast secreted DKK1 promotes the immunosuppressive tumor microenvironment and colorectal cancer resistance to chemotherapy.

Zhijie Yin, Yuning Zhou, Xudong Zhu, Ryan A Goettl, Chi Wang, Heidi L Weiss, B Mark Evers, Qingding Wang.

  Chemotherapy is the cornerstone of treatment for colorectal cancer (CRC). However, acquired resistance can lead to a decrease in the efficiency of chemotherapy. Here, we show that cancer-associated fibroblasts (CAFs) play a critical role in acquired resistance to chemotherapy. Treatment with 5-fluorouracil (5-FU), oxaliplatin, or sn38 (an active metabolite of irinotecan) increased DKK1 expression and secretion, activation of MEK/ERK, and upregulation of p53 in CAFs. Knockdown of p53 or inhibition of MEK/ERK blocked the increase in DKK1 expression induced by chemotherapeutic agents in CAFs. Consistently, elevated DKK1 and phospho-ERK levels were found in CAFs isolated from surgically resected samples of patients treated with neoadjuvant therapy compared with non-chemotherapy controls. Treatment with recombinant DKK1 promoted the tumor immunosuppressive functions of CAFs, as noted by the increased expression of immunosuppressive cytokines and chemokines. Administration of 5-FU in vivo increased DKK1 levels in the plasma. Treatment with anti-DKK1 neutralizing antibody blocked 5-FU increased DKK1, repressed myeloid-derived suppressor cell (MDSC) tumor infiltration, increased NK cell tumor infiltration, and concurrently enhanced the antitumor efficacy of 5-FU. The current study identified CAF-secreted DKK1 as a contributing factor to chemotherapy resistance. Importantly, our findings provide evidence for targeting DKK1 to counteract chemotherapy resistance in CRC.

Keywords:  Colorectal cancer; DKK1; chemotherapy; tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2025.218060
Nat Rev Cancer. 2025 Sep 25.

Identification, functional insights and therapeutic targeting of EMT tumour states.

Anqi Dong, Cédric Blanpain.

Epithelial-to-mesenchymal transition (EMT) is a cellular process during which cells lose their epithelial characteristics and acquire mesenchymal features with enhanced migration capacities. EMT has key roles in different aspects of tumorigenesis, including tumour initiation, progression, metastasis and resistance to therapy. Here, we have reviewed the recent advances in our understanding of EMT in cancer. Instead of being a binary switch as initially proposed, EMT has been shown to be composed of multiple tumour states residing in specific niches with distinct functional properties that are controlled by different gene regulatory networks. We discuss how the types of oncogenic mutations, signalling pathways, transcription factors, epigenetic regulators and microenvironmental cues regulate the different EMT states. We also highlight the mechanisms by which EMT controls resistance to anticancer therapy and how new approaches to pharmacologically target EMT in clinical settings have recently been developed.

DOI: https://doi.org/10.1038/s41568-025-00873-0
Mol Oncol. 2025 Sep 24.

Patient-specific pharmacogenomics demonstrates xCT as predictive therapeutic target in colon cancer with possible implications in tumor connectivity.

Marco Strecker, Keren Zohar, Martin Böttcher, Thomas Wartmann, Henry Freudenstein, Maximilian Doelling, Mihailo Andric, Wenjie Shi, Or Kakhlon, Katrin Hippe, Beatrix Jahnke, Dimitrios Mougiakakos, Franziska Baenke, Daniel Stange, Roland S Croner, Michal Linial, Ulf D Kahlert.

  Colorectal cancer (CRC) represents the third leading cause of cancer-related deaths. Integrating cellular and molecular data from individual patients has become valuable for diagnosis, prognosis, and treatment selection. Here, we present a comparative mRNA-seq analysis of tissue samples from 32 CRC patients, pairing tumors with adjacent healthy tissues. Differential expression gene (DEG) analysis revealed dysregulated metabolic programs. We focused on the impact of overexpressed SLC7A11 (xCT) and SLC3A2, which compose the cystine/glutamate transporter (Xc-) system. To assess the oncogenic potential of the Xc- system, we analyzed gene perturbations from CRISPR screens across various cell types and used functional assays in five primary patient-derived organoid models. We identified a previously uncharacterized cell surface protein signature predicting chemotherapy resistance and highlighted the causality and potential of pharmacological blockage of ferroptosis as a promising avenue for cancer therapy. Redox homeostasis, ion/amino acid transporters, and regulators of neuronal survival and differentiation were pathways associated with these co-dependent genes in patient specimens. This study highlights several potential clinical targets for CRC therapy and promotes the use of patient-derived organoids oids to functionally validate in silico predictions.

Keywords:  chemotherapy resistance; ferroptosis; patient‐derived organoids; tumor metabolism; xCT

DOI:  https://doi.org/10.1002/1878-0261.70129
Clin Cancer Res. 2025 Sep 22.

Patient-derived organoids predict treatment response in metastatic colorectal cancer.

Lidwien P Smabers, G Emerens Wensink, Carla S Verissimo, Mayke Doorn, Tao Yang, Timo Voskuilen, Maarten A Huismans, Liselot Valkenburg-van Iersel, Geert A Cirkel, Elske C Gootjes, Henk M W Verheul, Frank J Jeurissen, Guus M Bol, Hilde H Nienhuis, Manon N G J A Braat, Edwin Cuppen, Robert G J Vries, Frederieke H van der Baan, Sjoerd G Elias, Onno Kranenburg, Miriam Koopman, Sylvia F Boj, Jeanine M L Roodhart.

PURPOSE: Accurately predicting treatment response in metastatic colorectal cancer (mCRC) is critical to avoid unnecessary toxicity and improve patient outcomes. Patient-derived organoids (PDOs) are promising models, but larger prospective studies are needed to confirm their predictive value.
EXPERIMENTAL DESIGN: mCRC patients underwent a metastatic biopsy for PDO establishment, before starting new systemic treatment. Predictors of PDO establishment were identified. PDOs were incubated with a seven-drug panel, including the patient's treatment, to determine drug sensitivity as measured by CyQUANT cell viability (AUC, GRAUC, IC50, and GR50). Patient response was measured by size change of biopsied and all target lesions. The diagnostic performance was evaluated by PPV, NPV, and AUROC. Additionally, the association between PDO response and survival was assessed.
RESULTS: A total of 232 patients were included and 205 biopsies were obtained. PDO establishment success increased from 22% to 75%, yielding 52% overall. Male sex, increased lactate dehydrogenase, biopsy in academic hospitals, optimized culture conditions and experience were related to PDO establishment success. In this interim analysis, focused on oxaliplatin-based doublet chemotherapy, 42 PDOs were screened. PDO drug sensitivity significantly correlated with response of the biopsied lesion (R=0.41-0.49, p<0.011) and all target lesions (R=0.54-0.60, p<0.001) for all treatments combined. The 5-FU & oxaliplatin PDO screens demonstrated high predictive accuracy (PPV: 0.78, NPV: 0.80, AUROC: 0.78-0.88) and were associated with PFS and OS (p=0.016 and 0.049).
CONCLUSIONS: We identified predictors for successful mCRC PDO establishment and validated that PDOs can accurately predict patient outcomes during systemic treatment, specifically with 5-FU & oxaliplatin.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-1564
Curr Opin Genet Dev. 2025 Sep 24. pii: S0959-437X(25)00090-5. [Epub ahead of print]95 102398

Human gut evolution: insights from stem cell models and single-cell genomics.

Rubén López-Sandoval, Stefano Secchia, Joep Beumer, Jarrett Gray Camp.

The gastrointestinal (GI) tract evolved in response to dietary changes and pathogen exposures that varied throughout history. As a major interface between the host and environment, the GI epithelia have evolved specialized barrier and immune functions while optimizing nutrient processing and absorption. Recent technological breakthroughs in modeling human biology in vitro and comparative single-cell genomics are providing novel insights into the genetic, cellular, and ontogenic basis of human evolution. In this review, we provide a broad overview of human-specific gut changes and how GI organoids and single-cell technologies can offer a mechanistic understanding of the specific features of human GI tract physiology.

DOI: https://doi.org/10.1016/j.gde.2025.102398
Cancer Res. 2025 Sep 24.

TYK2 Promotes Immunosurveillance of Colorectal Cancer Liver Metastasis.

Bernadette Mödl, Daniela Zwolanek, Katharina Schwertner, Dana Krauß, Stefan Moritsch, Irene Scharf, Anne-Sophie Ebner, Veronica Moreno-Viedma, Cristiano de Sa Fernandes, Philipp Novoszel, Martin Holcmann, Martina Hammer, Nunzia Matrone, Michaela Schlederer, Birgit Strobl, Emilio Casanova, Caroline Lassnig, Dietmar Herndler-Brandstetter, Lukas Kenner, Mathias Müller, Maria Sibilia, Robert Eferl.

Colorectal cancer liver metastasis (CRLM) is a major clinical problem. The regulators of immunosurveillance of CRLM could hold potential for developing therapeutic strategies to prevent or treat metastasis. Here, using a murine colorectal cancer (CRC) organoid-based transplantation mode, we identified TYK2 as a key factor controlling CRLM. Evaluation of the effects of Tyk2 deletion in different subsets of immune cells and in CRC cells demonstrated that TYK2 was not required in cancer cells, macrophages, NK cells, T cells, or Kupffer cells. Instead, TYK2 controlled CRLM via a dendritic cell-dependent mechanism that relied on MHC-I-mediated cross presentation of antigens to CD8+ T cells. Analysis of single-cell RNA sequencing data from primary CRC and CRLM revealed that TYK2 was predominantly expressed in a dendritic cell population destined to present antigens in tumor-draining lymph nodes. Treatment with the TYK2 inhibitor deucravacitinib, which is approved by the FDA for treating plaque psoriasis and is under clinical investigation for other autoimmune diseases, promoted CRLM. Together, these data demonstrate that TYK2 controls CRLM immunosurveillance, which should be carefully considered when treating patients with TYK2 inhibitors.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4224
Nat Commun. 2025 Sep 25. 16(1): 8423

Artery formation in the intestinal wall and mesentery by intestine-derived Esm1+ endothelial cells.

Esther Bovay, Kai Kruse, Emma C Watson, Vishal Mohanakrishnan, Martin Stehling, Frank Berkenfeld, Mara E Pitulescu, Mark L Kahn, Ralf H Adams.

Arterial blood transport into peripheral organs is indispensable for developmental growth, homeostasis and tissue repair. While it is appreciated that defective formation or compromised function of arteries is associated with a range of human diseases, the cellular and molecular mechanisms mediating arterial development remain little understood for most organs. Here, we show with genetic approaches that a small subpopulation of endothelial cells inside the intestinal villi of the embryonic mouse, characterized by the expression of endothelial cell-specific molecule 1 (Esm1/endocan), gives rise to arterial endothelium in the intestinal wall but also in the distant mesenteric vasculature. This involves cell migration but also substantial changes in morphology and gene expression. Immunohistochemistry and single cell RNA-sequencing confirm that intestinal Esm1+ cells have a distinct molecular profile and the capacity to undergo arterial differentiation. Genetic approaches establish that artery formation by the progeny of Esm1+ cells requires integrin β1 and signaling by the growth factor VEGF-C and its receptor VEGFR3. The sum of these findings demonstrates that Esm1+ cells inside the villus capillary network contribute to the formation of intestinal and mesenteric arteries during development.

DOI: https://doi.org/10.1038/s41467-025-64047-0
Mol Cancer Ther. 2025 Sep 26.

Inhibiting arginine metabolism via ALDH2/ARG2 axis blockade potentiates immune checkpoint inhibitors in colorectal cancer.

Lu Cai, Yonglong Cao, Jiawei Zhang, Kaiwen Xi, Aimin Li, Hong Zhang.

Metabolic reprogramming constitutes a key mechanism driving immunotherapy resistance in colorectal cancer (CRC), though the immunomodulatory role of L-arginine metabolism remains poorly defined. Through metabolomic profiling, we identified aldehyde dehydrogenase 2 (ALDH2) as a critical regulator depleting intracellular L-arginine pools in CRC cells. High Performance Liquid Chromatography (HPLC) analysis of cell supernatants further demonstrated that ALDH2 overexpression significantly diminishes extracellular L-arginine availability. Functionally, this arginine deficiency suppressed CD8+ T cell proliferation while inducing the attenuation of anti-tumor efficacy. Mechanistic studies revealed that ALDH2 upregulates Pre-B-Cell Leukemia Homeobox 3 (PBX3), which enhances arginase 2 (ARG2) transcription to promote L-arginine catabolism. This process suppresses glycolysis in CD8+ T cells, ultimately compromising their effector functions. Notably, ALDH2-high tumors exhibited resistance to immune checkpoint blockade (ICB), whereas combinatorial ARG2 inhibition and ICB therapy synergistically restored antitumor immunity. These findings nominate ARG2 as a novel therapeutic target and propose dual metabolic-immunologic intervention as a promising strategy for ICB-resistant CRC.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0404
Sci Adv. 2025 Sep 26. 11(39): eadw1270

Gut epithelium modifies enteric behaviors during nutritional adversity via distinct peptidergic signaling axes.

Surojit Sural, Zion Walker, Oliver Hobert.

Interorgan signaling events are emerging as key regulators of behavioral plasticity. The foregut and hindgut circuits of the C. elegans enteric nervous system (ENS) control feeding and defecation behavior, respectively. Here, we show that epithelial cells in the midgut integrate feeding state information to control these behavioral outputs by releasing distinct neuropeptidergic signals. In favorable conditions, insulin and noninsulin peptides released from midgut epithelia activate foregut and hindgut enteric neurons, respectively, to sustain normal feeding and defecation behavior. During food scarcity, altered insulin signaling from sensory neurons activates the transcription factor DAF-16/FoxO in midgut epithelia, which blocks both peptidergic signaling axes to the ENS by transcriptionally shutting down the intestinal neuropeptide secretion machinery. Our findings demonstrate that midgut epithelial cells act as integrators relaying internal state information to distinct parts of the ENS to control animal behavior.

DOI: https://doi.org/10.1126/sciadv.adw1270
Anal Chem. 2025 Sep 22.

UCL-MetIsoLib: A Public High-Resolution Tandem Mass Spectrometry Library for HILIC-Based Isomer-Resolved Profiling of Glycolysis, Central Carbon Metabolism, and Beyond in Urine, Plasma, Tissues, Cells, and Patient-Derived Organoids.

Kristian Serafimov, Maria Virginia Giolito, Sébastien Ibanez, Ophélie Renoult, Sarah Srhir, Paula Varon Rugeles, Florine Laloux-Morris, Cyril Corbet, Julien Pierrard, Marc Van den Eynde, Michael Lämmerhofer, Olivier Feron.

We present UCL-MetIsoLib, a publicly accessible high-resolution tandem mass spectrometry (HRMS/MS) library developed for HILIC-based, ion-pairing-free, isomer-resolved metabolomics using a bioinert UHPLC system and the Acquity Premier BEH Amide column. The platform integrates two complementary methods operating under distinct chromatographic conditions (pH 3.5, ESI+; pH 11.0, ESI-), enabling broad metabolic coverage. A total of 334 metabolites are annotated in the library structure, with thiol derivatization incorporated into the extraction protocol to mitigate redox-driven artifacts. Metabolite identification is supported by 245 authentic reference standards and curated according to MSI Level 1 and Level 2 criteria. Validation followed FDA guidelines for bioanalytical method validation across five biological matrices─urine, plasma, tissues, cells, and patient-derived colorectal organoids. The method demonstrated high precision (<15% RSD intra/inter-day) and recovery (85-115% across all QC levels). To demonstrate biological applicability, UCL-MetIsoLib was applied to a case study comparing healthy and colorectal cancer-derived organoids. The method enabled confident annotation of metabolite isomers, including key glycolytic intermediates such as DHAP and GA3P, as well as sugar phosphates from the glycolysis and pentose phosphate pathways. Metabolic alterations were observed in tumor organoids, including accumulation of nucleotide derivatives and shifts in central carbon metabolism. The library is constantly under expansion and is freely available in its latest version at: https://github.com/kserafimov10/UCLMetIsoLib.

DOI: https://doi.org/10.1021/acs.analchem.5c03390
Cell Death Discov. 2025 Sep 25. 11(1): 422

TRIM21 promotes colorectal cancer development through regulating DNA replication by TCF3/MCM2/5 axis.

Xintian Zhang, Han Yao, Yichao Hou, Kun Zhou, Yu Liang, Lidan Hou, Xingming Zhang, Wenfeng Wang, Leilei Du, Mengfei Yao, Jianhua Wang, Xiangjun Meng.

Disrupting DNA replication has been employed for treating cancers. In the present study, we found that Tripartite motif containing 21 (TRIM21) was highly expressed in colorectal cancer (CRC) and could be valuable for predicting the prognosis of CRC patients. Further study demonstrated that TRIM21 positively regulated the expression of MCM2 and MCM5, DNA replication and proliferation of CRC cells both in vitro and in vivo. In addition, TRIM21 knockdown inhibited both replication initiation and velocity, and increased the chemosensitivity of CRC cells to 5-FU and SN-38. Our study also revealed that DNA replication inhibition following TRIM21 knockdown could not be restored by cell cycle checkpoint kinase inhibitors, but partially by Transcription Factor 3 (TCF3) knockdown. TCF3 directly suppressed MCM2 and MCM5 transcription, inhibiting DNA replication. In summary, TRIM21 could influence tumor development and chemosensitivity to replication inhibitors by regulating DNA replication through the TCF3/MCM2/5 axis, suggesting a promising potential for CRC in the clinic.

DOI: https://doi.org/10.1038/s41420-025-02722-3