bims-instec 2025-12-14 papers

bims-instec

Biomed News

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

Issue of 2025–12–14
twenty-six papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Dormancy in colorectal cancer: The functional core of resistance, metastasis, and relapse.
Chronic enteritis triggered by diet westernization is driven by epithelial ATG16L1-mediated autophagy.
A common food mutagen promotes intestinal carcinogenesis by multiple mechanisms in mouse models of Lynch syndrome.
Metabolic stress sensing by epithelial RXRα links westernization of diet with Crohn's disease.
The sour regulation of metabolism: acidity challenges tumor cells while fueling their metabolic survival.
Patient-derived colon epithelial organoids reveal lipid-related metabolic dysfunction in pediatric ulcerative colitis.
Dedifferentiation and metabolic reprogramming of human adipocytes in the tumor niche triggered by colorectal cancer cells.
Spatially defined multicellular functional units in colorectal cancer revealed from single cell and spatial transcriptomics.
Tissue-resident microbiota impacts colorectal cancer progression and prognosis.
Targeting ferroptosis in cancer.
Human gut M cells resemble dendritic cells and present gluten antigen.
ColoStem, a core oncofetal signature that identifies poor prognosis colorectal tumors.
European cancer research requires renewed urgency.
LBX2 promotes colorectal cancer progression via the glycosylation and lactylation positive feedback.
Pleiotropic effects of all-trans retinoic acid in attenuating the hallmarks of colorectal cancer- challenges and scope of differentiation therapy.
The impact of primary tumor location of colorectal cancer on the survival outcome of patients with brain metastasis: a systematic review and meta-analysis.
Dietary restriction-responsive genes define prognostic subtypes and predict metastasis in colorectal cancer.
Generation of Intestinal and Colonic Organoids Derived From Human Pluripotent Stem Cells.
Hypoxic migrasomes drive colorectal cancer liver metastasis by mediating CD5L+ macrophage efferocytosis via NRP2/PROX1 axis.
The key role of cellular plasticity in the development of colorectal cancer.
Nidogen 1-enriched extracellular vesicles promote liver metastasis by inducing EMT and activating stellate cells.
Integrated Multi-Omics Profiling to Characterize Molecular Subtypes and Reveal Potential Therapeutic Strategies for Colorectal Cancer.
Cancer-associated adipocytes promote peritoneal metastasis of colorectal signet ring cell carcinoma via FABP4 induction.
The KDM6B/SLC10A2 Axis Suppresses MDSCs Recruitment via ERK/AP-1 Signaling in Colorectal Cancer.
A hyperactive splice variant of STAT3 promotes colonic inflammation-associated tumorigenesis in mice.
Colorectal Cancer Cell's Weapon: RNF32 Engages SPP1+ Macrophages to Foster Liver Metastasis, Targeted by Indole-3-Acetic Acid.

Crit Rev Oncol Hematol. 2025 Dec 09. pii: S1040-8428(25)00469-X. [Epub ahead of print]218 105081

Dormancy in colorectal cancer: The functional core of resistance, metastasis, and relapse.

Eduardo Alvarado-Ortiz, Angela Patricia Moreno-Londoño, Miguel Ángel Sarabia-Sánchez.

  Current treatments for colorectal cancer (CRC) can induce apparent disease remission; unfortunately, CRC eventually relapses in many patients. CRC recurrence has been associated with the presence of dormant cancer cells, which are difficult to detect and are maintained in a resilient state characterized by a low cell cycling rate. Dormant cancer cells evade immune surveillance, are not eliminated by conventional therapy, and employ specific metabolic programs enabling them to remain hidden for extended periods. Furthermore, the period elapsed since the onset of the disease, represents the opportunity where tumor has early spread to distant sites. Importantly, cellular dormancy and awakening are also involved in metastasis. This review explores the nuanced mechanisms involved in cellular dormancy, from remnant cancer cells of the primary tumor to metastatic cancer cells. The insights in this field hold promise to contribute clinical innovations for the improvement of predictive biomarkers or targeted therapies. Indeed, we address cell dormancy by unifying a set of concepts from modern oncology in light of the unique characteristics of CRC. Here, we discuss the immune system, metabolic imbalance, and drug tolerance; the major challenges that dormant cancer cells must overcome once awakened. This review reinforces the translational value of cellular dormancy as the foremost cause of recurrence and poor prognosis in colorectal cancer, with the aim of guiding the development of potential emergent treatments that can be combined with existing approaches such as chemotherapy and immunotherapy.

Keywords:  Colorectal cancer (CRC); Dormancy; Drug tolerance; Immune escape; Metastasis; Nutrient metabolism; Quiescence; Relapse

DOI:  https://doi.org/10.1016/j.critrevonc.2025.105081
Autophagy. 2025 Dec 11.

Chronic enteritis triggered by diet westernization is driven by epithelial ATG16L1-mediated autophagy.

Lisa Mayr, Julian Schwärzler, Laura Scheffauer, Zhigang Rao, Dietmar Rieder, Felix Grabherr, Moritz Meyer, Jakob Scheler, Almina Jukic, Luis Zundel, Verena Wieser, Andreas Zollner, Anna Simonini, Stefanie Auer, Lisa Amann, Maureen Philipp, Johannes Leierer, Richard Hilbe, Günter Weiss, Patrizia Moser, Philip Rosenstiel, Qitao Ran, Richard S Blumberg, Arthur Kaser, Andreas Koeberle, Zlatko Trajanoski, Herbert Tilg, Timon E Adolph.

  Macroautophagy/autophagy exerts multilayered protective functions in intestinal epithelial cells (IECs) while a loss-of-function genetic variant in ATG16L1 (autophagy related 16 like 1) is associated with risk for developing Crohn disease (CD). Westernization of diet, partly characterized by excess of long-chain fatty acids, contributes to CD, and a metabolic control of intestinal inflammation is emerging. Here, we report an unexpected inflammatory function for ATG16L1-mediated autophagy in Crohn-like metabolic enteritis of mice induced by polyunsaturated fatty acid (PUFA) excess in a western diet. Dietary PUFAs induce ATG16L1-mediated conventional autophagy in IECs, which is required for PUFA-induced chemokine production and metabolic enteritis. By transcriptomic and lipidomic profiling of IECs, we demonstrate that ATG16L1 is required for PUFA-induced inflammatory stress signaling specifically mediated by TLR2 (toll-like receptor 2) and the production of arachidonic acid metabolites. Our study identifies ATG16L1-mediated autophagy in IECs as an inflammatory hub driving metabolic enteritis, which challenges the perception of protective autophagy in the context of diet westernization.Abbreviations: AA: arachidonic acid; ATG16L1: autophagy related 16 like 1; CD: Crohn disease; CXCL1: C-X-C motif chemokine ligand 1; ER: endoplasmic reticulum; GFP: green fluorescent protein; GPX4: glutathione peroxidase 4; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; PTGS2/COX2: prostaglandin-endoperoxide synthase 2; PUFA: polyunsaturated fatty acid; SDA: stearidonic acid; TLR2: toll-like receptor 2; WT: wild-type.

Keywords:  ATG16L1; Crohn disease; glutathione peroxidase 4; intestinal epithelial cells; intestinal inflammation; polyunsaturated fatty acids

DOI:  https://doi.org/10.1080/15548627.2025.2600906
NAR Cancer. 2025 Dec;7(4): zcaf045

A common food mutagen promotes intestinal carcinogenesis by multiple mechanisms in mouse models of Lynch syndrome.

Emily Rayner, Anastasia Tsaalbi-Shtylik, Lemelinda Marques, Cedrick Agaser, Hailiang Mei, Davy Cats, Sophie van Zanen-Gerhardt, Daniela Salvatori, Niels de Wind.

Lynch syndrome (LS) is a colorectal cancer predisposition caused by an inherited heterozygous defect in any of four DNA mismatch repair (MMR) genes. MMR prevents nucleotide substitution mutations by correcting errors of replication opposite undamaged or subtly altered nucleotides. Here, we investigated whether dietary mutagens, which generally induce helix-distorting nucleotide lesions, affect LS-associated carcinogenesis. To this aim, we exposed mouse models of LS to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a food-derived heterocyclic amine that selectively adducts guanines. PhIP exposure induced loss of the wild-type MMR allele in heterozygous intestinal stem cells, leading to MMR deficiency and to impaired DNA damage signalling associated with the clonal expansion of MMR-deficient intestinal stem cells. Whole-genome sequencing revealed that PhIP becomes significantly more mutagenic in intestinal stem cells when MMR is lost, inducing not only PhIP-guanine adduct-mediated C:G>A:T transversions but also a broader substitution spectrum that resembles the spontaneous mutational signature of LS-associated colorectal cancer. Thus, MMR corrects PhIP-induced misincorporations outside of adducted guanines. Chronic PhIP exposure of intestine-specific MMR-deficient mice induced adenocarcinomas with histopathological features of LS-associated CRC. This study implicates food-derived mutagens in multiple stages of LS-associated carcinogenesis, including allelic loss, and defective DNA damage signalling and compound hypermutagenesis in the resulting MMR-deficient cells.

DOI: https://doi.org/10.1093/narcan/zcaf045
Cell Metab. 2025 Dec 08. pii: S1550-4131(25)00492-9. [Epub ahead of print]

Metabolic stress sensing by epithelial RXRα links westernization of diet with Crohn's disease.

IBDome Consortium

  Westernization of diet, partly characterized by long-chain fatty acid excess, perturbs intestinal immune responses in Crohn's disease (CD). The cellular and molecular framework of lipid sensing in intestinal inflammation remains enigmatic. By small intestinal transcriptional profiling of CD, we identified increased transcriptional activity of retinoid X receptor alpha (RXRα) specifically in intestinal epithelial cells (IECs). Transcriptional RXRα activity was induced in IECs of mice by ω-3 and ω-6 polyunsaturated fatty acid (PUFA) excess in a Western diet. PUFA-induced RXRα activity in Paneth cells governed chronic transmural enteritis by enabling the expression of CXCL1. Oral exposure to isotretinoin ameliorated PUFA-induced metabolic enteritis in two mouse models, and isotretinoin therapy reduced the odds of developing CD in an analysis of electronic health care records from 170,597 patients. Collectively, we identify RXRα in Paneth cells as a metabolic stress sensor that enables enteritis, providing novel perspectives for the prevention and treatment of CD.

Keywords:  CD; Crohn’s disease; IBD; Paneth cell; RXRa; Western diet; inflammatory bowel diseases; intestinal inflammation; metabolic inflammation; retinoid X receptor alpha

DOI:  https://doi.org/10.1016/j.cmet.2025.11.008
Cancer Res. 2025 Dec 11.

The sour regulation of metabolism: acidity challenges tumor cells while fueling their metabolic survival.

Bruna Martins Garcia, Patricia Altea-Manzano.

The tumor microenvironment imposes diverse metabolic challenges to cancer cells. Overcoming these challenges is essential for survival, proliferation, and dissemination. However, how cancer cells cope with the harsh environment and how the different coexisting stresses affect the tumor in vivo is unknown. Recently, Groessl, Kalis and colleagues published their findings in Science showing that acidosis outweighs all other stresses and plays a major role in the adaptation to them. Mechanistically, acidosis inhibits the ERK-DRP1 pathway, resulting in mitochondria elongation, which triggers a metabolic shift from glycolysis to oxidative phosphorylation. These findings highlight the plasticity of cancer cell mitochondria and refute the previous belief that cancer mitochondria are inherently dysfunctional. Indeed, inhibition of mitochondrial fusion or oxidative phosphorylation in acidic tumors is sufficient to promote cell death. Thus, enhancing respiration under acidosis comes to light as an essential metabolic adaptation to cancer survival and proliferation and targeting how cancer cells adapt to acidosis emerges as a new avenue for therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-5633
Nat Commun. 2025 Dec 10. 16(1): 11026

Patient-derived colon epithelial organoids reveal lipid-related metabolic dysfunction in pediatric ulcerative colitis.

Babajide A Ojo, Ying Zhu, Lyong Heo, Sejal R Fox, Yanli Qiao, Amanda Waddell, Maria E Moreno-Fernandez, Marielle Gibson, Tracy Tran, Ashley L Dunn, Essam I A Elknawy, Neetu Saini, Javier A López-Rivera, Senad Divanovic, Yuqin Dai, Vinicio A de Jesus Perez, Michael J Rosen.

Ulcerative colitis (UC) is associated with epithelial metabolic derangements which exacerbate gut inflammation. Here, we develop colon organoid (colonoid) lines from pediatric patients with endoscopically active UC, inactive UC, and those without intestinal inflammation to interrogate functional metabolic differences in the colon epithelia. We demonstrate that active UC colonoids exhibit hypermetabolic features and cellular stress, specifically during differentiation. Hypermetabolism in active UC colonoids is driven, in part, by increased proton leak, and excess lipid accumulation. Active UC colonoids exhibit heightened activation of the master lipid regulator PPAR-α and its transcriptional pathways. Pharmacological PPAR-α inhibition limits lipid accumulation, induces a metabolic shift towards glucose utilization, suppresses hypermetabolism, and reduces chemokine secretion and cellular stress markers. Collectively, our findings identify lipid-related metabolic dysfunction as a key pathologic feature of the pediatric UC epithelium and highlight the potential of patient-derived colonoids as a preclinical model for evaluating epithelial-targeted therapies addressing this dysfunction.

DOI: https://doi.org/10.1038/s41467-025-65988-2
Biol Res. 2025 Dec 06.

Dedifferentiation and metabolic reprogramming of human adipocytes in the tumor niche triggered by colorectal cancer cells.

Katarzyna Pietraszek-Gremplewicz, Joanna Olszańska, Mikołaj Domagalski, Agata Tymińska, Aneta Skoniecka, Michał Pikuła, Dorota Nowak.



Keywords:  Adipocytes; Cancer-associated adipocytes; Colorectal cancer (CRC); Metabolic reprogramming; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1186/s40659-025-00660-z
Elife. 2025 Dec 12. pii: RP104815. [Epub ahead of print]14

Spatially defined multicellular functional units in colorectal cancer revealed from single cell and spatial transcriptomics.

Inbal Avraham-Davidi, Simon Mages, Johanna Klughammer, Noa Moriel, Shinya Imada, Matan Hofree, Evan Murray, Jonathan Chen, Karin Pelka, Arnav Mehta, Genevieve M Boland, Toni Delorey, Leah Caplan, Danielle Dionne, Robert Strasser, Jana Lalakova, Anezka Niesnerova, Hao Xu, Morgane Rouault, Itay Tirosh, Hacohen Nir, Fei Chen, Omer Yilmaz, Jatin Roper, Orit Rozenblatt-Rosen, Mor Nitzan, Aviv Regev.

  While advances in single-cell genomics have helped to chart the cellular components of tumor ecosystems, it has been more challenging to characterize their specific spatial organization and functional interactions. Here, we combine single-cell RNA-seq, spatial transcriptomics by Slide-seq, and in situ multiplex RNA analysis to create a detailed spatial map of healthy and dysplastic colon cellular ecosystems and their association with disease progression. We profiled inducible genetic CRC mouse models that recapitulate key features of human CRC, assigned cell types and epithelial expression programs to spatial tissue locations in tumors, and computationally used them to identify the regional features spanning different cells in the same spatial niche. We find that tumors were organized in cellular neighborhoods, each with a distinct composition of cell subtypes, expression programs, and local cellular interactions. Comparing to scRNA-seq and bulk RNA-seq data from human CRC, we find that both cell composition and layout features were conserved between the species, with mouse neighborhoods correlating with malignancy and clinical outcome in human patient tumors, highlighting the relevance of our findings to human disease. Our work offers a comprehensive framework that is applicable across various tissues, tumors, and disease conditions, with tools for the extrapolation of findings from experimental mouse models to human diseases.

Keywords:  cancer biology; colorectal cancer; mouse; spatial transcriptomics; tumor microenvironment

DOI:  https://doi.org/10.7554/eLife.104815
Nat Commun. 2025 Dec 07.

Tissue-resident microbiota impacts colorectal cancer progression and prognosis.

Zhun Shi, Huahui Ren, Cong Lin, Fuqiang Li, Meizhen Wu, Fangming Yang, Tian Luo, Luís Nunes, Anders Isaksson, Klara Hammarström, Ting Zhu, Shida Zhu, Yiyi Zhong, Ingrid Ljuslinder, Mathias Uhlén, Richard Palmqvist, Bengt Glimelius, Kui Wu, Tobias Sjöblom, Huanzi Zhong.

To deepen the understanding of tissue-resident microbiota in colorectal cancer (CRC), we analyzed whole-genome and transcriptome data from 937 patients. We identified 249 genera and 361 species commonly present in both tumors and adjacent normal tissues (NATs). Distinct microbial signatures were associated with anatomical location, tumor stages, hypermutation status, mutations in CRC driver and DNA damage repair genes, as well as consensus molecular subtypes (CMSs). Notably, the presence of the pks island and elevated abundance of Enterobacteriaceae were linked to poor prognosis specifically in CMS2 tumors. Finally, microbial risk scores derived from taxa present in tumor or NATs predicted patient prognosis independently of established clinico-molecular factors. Prognostic taxa were strongly associated with tumor transcriptomic pathways related to hypoxia, immune response, and metabolic status. These findings revealed the heterogeneity of tissue-resident microbiota and their critical role in CRC progression, highlighting potential avenues for targeted intervention.

DOI: https://doi.org/10.1038/s41467-025-67047-2
Nat Genet. 2025 Dec;57(12): 2942

Targeting ferroptosis in cancer.

Safia Danovi.

DOI: https://doi.org/10.1038/s41588-025-02456-z
Nature. 2025 Dec 10.

Human gut M cells resemble dendritic cells and present gluten antigen.

Daisong Wang, Sangho Lim, Willine J van de Wetering, Carmen Lopez-Iglesias, Yuu Okura, Yuri Teranishi-Ikawa, Akihiko Mizoroki, Willem Kasper Spoelstra, Talya Dayton, Gijs J F van Son, Apollo Pronk, Niels Smakman, Gieneke B C Gonera-de Jong, Sebo Withoff, Iris H Jonkers, Jeroen S van Zon, Sander J Tans, Peter J Peters, Johan H van Es, Hans Clevers.

Microfold (M) cells are rare intestinal epithelial cells that reside in the follicle-associated epithelium of Peyer's patches1. M cells transport luminal antigens to submucosal antigen-presenting cells2,3. These insights primarily derive from transmission electron microscopy and studies using genetically modified mice2-4. Here we establish an intestinal organoid model to study human M cells and reconstruct the differentiation trajectory of M cells through transcriptome profiling. The results indicate that as well as facilitating luminal antigen transport, human M cells also directly present antigens via the class II major histocompatibility complex (MHC-II). Notably, the related enterocytes only express MHC-II in chronic inflammatory states and do not express typical dendritic cell markers. Human M cells physiologically express a gene profile that resembles that of dendritic cells. Similar to dendritic cells, M cell development is induced by RANKL and CSF2 and requires the transcription factors SPIB and RUNX2. HLA-DQ2.5 M cells process and present gluten antigen as demonstrated in organoid-T cell co-culture assays. These findings suggest that M cells may have a central role in coeliac disease.

DOI: https://doi.org/10.1038/s41586-025-09829-8
Br J Cancer. 2025 Dec 10.

ColoStem, a core oncofetal signature that identifies poor prognosis colorectal tumors.

Laura Solé, Eric Canton, María Maqueda, Teresa Lobo-Jarne, Antonio Barbáchano, Ferran Torres, Julia-Jié Cabré-Romans, Ángela Montoto, Lierni Fernández-Ibarrondo, Daniel Martínez-Garcia, Marta Guix, Mónica Larrubia-Loring, Clara Montagut, Alberto Muñoz, Anna Bigas, Mar Iglesias, Beatriz Bellosillo, Lluís Espinosa.

BACKGROUND: We have previously shown that non-curative chemotherapy imposes fetal conversion and high metastatic capacity to cancer cells. Analysis of public colorectal cancer datasets confirms the existence of a oncofetal signature consisting of 28 upregulated and 8 downregulated genes that stratify patients with worse prognosis.
METHODS: We have generated and analyzed a metacohort which integrates 1118 samples from six colorectal cancer public datasets and performed qPCR analysis of paraffin-embedded and plasma samples from our in-house cohort of colorectal cancer tumors.
RESULTS: We uncovered a core oncofetal signature, which we have called ColoStem, composed of 5 genes upregulated and 3 genes downregulated that displays prognosis value in a multivariate analysis. We also defined EpiColoStem, a reduction of ColoStem, as a pure epithelial signature with comparable prognosis value as ColoStem. By qPCR analysis of RNA extracted from paraffin-embedded tissues, we demonstrated the actual possibility of using ColoStem and EpiColoStem to refine the prognosis of CRC patients with a simple an affordable method. Initial analysis of plasma samples indicated that both signatures could be adapted for its use in liquid biopsy.
CONCLUSIONS: Our results reveal ColoStem and EpiColoStem tests as valuable tools for refining patient prognosis through the identification of fetal-type CRC tumors.

DOI: https://doi.org/10.1038/s41416-025-03280-2
Nat Cancer. 2025 Dec 10.

European cancer research requires renewed urgency.

René Bernards, Anton Berns, Johanna A Joyce, Michael Baumann.

DOI: https://doi.org/10.1038/s43018-025-01062-6
Cell Death Discov. 2025 Dec 12. 11(1): 556

LBX2 promotes colorectal cancer progression via the glycosylation and lactylation positive feedback.

Yiwen Jiang, Lude Wang, Lin Chen, Kai Shen, Jie Chang, Shicong Zheng, Zewei Chen, Chenyang Ge, Min Yu, Shian Yu, Haiping Lin.

Colorectal cancer (CRC) ranks as a leading cause of cancer-related mortality worldwide, yet its molecular mechanisms remain incompletely understood. The transcription factor LBX2 regulates morphogenesis of multiple organ systems in vertebrates, yet its role in CRC progression remains poorly understood. In the study, we found that LBX2 knockdown suppresses CRC proliferation in vitro and in vivo. ChIP-seq/RNA-seq identifies GFPT2 as a direct transcriptional target of LBX2. The LBX2/GFPT2 axis elevates UDP-GlcNAc levels and O-GlcNAcylation, promoting Raptor T700 glycosylation. This modification enhances mTORC1 activation by strengthening Raptor-Rag interactions, accelerating glycolysis and lactate production. Accumulated lactate induces histone H4K12 lactylation, which further upregulates LBX2 transcription, forming a positive feedback loop. Clinically, high LBX2 expression correlates with elevated PET-CT SUVmax values (indicating hyperglycolysis) in CRC patients. Patient-derived organoids with high LBX2 show increased sensitivity to the GLUT1 inhibitor. LBX2 thus serves as both a metabolic driver and a potential biomarker for CRC-targeted therapies.

DOI: https://doi.org/10.1038/s41420-025-02888-w
Cancer Gene Ther. 2025 Dec 10.

Pleiotropic effects of all-trans retinoic acid in attenuating the hallmarks of colorectal cancer- challenges and scope of differentiation therapy.

Antony Anista Michael, Pavithra Balakrishnan, Priyadharshini Tamizhmani, Kishore Thirunavukarasu, Selvakumar Subramaniam, Thirunavukkarasu Velusamy.

Colorectal Cancer (CRC) is a heterogenous malignancy, attributed by a vast array of mutations that govern the adenoma-carcinoma sequence. The underlying molecular mechanism of CRC recurrence is diverse and complex, in which cancer stem cells (CSCs) remain a major determinant of therapy discontinuation and refractoriness. In contrast to reigning cytotoxic therapies in abolishing cancer cells, leveraging the cytodifferentiation approach offers an effective modality while sparing normal cells. The concept of differentiation therapy fosters from the notion that such cancer stem cells can be either reverted back to their lineage or terminally differentiated cancer cells upon exposure to differentiation inducing agents like All-trans retinoic acid (ATRA). Beyond driving cellular differentiation, ATRA mediates other cellular processes like cell cycle arrest, apoptosis, and abrogates metabolic plasticity, EMT and angiogenesis in cancer cells. These pleiotropic effects of ATRA in modulating the typical hallmarks of cancer and its therapeutic limitations are being studied since 1900s. Despite this, its mode of action and factors impeding its therapeutic effects have not been elucidated in detail and thus remains obscure. However, over the years, various molecular signatures and pathways implicated in the therapeutic effects of ATRA has been unravelled in pieces. In an attempt towards a better picture, the current review aims to highlight the molecular mechanism of ATRA in attenuating the hallmarks of CRC and the factors affecting its therapeutic efficacy from a holistic perspective.

DOI: https://doi.org/10.1038/s41417-025-00996-4
Eur J Med Res. 2025 Dec 10.

The impact of primary tumor location of colorectal cancer on the survival outcome of patients with brain metastasis: a systematic review and meta-analysis.

Tsung-Chiao Tsai, Hany Atwan, Chaeseong Yim, Junmin Song, Roha Saeed Memon, Muhammad Fahimuddin, Changlin Gong, Yu Chang, Abhishek Kumar.

   OBJECTIVES: Several prior studies have shown that in metastasized colorectal cancer, the primary cancer's location influences patients' survival rates, with left-sided colorectal cancer being associated with longer survival than right-sided colorectal cancer. This study aimed to explore the influence of the primary location of colorectal cancer on survival following brain metastasis.
METHODS: To address this clinical question, we conducted a systematic review and meta-analysis. We included studies focused on patients diagnosed with brain metastasis from colorectal cancer. These studies reported survival outcomes based on different primary tumor sites (right versus left and colon versus rectum). The primary outcome was to aggregate the hazard ratio (HR) of left-sided colorectal cancer when metastasized to the brain compared with right-sided colorectal cancer. The secondary outcome was to aggregate the HR of rectal cancer when it metastasized to the brain compared with colon cancer.
RESULTS: Ten studies with a total of 1792 patients were included in the meta-analysis, and combined HR was calculated. Left-sided colon cancer showed higher overall survival compared with right-sided colon cancer when metastasized to the brain (HR: 0.71, 95% CI: 0.54-0.94, I2 = 0%). Rectal cancer did not show a statistically significant difference in overall survival compared with colon cancer (HR: 0.75, 95% CI: 0.40-1.41, I2 = 81%).
CONCLUSIONS: Concordant with lung and liver metastases, the primary location of colorectal cancer influenced overall survival when metastasized to the brain. Left-sided colon cancer demonstrated higher overall survival than right-sided colon cancer.

Keywords:  Brain metastasis; Colorectal cancer; Left colon cancer; Rectal cancer; Right colon cancer

DOI:  https://doi.org/10.1186/s40001-025-03614-z
Transl Cancer Res. 2025 Nov 30. 14(11): 7790-7809

Dietary restriction-responsive genes define prognostic subtypes and predict metastasis in colorectal cancer.

Qibin Li, Zengtao Wang, Jinyi Long, Ziyang Xu, Jie Zhang.

   Background: Colorectal cancer (CRC) is a major cause of cancer-related death, with a poor prognosis often due to metastasis and recurrence. Dietary restriction (DR) is known to delay tumor progression and extend lifespan, but the roles of dietary restriction-responsive genes (DRRGs) in CRC remain unclear. This study aimed to identify prognostic DRRGs and explore their associations with tumor behavior and immune features.
Methods: Transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed alongside 276 DRRGs from the GenDR database. Differentially expressed DRRGs were identified, followed by univariate Cox regression to assess prognostic relevance. A least absolute shrinkage and selection operator (LASSO)-Cox model was used to construct a prognostic signature, which was validated in external cohorts. Immune cell infiltration, functional enrichment, and unsupervised clustering were performed to evaluate the biological roles of DRRGs. Associations of the risk score with clinicopathological features, genomic alterations, and immunotherapy response (IPS) were further evaluated. Machine learning (ML) models were built to predict metastasis and recurrence using Shapley Additive exPlanations (SHAP) analysis.
Results: A total of 11 DRRGs were found to be significantly associated with CRC prognosis. A four-gene signature (RGS16, PLIN4, SLC13A2, FOXD2) effectively stratified patients into high- and low-risk groups with distinct survival outcomes. High-risk patients exhibited enrichment of extracellular matrix (ECM) and inflammatory pathways, whereas low-risk patients were associated with mitochondrial metabolism. Immune profiling revealed increased fibroblasts and myeloid cells in the high-risk group. Clustering based on DRRGs identified two molecular subtypes with different metabolic and immune features. High-risk tumors exhibited elevated tumor mutational burden (TMB) and microsatellite instability-high (MSI-H) frequency, while risk scores were inversely associated with stemness. IPS analysis further indicated that low-risk patients may derive greater benefit from CTLA-4 blockade. In metastasis prediction (GSE41258), the XGBoost model achieved an area under the receiver operating characteristic curve (AUC) of 0.855, with Matrix Gla Protein (MGP) identified as a key contributor via SHAP analysis.
Conclusions: We established a DRRG-based prognostic model for CRC and uncovered their links to metabolic regulation, immune infiltration, and metastasis. These findings highlight DRRGs as potential biomarkers and therapeutic targets and suggest that DR-mimicking strategies may benefit CRC management.

Keywords:  Dietary restriction (DR); Shapley Additive exPlanations analysis (SHAP analysis); colorectal cancer (CRC); metastasis prediction; prognostic gene signature

DOI:  https://doi.org/10.21037/tcr-2025-1329
Biol Cell. 2025 Dec;117(12): e70044

Generation of Intestinal and Colonic Organoids Derived From Human Pluripotent Stem Cells.

Lola Bonneau, Lisa Brossard, Theo Noël, Victor Perreaux, Laura Bachir, Archie Khan, Simon Vales, Maxime M Mahe.

  Over the past decade, significant advancements have been made in understanding the developmental mechanisms involved in human gastrointestinal formation, with organoids emerging as key experimental models. These three-dimensional in vitro cellular structures mimic the organization and functions of various gut regions, providing a powerful tool for research. By replicating critical stages of gut development, we can now direct the differentiation of cells into specific gastrointestinal tissues. In this protocol, we outline how to generate two types of organoids derived from human pluripotent stem cells (hPSCs): human intestinal organoids (HIOs) and human colonic organoids (HCOs). First, we induce definitive endoderm formation to produce these organoids and specify midgut/hindgut tissues. Three-dimensional spheroids form spontaneously, can be collected, embedded in an extracellular matrix, and cultured over time. During this phase, the organoid epithelium develops, supported by a mesenchymal layer that promotes maturation and differentiation. After a month of culture, HIOs and HCOs reach a developmental and maturation stage comparable to that of the human fetal intestine. These organoids can be used to study human gastrointestinal development, model diseases, and test therapeutic agents.

Keywords:  colon; directed differentiation; human pluripotent stem cells; organoid; small intestine

DOI:  https://doi.org/10.1111/boc.70044
J Transl Med. 2025 Dec 08. 23(1): 1384

Hypoxic migrasomes drive colorectal cancer liver metastasis by mediating CD5L+ macrophage efferocytosis via NRP2/PROX1 axis.

Yuqi Luo, Yiwen Huang, Yaoxing Huang, Longzhen Chen.

   OBJECTIVE: Migrasomes are a newly discovered class of extracellular vesicles, yet their roles in colorectal cancer (CRC) metastasis remain poorly understood. This study aimed to investigate the functional significance of CRC-derived migrasomes, particularly under hypoxic conditions, in promoting liver metastasis and modulating the tumor immune microenvironment.
METHODS: Migrasomes in CRC tissues and cells were characterized using transmission electron microscopy or immunofluorescence. A mouse liver metastasis model and single-cell RNA sequencing (scRNA-seq) were employed to explore functional outcomes and cellular interactions.
RESULTS: Migrasome structures were observed in both primary CRC and metastatic liver tissues, and live-cell imaging revealed hypoxic CRC cells released increased numbers of migrasomes. In vivo imaging demonstrated hepatic accumulation of hypoxic migrasomes and enhanced liver metastasis in mice. ScRNA-seq of liver metastases revealed that hypoxic migrasomes reprogrammed the tumor microenvironment, notably expanding a Tmem45a⁺ fibroblast subset with myofibroblast features and promoting CD5L⁺ macrophage differentiation with elevated efferocytic capacity. Mechanistically, NRP2, enriched in migrasomes derived from hypoxic CRC cells, was transferred to macrophages, binding with PROX1 to drive CD5L expression and upregulate of efferocytosis receptors. NRP2 knockdown in CRC cells abrogated migrasome-induced CD5L⁺ macrophage polarization and impaired apoptotic tumor cell clearance.
CONCLUSION: These findings demonstrate that hypoxic CRC-derived migrasomes facilitate liver metastasis by reprogramming stromal and immune compartments, particularly through NRP2/PROX1-mediated education of macrophages toward a pro-efferocytic CD5L⁺ phenotype. Our study reveals a previously unrecognized intercellular communication axis involving migrasomes in CRC progression and provides a potential therapeutic target for metastatic disease.

Keywords:  Colorectal cancer liver metastasis; Hypoxic migrasome; Macrophage efferocytosis

DOI:  https://doi.org/10.1186/s12967-025-07485-0
Transl Res. 2025 Dec 04. pii: S1931-5244(25)00116-1. [Epub ahead of print]

The key role of cellular plasticity in the development of colorectal cancer.

Lingqiao Lou, Yanghui Cao, Zhiyuan Ma, Bei Ji, Shuhui Liu, Kenichi Mizuno, Shuji Terai, Biguang Tuo, Taolang Li, Xuemei Liu.

  The development of colorectal cancer, which is a malignant tumor demonstrating high morbidity and mortality worldwide, involves complex molecular mechanisms and biological processes. Early-stage colorectal cancer patients do not exhibit obvious clinical symptoms; thus, they are often diagnosed with middle-stage to late-stage disease. The overall survival of advanced colorectal cancer patients with metastasis and treatment resistance is poor. Notably, tumor cell plasticity promotes tumorigenesis, metastasis, and therapeutic resistance, thus leading to the high incidence and mortality of colorectal cancer. In-depth studies of cellular plasticity are expected to lead to the identification of new therapeutic targets. In this review, we systematically summarize the role of cellular plasticity in colorectal cancer development and explore the regulatory mechanisms associated with cellular plasticity in colorectal cancer, with the aim of providing a theoretical basis for the development of innovative therapeutic strategies for this type of cancer.

Keywords:  Cellular Plasticity; Colorectal Cancer; Regulatory Mechanism; Treatment; Tumorigenesis

DOI:  https://doi.org/10.1016/j.trsl.2025.12.002
iScience. 2025 Dec 19. 28(12): 113975

Nidogen 1-enriched extracellular vesicles promote liver metastasis by inducing EMT and activating stellate cells.

Haipeng Chen, Hengchang Liu, Lin Wang, Jialiang Liu, Tianli Chen, You Zuo, Hanqing Hu, Xishan Wang, Guiyu Wang.

  The liver is frequently affected by metastasis in colorectal cancer patients; however, the precise interaction between the liver microenvironment and metastatic colorectal cancer cells remains elusive. Our study revealed that NID1, present in extracellular vesicles (EVs) derived from metastatic colorectal cancer, plays a pivotal role in promoting colorectal cancer liver metastasis (CRLM). EV-NID1 facilitates epithelial-mesenchymal transition (EMT) in colorectal cancer cells by modulating EMT-associated genes. Moreover, EV-NID1 activates hepatic stellate cells (HSCs), which in turn stimulate neutrophil infiltration and induce the formation of neutrophil-trapping networks (NETs) within the hepatic metastatic microenvironment via interleukin-11 (IL-11) secretion. This process ultimately reshapes the tumor microenvironment (TME) and fosters the establishment of a metastatic niche conducive to CRLM. Notably, targeted inhibition of IL-11 signaling via anti-IL-11 monoclonal antibodies effectively suppressed EV-NID1-induced liver metastasis in a murine model. In summary, our findings elucidate the mechanism underlying EV-NID1-mediated regulation of CRLM, identifying a promising therapeutic target for intervention in this disease.

Keywords:  Biological sciences; Cancer; Cell biology

DOI:  https://doi.org/10.1016/j.isci.2025.113975
MedComm (2020). 2025 Dec;6(12): e70492

Integrated Multi-Omics Profiling to Characterize Molecular Subtypes and Reveal Potential Therapeutic Strategies for Colorectal Cancer.

Xin Guo, Saisai Tian, Xinxing Li, Hongwei Zhang, Anqi Wang, Yan Jin, Ce Bian, Jiayi Lin, Sanhong Liu, Min Tang, Lijun Zhang, Xin Luan, Haiyang Zhou, Weidong Zhang.

  Colorectal cancer (CRC) is a complex and heterogeneous disease with limited effective treatment options. To investigate the molecular features and potential therapeutic strategies for CRC patients, including both early-onset colorectal cancer (EOCRC) and late-onset colorectal cancer (LOCRC) cases, a comprehensive multi-omics approach was employed. Whole exome sequencing (WES), RNA sequencing (RNA-seq), and proteomic and phosphoproteomic profiling were performed on paired tumor and normal adjacent tissue (NAT) from 144 CRC patients, totaling 672 samples. Three distinct molecular subtypes were identified, each exhibiting unique clinical prognoses and molecular characteristics. The S_I subtype was associated with the worst prognosis and a greater prevalence of EOCRC. Moreover, it exhibited a higher stromal score, characterized by increased infiltration of fibroblasts, mesenchymal stem cells, and adipocytes, when compared with the S_II and S_III subtypes. Additionally, the S_II subtype showed a higher immune score. Drug testing using cell lines and patient-derived three-dimensional (3D) bioprinted models revealed that S_I tumors were more responsive to Alisertib, suggesting subtype-specific therapeutic potential. Our study characterized the multi-omics landscape of CRC, offering critical insights into its molecular heterogeneity. These findings enhance our understanding of the molecular mechanisms underlying CRC and contribute to the development of personalized treatment strategies.

Keywords:  colorectal cancer (CRC); molecular subtype; multi‐omics; therapeutic strategy

DOI:  https://doi.org/10.1002/mco2.70492
Cell Commun Signal. 2025 Dec 08.

Cancer-associated adipocytes promote peritoneal metastasis of colorectal signet ring cell carcinoma via FABP4 induction.

Weixing Dai, Wenqin Luo, Hongsheng Fang, Ruiqi Gu, Guoxiang Cai, Yikuan Chen, Senlin Zhao, Renjie Wang.

BACKGROUND: Colorectal signet ring cell carcinoma (SRCC) is a rare and aggressive subtype with a high propensity for peritoneal metastasis, yet the underlying mechanisms remain poorly understood.
METHODS: We isolated cancer-associated adipocytes (CAAs) from omental tissue adjacent to SRCC peritoneal metastases and examined their morphological and metabolic features compared to normal adipocytes (NAs). Co-culture systems, patient-derived organoids (PDOs), transcriptomic/metabolomic profiling, and peritoneal metastasis mouse models were employed to assess the functional impact of CAAs. The role of fatty acid binding protein 4 (FABP4) and its regulation via CAA-derived exosomes was also investigated.
RESULTS: CAAs exhibited a dedifferentiated phenotype, enhanced free fatty acid secretion, and upregulation of matrix metalloproteinases. Co-culture with CAAs significantly promoted SRCC PDO proliferation, stemness, and peritoneal metastasis, accompanied by a metabolic shift toward fatty acid utilization. Among fatty acid metabolism-related genes, FABP4 was markedly upregulated in peritoneal metastases and associated with poor prognosis. Functional assays confirmed that FABP4 promoted fatty acid oxidation (FAO), stemness, and metastasis in PDOs, while FABP4 knockdown abrogated these effects. Mechanistically, CAA-derived exosomes induced FABP4 expression in PDOs, and inhibition of exosome release reversed the pro-tumorigenic phenotypes.
CONCLUSIONS: CAA-derived exosomal signaling promotes SRCC aggressiveness through FABP4-mediated fatty acid metabolic reprogramming, identifying FABP4 as a potential therapeutic target for peritoneal metastasis in colorectal SRCC.

DOI: https://doi.org/10.1186/s12964-025-02569-2
Adv Sci (Weinh). 2025 Dec 12. e14086

The KDM6B/SLC10A2 Axis Suppresses MDSCs Recruitment via ERK/AP-1 Signaling in Colorectal Cancer.

Zhibo Hu, Jing Xun, Bin Liu, Xiaolin Jiang, Yingdi Han, Huichao Yang, Qi Gao, Ruifang Gao, Aimin Zhang, Xueliang Wu, Dapeng Zhang, Dihua Li, Tian Li, Shimin Yang, Ximo Wang, Xiangyang Yu, Qi Zhang.

  Colorectal cancer (CRC) progression is regulated by an immunosuppressive tumor microenvironment, but the epigenetic mechanisms governing this milieu remain unclear. This study identifies the histone demethylase KDM6B as a key regulator of myeloid-derived suppressor cells (MDSCs) recruitment in CRC. Intestinal epithelial-specific KDM6B deletion promotes tumor growth by increasing MDSCs-mediated immunosuppression. Mechanistically, KDM6B directly transcriptionally activates solute carrier family 10 member 2 (SLC10A2), whereas its loss increased H3K27me3 repression at the SLC10A2 promoter, activating the ERK/AP-1 pathway and subsequent CXCL/CXCR2-dependent MDSC recruitment. Clinically, KDM6B expression positively correlated with SLC10A2 levels and inversely correlated with MDSC infiltration in human CRC specimens. More importantly, KDM6B knockdown conferred resistance to anti-PD-1 therapy in CRC, whereas its overexpression synergized with anti-PD-1 therapy. In conclusion, this study establishes the KDM6B-SLC10A2 axis as a novel epigenetic immune checkpoint, highlighting its potential as a therapeutic target for reprogramming the immunosuppressive microenvironment in CRC.

Keywords:  colorectal cancer; immunosuppressive; lysine‐specific demethylase 6B (KDM6B); myeloid‐derived suppressor cells (MDSCs); solute carrier family 10 member 2 (SLC10A2)

DOI:  https://doi.org/10.1002/advs.202514086
Sci Transl Med. 2025 Dec 10. 17(828): eadu8484

A hyperactive splice variant of STAT3 promotes colonic inflammation-associated tumorigenesis in mice.

Meng Xu, Dingju Wei, Shu Zhong, Weicheng Liu, Mei Ye, Jie Luo, Shuangdie Zhu, Zhenzhen Lai, Zhiping Zheng, Rui Hu, Qin Chen, Ningning Guo, Jian Lv, Wenmin Tian, Yang Chen, Guangfu Yang, Zhihua Wang, Jingjing Tong.

Signal transducer and activator of transcription 3 (STAT3) is essential for cell signaling in response to extracellular stimuli, and its overactivation is a hallmark of inflammation and tumorigenesis. The differential mechanisms underlying the physiological and pathological regulation of STAT3 remain elusive. Here, we demonstrated that cryptic splice sites in STAT3 generated heterogeneous isoforms with or without a single amino acid Ser701 (wS701/ΔS701), with the latter being more abundant in colon cancers. Intrinsic S701 underwent reversible phosphorylation catalyzed by mechanistic target of rapamycin complex 1 (mTORC1) and protein phosphatase 2A (PP2A). Upon inflammatory stimulation, phosphorylation at S701 (p-S701) sequestered Y705 phosphorylation (p-Y705) by interfering with the access of Janus kinase 1/2 and restricting STAT3 overactivation. In contrast, the STAT3_ΔS701 isoform was hyperactive because of the absence of this self-restricting mechanism. Deletion of S701 in mice increased susceptibility to colonic inflammation and tumorigenesis. Pharmacological inhibition of PP2A sustained p-S701 and alleviated colon inflammation in wild-type but not in ΔS701 mice. Our findings highlight the importance of STAT3 heterogeneity in colonic inflammation and colorectal cancer.

DOI: https://doi.org/10.1126/scitranslmed.adu8484
Adv Sci (Weinh). 2025 Dec 12. e19735

Colorectal Cancer Cell's Weapon: RNF32 Engages SPP1+ Macrophages to Foster Liver Metastasis, Targeted by Indole-3-Acetic Acid.

Hongyu Wang, Shipeng Dai, Yuchen Xie, Pengyu Chen, Yue Chai, Chongyu Wang, Xueying Huang, Xiao Dong, Junfeng Shi, Yongxiang Xia, Xiaofeng Qian, Weiwei Tang, Yichan Zhou.

  Colorectal cancer liver metastasis (CRLM) involves complex molecular mechanisms. By integrating The Cancer Genome Atlas (TCGA) data and employing Cox regression, Weighted Gene Co-expression Network Analysis (WGCNA), and single-cell RNA sequencing, this study identifies RNF32 as a key gene linking poor prognosis to metastasis. Functional assays demonstrate that RNF32 promotes tumor cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) in vitro, and drives tumor growth and liver metastasis in vivo. Mechanistically, RNF32 catalyzes K48-linked ubiquitination at the K60 site of GSK3β, stabilizing β-catenin and activating the Wnt signaling pathway, thereby upregulating CCL2. Mass cytometry and other experiments further reveal that RNF32 recruits SPP1+ macrophages via CCL2 to remodel the metastatic niche, a process dependent on the CCR2/FABP1/PPARG axis. Macrophage depletion abrogates metastasis, while the FABP1 inhibitor orlistat reverses SPP1 upregulation in macrophages. Moreover, SPP1+ macrophages interact with tumor cell CD44, synergizing with RNF32 to enhance cancer stemness via Wnt signaling. Importantly, virtual screening identifies indole-3-acetic acid (IAA) as an RNF32 inhibitor that suppresses liver metastasis and reverses immunosuppression in vivo. This study establishes RNF32 as a dual-functional driver of metastasis and proposes IAA as a promising therapeutic agent, offering new hope for targeting both tumor-intrinsic EMT and the immune microenvironment in CRC liver metastasis.

Keywords:  RNF32; SPP1+ macrophage; colorectal cancer liver metastasis; epithelial‐mesenchymal transition; indole‐3‐acetic acid

DOI:  https://doi.org/10.1002/advs.202519735