bims-instec 2026-03-29 papers

bims-instec

Biomed News

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

Issue of 2026–03–29
seventeen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

HAT1 Regulates Intestinal Stem Cell Proliferation and Differentiation.
Maternal obesity induces developmental programming of Intestinal stem cells through an IL-17A/PPAR immune-epithelial axis.
O-GlcNAcylation regulates PPAR-driven metabolic programming in intestinal stem cells.
A Rare T-Cell Factor 4 Lineage-negative Epithelial Stem Cell Supports Wound Repair and APC-deletion-induced Colon Tumorigenesis.
A murine small intestinal two-dimensional monolayer platform that induces fate commitment toward a revival stem cell state.
Fasting primes small intestinal regeneration after damage via a microbiome-metabolite-chromatin axis.
Non-gonadal PIWIL1/Aubergine drives regenerative and tumorigenic stem cell proliferation and tumorigenesis in the intestine.
MEX3A modulates PPARγ pathway activity and colorectal cancer growth.
Watching cancer begin: emerging tools to visualize the first steps of tumorigenesis.
BRAFV600E patient derived colon cancer organoids identify biomarkers of response to EGFR and BRAF inhibition and replicate clinical data.
Biology and preclinical models of colorectal cancer metastasis.
A cross-kingdom alliance driving colorectal cancer.
Metabolic profiling of the TME uncovers the contrasting impacts of CKMT2 and PDE2A in CRC progression and therapeutic response.
HIF-1α suppresses SNPH expression to facilitate liver metastasis of colorectal cancer through regulating mitochondrial dynamics and filopodia formation.
Modulating efferocytosis in the intestinal epithelial cells during colorectal cancer.
Visceral and subcutaneous adipose stem cells modulate colorectal cancer cell progression: direct and indirect contact distinctly accelerate tumor aggressiveness.
Dietary palmitic acid inhibits colorectal cancer progression through enhancing bisecting GlcNAc.

bioRxiv. 2026 Mar 17. pii: 2026.03.16.712164. [Epub ahead of print]

HAT1 Regulates Intestinal Stem Cell Proliferation and Differentiation.

Prabakaran Nagarajan, Caden J Martin, Andrea R Keller, Kübra B Akkaya-Colak, Maria H Festing, Maria M Mihaylova, Mark R Parthun.

Stem cells are critical for the development and maintenance of tissue integrity. An important example is intestinal stem cells (ISCs) that generate all epithelial cell types necessary for formation of the intestinal lining. HAT1, a histone acetyltransferase that acetylates newly synthesized histone H4 molecules on lysine residues 5 and 12 during replication-coupled chromatin assembly, is specifically expressed in intestinal stem and progenitor cells located in intestinal crypts. To determine if HAT1 is important for intestinal stem and progenitor cell function, we generated an inducible deletion of the HAT1 gene in intestinal epithelial cells. Loss of HAT1 resulted in morphological defects in the proximal end of the small intestine. Following loss of HAT1, intestinal crypts became elongated, with an increase in stem and progenitor cell proliferation and an increase in the population of OLFM+ cells. Loss of HAT1 also resulted in alterations in intestinal stem cell differentiation, including an increase in the number of Goblet cells and the mislocalization of Paneth cells into villi. HAT1 is specifically responsible for the acetylation of histone H4 lysine 5 (H4K5ac) in intestinal stem cells. Genome-wide characterization of HAT1-dependent H4K5ac in intestinal crypt cells indicates that the most significant loss of H4K5ac occurs in lamina-associated domains (LADs). Loss of H4K5ac in LADs is accompanied by an increase in histone H3 K9 tri-methylation indicating that HAT1 regulates LAD chromatin structure in intestinal crypt cells. A direct role for HAT1 in intestinal stem cell function was demonstrated using organoids in culture. HAT1 is required for differentiation in organoids and for the maintenance of Lgr5+ stem cells. These results indicate that HAT1 is required for the proper regulation of intestinal stem cell renewal and differentiation.

DOI: https://doi.org/10.64898/2026.03.16.712164
bioRxiv. 2026 Mar 16. pii: 2026.03.15.711939. [Epub ahead of print]

Maternal obesity induces developmental programming of Intestinal stem cells through an IL-17A/PPAR immune-epithelial axis.

Gourab Lahiri, Yesenia Barrera Millan, Swathi Sankar, Karla Mullen, Thomas Hartley McDermott, Dominic R Saiz, Fiona Farnsworth, Matt Torel, Madeline Blatt, Ana Cristina Roginski, Abhigyan Shukla, Esther Florsheim, Benjamin B Bartelle, Khashayarsha Khazaie, Fotini Gounari, Miyeko D Mana.

Maternal obesity is associated with increased risk of sporadic colorectal cancer (CRC) in offspring, suggesting that early-life environmental exposures durably shape disease susceptibility. Intestinal stem cells (ISCs), long-lived drivers of epithelial renewal and tumor initiation, are well poised to mediate this effect; however, how maternal obesity influences ISC programming during development remains poorly understood. Using mouse models of diet-induced obesity, we show that exposure to a maternal high-fat Western diet (mHFD) during pre- and postnatal development stably programs colonic ISCs. Offspring exhibit increased ISC proliferation, enhanced self-renewal, a hypermetabolic state, and altered epithelial lineage composition that persists into adulthood despite dietary normalization. These changes are accompanied by increased tumor burden following loss of Apc heterozygosity. Mechanistically, we identify the pro-inflammatory cytokine IL-17A as a key extrinsic driver and PPARd/a nuclear receptors as intrinsic mediators of the mHFD phenotype, revealing an immune-epithelial axis that programs ISC function during early life. Together, our findings demonstrate that maternal metabolic environments durably enhance stem cell fitness, providing a mechanistic link between developmental exposure and adult disease risk.

DOI: https://doi.org/10.64898/2026.03.15.711939
bioRxiv. 2026 Mar 16. pii: 2026.03.13.711696. [Epub ahead of print]

O-GlcNAcylation regulates PPAR-driven metabolic programming in intestinal stem cells.

Thomas Hartley McDermott, Dominic R Saiz, Yesenia Barrera Millan, Ngoc Bao Phuong Ho, Matthew Torel, Eric Uher, Caleb Aboagye, Fiona Farnsworth, Gourab Lahiri, Venkataramana Thiriveedi, Jinhua Chi, Haiwei Gu, Charlie Fehl, Benjamin B Bartelle, Miyeko D Mana.

Diet deeply influences health and disease risk by reshaping cellular metabolism. In the intestine, dietary nutrients directly affect intestinal stem cell (ISC) behavior, yet the regulatory mechanisms linking metabolism to transcriptional control remain poorly defined. Because mitochondria function as central metabolic hubs, we focused on mitochondrial signaling to understand how nutrient utilization governs ISC function. Using the MITO-Tag mouse, we isolated metabolites specifically from ISC mitochondria and found that the sugar-derived metabolite UDP-GlcNAc was reduced in ISCs from mice fed a high-fat diet. Moreover, we identified that reducing O-GlcNAcylation (OGN) rapidly increased stem cell frequency, proliferation, regenerative capacity, and the abundance of PPAR target proteins. Mechanistically, these effects depend on PPAR signaling, as genetic loss of Ppar-d/a blocks the ISC phenotypes induced by reduced OGN. These results reveal an OGN-PPAR signaling axis that translates dietary metabolic cues into transcriptional programs governing fuel utilization and ISC behavior in the intestine. Collectively, our findings highlight that OGN is a previously unrecognized regulator of PPAR signaling in intestinal stem cells.

DOI: https://doi.org/10.64898/2026.03.13.711696
bioRxiv. 2026 Mar 18. pii: 2026.03.17.712502. [Epub ahead of print]

A Rare T-Cell Factor 4 Lineage-negative Epithelial Stem Cell Supports Wound Repair and APC-deletion-induced Colon Tumorigenesis.

Annika V Thorpe, Tim Mosbruger, Stephanie J Georges, Olivia M Crowley, Therese Tuohy, Brian Dalley, Benjamin D Bice, Andrew K Fuller, Julio R Hidalgo, Christopher D Green, Saher Sue Hammoud, Melinda L Angus-Hill.

To maintain barrier homeostasis, the colonic and intestinal epithelial lining is continually renewed by rapidly proliferating epithelial crypt base columnar (CBC) stem cells that reside at the base of crypts. Using mouse lineage tracing, immunohistochemistry, and single-cell sequencing, we have identified a rare, non-CBC, T-cell factor 4 lineage-negative ( Tcf4 Lin-) stem cell population that gives rise to secretory and absorptive precursors. Following endoscopic biopsy-induced injury, Tcf4 Lin- stem cells are recruited to the wound bed and to the site of expanding crypts and function in barrier restoration and wound repair. We show that in a Tcf4 -haploinsufficient background, the Tcf4 Lin-, but not the Tcf4 Lin+, cell population represents the cell of origin for colon tumors driven by deletion of Apc . Our results provide a foundation for understanding Apc -allele-specific differences during colon tumorigenesis and identify a new stem-cell population that may prove valuable in the treatment of diseases caused by intestinal barrier homeostasis defects.

DOI: https://doi.org/10.64898/2026.03.17.712502
Biochem Biophys Res Commun. 2026 Mar 18. pii: S0006-291X(26)00409-2. [Epub ahead of print]814 153645

A murine small intestinal two-dimensional monolayer platform that induces fate commitment toward a revival stem cell state.

Fumiya Uefune, Shiro Yui.

  Yes-associated protein (YAP) signaling is a key regulator of intestinal epithelial regeneration and drives fetal-like reprogramming that generates revival stem cells (revSC). Because YAP activity is sensitive to extracellular matrix properties and substrate stiffness, we asked whether a stiff plastic substrate could provide a mechanically defined platform to induce a revSC-like state in vitro. We established Matrigel-derived murine small intestinal organoids cultured in Wnt-containing medium, dissociated them into single cells, and plated them onto collagen I/IV-coated plastic plates to generate a two-dimensional (2D) monolayer. The resulting monolayer formed a continuous, proliferative epithelial sheet with abundant Ki67-positive cells. Immunostaining revealed ubiquitous nuclear retention of YAP. RT-qPCR showed induction of canonical YAP target genes (Ctgf, Cyr61, Ankrd1) and upregulation of revSC markers (Ly6a, Clu), accompanied by marked suppression of crypt basal columnar (CBC) markers (Lgr5, Ascl2, Olfm4), compared with a homeostatic Matrigel organoid control. Notably, after withdrawal of the Wnt3a alternative peptide PG-008 from day 3 onward, the 2D monolayer remained viable through day 8 and retained elevated Ly6a and Clu expression, while CBC and all other differentiated lineage markers (Alpi, Defa6, Muc2, Chga) remained strongly repressed. These findings establish a plastic-based 2D monolayer as a complementary in vitro revSC model characterized by high YAP activity and sustained revSC-like properties with reduced dependence on exogenous Wnt stimulation.

Keywords:  2D monolayer culture; Revival stem cells; Small intestinal organoids; YAP

DOI:  https://doi.org/10.1016/j.bbrc.2026.153645
bioRxiv. 2026 Mar 08. pii: 2026.03.06.710208. [Epub ahead of print]

Fasting primes small intestinal regeneration after damage via a microbiome-metabolite-chromatin axis.

Praveen Barrodia, Ajay Kumar Saw, Sabrina L Jeter-Jones, Chia-Chi Chang, Jiansu Shao, Emre Arslan, Anand K Singh, Suresh Satpati, Robert R Jenq, Kunal Rai, Helen Piwnica-Worms.

Fasting enhances small intestinal regeneration after radiation but the contribution of the gut microbiome to this process remains uncharacterized. We identify Akkermansia muciniphila ( AKK ) as a key mediator of this response. AKK was enriched in fasted mice and its antibiotic depletion abrogated radioprotection whereas reintroduction restored both organismal survival and intestinal integrity. Fasting elevated propionic acid, consistent with AKK 's metabolic output. AKK -conditioned medium and propionate induced histone H3 acetylation in intestinal stem cell cultures while in vivo fasting induced AKK -dependent H3K27ac and H3K9ac, remodeling promoter-enhancer landscapes in crypt epithelial cells. Epigenetic profiling revealed a rewired core regulatory program enriched for pioneer transcription factors (Foxa, Gata, Klf), architectural organizers (Ctcf, Boris), and lineage-defining and metabolic regulators (Cdx2, Hnf4). This program supports expansion of a population of persister stem cells characterized by open chromatin accessibility at key stem and regenerative-associated loci including Clu , Olfm4 , Lgr5, Ascl2, Lrig1, Sox9, Rnf43, and Axin2. These findings define a fasting-induced microbiome-metabolite-chromatin axis that epigenetically primes highly plastic persister stem cells for rapid regeneration of the intestinal epithelium following radiation-induced injury.
Significance Statement: Fasting changes the gut microbiome, but how these changes help the body recover from damage is not well understood. We found that fasting increases a helpful bacterium, Akkermansia muciniphila , which produces propionate, which drives epigenetic changes by modifying histones and regulating gene activity. These changes promote the expansion of persister stem cells that help the intestine recover after radiation. This study shows how fasting and gut bacteria work together to protect healthy tissue and suggests that diet or microbial treatments could help reduce side effects of cancer radiotherapy.

DOI: https://doi.org/10.64898/2026.03.06.710208
Cell Rep. 2026 Mar 26. pii: S2211-1247(26)00264-0. [Epub ahead of print]45(4): 117186

Non-gonadal PIWIL1/Aubergine drives regenerative and tumorigenic stem cell proliferation and tumorigenesis in the intestine.

Karen Bellec, Lynsey R Carroll, Kathryn A F Pennel, Yuanliangzi Tian, Yachuan Yu, Aslihan Bastem Akan, Caroline V Billard, Nora Doleschall, Alexander R Cameron, Fabiana Herédia, Alisson M Gontijo, Anna M Ochocka-Fox, James P Blackmur, Farhat V N Din, Malcolm G Dunlop, Joanne Edwards, Kevin Myant, Rippei Hayashi, Julia B Cordero.

  The PIWI-interacting RNA (piRNA) biosynthesis pathway is best studied for its role in suppressing Drosophila germline transposable elements. Piwi, the founding member of the pathway, is involved in adult intestinal stem cell (ISC) homeostasis. Whether a broader role of the PIWI pathway exists in the intestine remains unknown. Here, we characterize a role of the PIWI family protein Aubergine (Aub) in ISCs. While dispensable for basal ISC self-renewal, upregulation of Aub by damage-induced reactive oxygen species drives regenerative ISC proliferation through increased protein synthesis, including translation of ISC factors Myc and Sox21a. Unexpectedly, such roles of Aub in ISCs appear uncoupled from its piRNA regulatory function. Additionally, Aub and mammalian PIWIL1 mediate tumorigenic intestinal growth in Drosophila and human organoids, respectively. Our results reveal regulated protein translation as a fundamental aspect of regenerative ISC function and discover a central role of Aub in such process.

Keywords:  CP: cancer; CP: stem cell research; Drosophila; PIWIL1; aubergine; colorectal cancer; human intestinal organoids; intestinal regeneration; intestinal stem cells; protein translation

DOI:  https://doi.org/10.1016/j.celrep.2026.117186
Cell Mol Gastroenterol Hepatol. 2026 Mar 23. pii: S2352-345X(26)00049-4. [Epub ahead of print] 101771

MEX3A modulates PPARγ pathway activity and colorectal cancer growth.

Ana R Silva, Alexandre Coelho, Vanessa Machado, Morgana Russel, Dalila Mexieiro, Ana L Amaral, Bruno Cavadas, Nuno Mendes, Carina Carvalho-Maia, Davide Gigliano, Carmen Jerónimo, Raquel Almeida, Bruno Pereira.

   BACKGROUND AND AIMS: RNA-binding proteins (RBPs) are major effectors of post-transcriptional regulation. Recently, we described the role of MEX3A in maintaining LGR5+ intestinal stem cells identity and epithelial renewal. This work aimed to study MEX3A functional impact in colorectal cancer (CRC).
METHODS: We characterized MEX3A expression profile in CRC mouse models and a cohort of CRC cases (n = 172). Mouse CRC tissues were used for the establishment of tumoroids and CRISPR/Cas9-mediated MEX3A knockout was performed in patient-derived CRC tumoroids to further understand its biological and therapeutic relevance. Simultaneously, we implemented the high-throughput technique HyperTRIBE to uncover MEX3A RNA targets.
RESULTS: Intestinal adenomas from Apc+/fl mice have increased Mex3a expression and Apc+/fl;Mex3a+/- animals presented a significant reduction in tumor burden. Apc+/fl;Kras+/G12D;Mex3a+/- compound mice exhibited reduced tumor area, while corresponding tumoroids had reduced growth ability and enhanced differentiation potential associated with increased peroxisome proliferator-activated receptor gamma (PPARγ) signalling. MEX3A overexpression was observed in 85% of human CRC cases, while 72% presented PPARγ downregulation, with a significant inverse correlation (P = .039). Accordingly, MEX3A-depleted patient-derived CRC tumoroids showed decreased LGR5 expression, accompanied by increased PPARγ expression and higher sensitivity to 5-Fluorouracil/Oxaliplatin (FOLFOX)-based chemotherapy. HyperTRIBE results revealed a direct interaction between MEX3A and PPARG transcripts.
CONCLUSION: MEX3A contributes to colorectal carcinogenesis, in association with PPARγ signalling modulation, impacting tumor development and therapeutic response.

Keywords:  Colorectal cancer; Mouse models; Patient-derived tumoroids; RNA

DOI:  https://doi.org/10.1016/j.jcmgh.2026.101771
Trends Cancer. 2026 Mar 24. pii: S2405-8033(26)00038-5. [Epub ahead of print]

Watching cancer begin: emerging tools to visualize the first steps of tumorigenesis.

Hendrik A Messal, Larissa Mourao, Lea Dörner, Colinda L G J Scheele, Jacco van Rheenen.

  Understanding tumor initiation is crucial for early interception and prevention. Tumors arise from genetic alterations and microenvironmental changes that together create a niche for malignant growth. Previously, the spatiotemporal dynamics of tumorigenesis were difficult to study. Recent advances in high-resolution intravital microscopy, tissue clearing, and spatial molecular profiling enable direct visualization of mutated cells and clones within their microenvironment in situ. These tools transform tumor initiation from a theoretical construct into a mechanistically dissectible process. Here, we synthesize recent insights into how mutated clones expand or regress, how clonal dynamics drive transformation, and how niche signals shape tumor-initiating cell fate. We highlight key imaging innovations and outline limitations and opportunities for capturing tumor initiation in vivo.

Keywords:  clonal dynamics; intravital microscopy; spatial transcriptomics; tissue clearing; tumor initiation; tumor microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2026.02.007
J Exp Clin Cancer Res. 2026 Mar 25.

BRAFV600E patient derived colon cancer organoids identify biomarkers of response to EGFR and BRAF inhibition and replicate clinical data.

Anna Kotarac, Hiroki Osumi, Alexander Malt, Keziban Merve Alp, Armin Jarosch, Johannes Werner, Manuela Benary, Christopher C M Neumann, Ryoji Yao, Philipp Mertins, Roland Eils, Dieter Beule, Christine Sers, Ulrich Keilholz, Naveed Ishaque, Sebastian Stintzing, Loredana Vecchione.



Keywords:   BRAF V600E mutated Colorectal cancer; AKT; BRAF; Drug resistance; Encorafenib and cetuximab; PI3K; PTEN; Patient derived organoids; ROS pathway

DOI:  https://doi.org/10.1186/s13046-026-03699-2
Intest Res. 2026 Mar 26.

Biology and preclinical models of colorectal cancer metastasis.

Yoojeong Seo, Jinho Jang, Jae-Il Park.

  Metastatic colorectal cancer (mCRC) is the principal cause of CRC-related mortality, yet the biology of mCRC remains only partly understood and challenging to interrogate experimentally. Despite recent progress in mapping recurrent genetic and epigenetic alterations and treatment responses of mCRC, these efforts provide limited insight into how heterogeneous primary tumors breach tissue barriers, survive in circulation, and colonize distant organs. In this review, we summarize current experimental systems for studying mCRC, including genetically engineered mouse models, carcinogen-induced and transplant models, and patient-derived organoid and xenograft platforms, and discuss how each captures or fails to capture key steps of the metastatic cascade and organ-specific microenvironments. We highlight practical obstacles to longitudinal sampling and quantitative readouts of metastatic burden, as well as conceptual gaps in modeling immune and stromal influences. Finally, we outline how emerging approaches, including single-cell and spatial transcriptomics, and advances in longitudinal tracking of metastatic burden could be combined into an integrated framework that more faithfully links mechanistic insight to clinical behavior and ultimately to metastasis-specific therapies.

Keywords:  Colorectal neoplasms; Mice; Multiomics; Neoplasm metastasis; Organoids

DOI:  https://doi.org/10.5217/ir.2025.00315
Cancer Cell. 2026 Mar 26. pii: S1535-6108(26)00158-3. [Epub ahead of print]

A cross-kingdom alliance driving colorectal cancer.

Lior Lobel.

In this issue of Cancer Cell, Li et al. show that Candida albicans and Fusobacterium nucleatum form a cross-kingdom interaction through Flo9-RadD binding that accelerates colorectal cancer (CRC) progression. Disrupting this interaction with L-arginine reduces tumor burden, highlighting targeting microbial cooperation as a potential therapeutic strategy for CRC.

DOI: https://doi.org/10.1016/j.ccell.2026.03.006
Front Pharmacol. 2026 ;17 1732137

Metabolic profiling of the TME uncovers the contrasting impacts of CKMT2 and PDE2A in CRC progression and therapeutic response.

Yuxiang Fu, Jianbo Lai, Kaibin Huang, Liping Liu, Guixiang Liao.

   Background: Colorectal cancer (CRC) remains a major cause of cancer-related morbidity and mortality, with high recurrence rates and limited treatment options for metastatic disease. The tumor microenvironment (TME) and metabolic reprogramming are critical drivers of CRC progression, influencing immune responses, therapeutic resistance, and patient outcomes.
Objective: This study explores the interplay between metabolic reprogramming and the TME in CRC using transcriptomic data and bioinformatics approaches to identify metabolically and microenvironmentally defined CRC subtypes and candidate biomarkers.
Methods: Gene expression and clinical data were obtained from TCGA colorectal adenocarcinoma (COAD), rectal adenocarcinoma (READ), and six GEO CRC datasets. Immunohistochemistry (IHC) was performed to validate PDE2A and CKMT2 expression in CRC tissues. Bioinformatic analyses were conducted using R software v4.0.3.
Results: We identified 220 TME- and 40 metabolism-related differentially expressed genes (DEGs) in CRC. Consensus clustering of these TMET genes revealed two distinct subtypes: Cluster 1 (C1), associated with poorer survival, an immune-mesenchymal phenotype, and frequent mutations in TTN and BRAF, and Cluster 2 (C2), characterized by enriched TP53 and APC mutations, classic tumor suppressor pathway activation, and higher genomic instability. Metabolically, C1 was characterized by lipid metabolism and extracellular matrix remodeling, whereas C2 showed enrichment of nucleotide and amino acid metabolism linked to cell cycle progression and DNA repair. Single-cell RNA sequencing confirmed these distinctions, revealing that C1-upregulated genes were predominantly expressed in immune and stromal compartments, whereas C2-upregulated genes were enriched in epithelial and malignant cells. PDE2A, primarily expressed by endothelial cells, was identified as a metabolic biomarker of C1, while CKMT2, expressed in malignant cells, defined C2. These genes serve as key metabolic markers distinguishing CRC subtypes based on molecular heterogeneity and prognosis.
Conclusion: PDE2A and CKMT2 were identified as critical metabolic biomarkers associated with distinct CRC subtypes and TME compositions. These findings highlight the intricate relationship between metabolic reprogramming, the tumor microenvironment, and tumor heterogeneity, providing insights into CRC molecular subtypes and their prognostic significance.

Keywords:  RNA sequencing; cancer hallmarks; colorectal cancer; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3389/fphar.2026.1732137
Cell Death Dis. 2026 Mar 26.

HIF-1α suppresses SNPH expression to facilitate liver metastasis of colorectal cancer through regulating mitochondrial dynamics and filopodia formation.

Lei Zhan, Xiaoxi Li, Xiaoyan Li, Qian Fei, Yue Jin, Jiaxing Yu, Luyao Tian, Feifei Li, Chunning Li, Qian Dong, Yong Zhang, Shulan Sun, Jingdong Zhang.

Colorectal cancer (CRC) is a leading cause of cancer-associated deaths, with liver metastases developing in about 50% of patients. Mitochondrial dynamics play critical roles in a diverse range of cellular functions, including cell migration and cancer metastasis. However, the influence of mitochondrial dynamics deregulation in CRC liver metastasis is incompletely understood. Through multiple transcriptomic data analysis and validation, we found that low expression of SNPH significantly correlated with poor prognosis of CRC patients. SNPH knockdown altered mitochondrial dynamics to increase cell migration and invasion by promoting filopodia formation. Moreover, the reduced levels of SNPH were linked to HIF-1α expression. Luciferase reporter assay revealed that HIF-1α transcriptionally activated miR-130a-3p expression, which targeted SNPH mRNA to inhibit its protein levels. Furthermore, miR-130a-3p inhibitor suppressed SNPH downregulation, filopodia formation, and CRC cells metastasis under hypoxic conditions. Mechanistically, SNPH downregulation promoted ROS production, resulting in the activation of the AKT/cdc42 pathway and downstream PAK1/Cofilin cascade. The overexpression of SNPH increased mitochondrial fusion and deterred the liver metastasis ability of CRC cells in vivo. Together, our results suggest that SNPH suppression imposed by the HIF-1α/miRNA-130a-3p axis under hypoxia conditions promotes the liver metastasis of CRC cells by activating the AKT/cdc42-PAK1/Cofilin cascade through mitochondrial dynamics-mediated ROS production.

DOI: https://doi.org/10.1038/s41419-026-08551-1
Front Oncol. 2026 ;16 1740918

Modulating efferocytosis in the intestinal epithelial cells during colorectal cancer.

Laura Boeckaerts, Tania Løve Aaes, Evi Scheirlinckx, Sze Men Choi, Yunus Incik, Amanda Gonçalves, Tino Hochepied, Lars Vereecke, Kodi S Ravichandran.

   Introduction: Colorectal cancer (CRC) is the thirdmost common cancer and a leading cause of cancer deaths worldwide, with over 1.9 million cases diagnosed in 2022. Due to poor response to classical cancer treatments, CRC is associated with low survival rates. This creates an urgent need for better understanding of CRC pathology. Cell death occurs continuously in solid tumors, and is also induced acutely, during chemotherapy. Dead cells are cleared by phagocytes via 'efferocytosis', an anti-inflammatory process that can lead to immune escape and reduced therapeutic efficacy. We hypothesized that efferocytosis might contribute to tumor development and that manipulating this process could be beneficial for CRC therapy.
Materials and Methods: Here, we asked whether known approaches to enhance efferocytosis may alter disease parameters in experimental and genetic CRC mouse models. In the first approach, we chose transgenic expression of a chimeric efferocytosis receptor (BELMOTg) that removes dying cells in an anti-inflammatory manner, and in the second, we chose deleting a chloride transporter (Slc12a2KO) that increases efferocytosis but in a pro-inflammatory fashion.
Results: Despite detectable expression of the transgenic proteins, many parameters of CRC including CRC pathogenesis were not significantly altered in mice with BELMO overexpression or Slc12a2 knockout in the intestinal epithelial cells.
Discussion: This suggests that these two approaches to clearing apoptotic cells is not sufficient to alter CRC progression. Targeting other phagocytic cell types or using other models of CRC might reveal a role (or otherwise) for efferocytosis in mitigating CRC in the future.

Keywords:  Chimeric receptor; DSS colitis; ELMO; SLC12A2; ZEB2; colorectal cancer; efferocytosis

DOI:  https://doi.org/10.3389/fonc.2026.1740918
Mol Med. 2026 Mar 23.

Visceral and subcutaneous adipose stem cells modulate colorectal cancer cell progression: direct and indirect contact distinctly accelerate tumor aggressiveness.

Mikołaj Domagalski, Dorota Nowak, Piotr Schmidt, Katarzyna Pietraszek-Gremplewicz.

   BACKGROUND: Adipose tissue is increasingly recognized as an important component of the tumor microenvironment of colorectal cancer (CRC) and actively contributes to the progression of the disease. Adipose stem cells (ASCs), one of its key constituents, can interact with cancer cells and contribute to tumorigenic processes. However, there is a poor understanding of the underlying basis of ASC-mediated support in the progression of CRC.
METHODOLOGY: In this study, we employed direct and indirect co-culture models to investigate interactions between ASCs and colorectal cancer cells. The study was performed using human visceral ASCs (V-ASCs) and subcutaneous ASCs (S-ASCs), along with three colorectal cancer cell lines. The analyses primarily focused on the characteristics of CRC cell progression in 2D and 3D conditions. Cell proliferation and migration after indirect co-culture were assessed using video microscopy, XTT assay, wound healing, and spontaneous migration assay. Corresponding measurements for direct co-culture were performed using high-throughput confocal microscopy. Changes in the epithelial-mesenchymal transition (EMT) such as the phenotype and stemness features were evaluated by confocal microscopy imaging, while gene and protein expression were analyzed using qRT-PCR and Western blotting. Additional analyses were conducted using cells cultured in spheroid models with both indirect and direct cell-cell interaction to assess the spheroid formation capacity, phenotypic characteristics, and the ability of cells to migrate out of the spheroids.
RESULTS: The results demonstrate that paracrine interaction with ASCs results in increased migration and proliferation of CRC cells accompanied by EMT-related transcriptional and phenotypic changes and reduced levels of stemness-associated molecules. Notably, direct contact with ASCs potentiated these effects, which suggests more aggressive behavior of the CRC cells. The spheroid assays showed increases in spheroid formation and dispersal capacity of CRC cells with ASCs present under direct co-culture conditions. The findings indicate that both S-ASCs and V-ASCs were associated with comparable changes in CRC cell behavior, despite originating from distinct fat depots.
CONCLUSIONS: The results suggest a potential role of ASCs in modulating the plasticity of CRC cells and specific aspects of aggressive behavior, including increased growth and motility, as well as an association with loss of stemness features through distinct interactions that affect tumor progression. This study indicates that targeting physical interactions may be a relevant complement to strategies focused on paracrine signaling within the tumor microenvironment in the development of new therapeutic approaches.

Keywords:  Adipose stem cells; Colon cancer; Direct co-culture; Indirect co-culture; Spheroid models; Tumor microenvironment

DOI:  https://doi.org/10.1186/s10020-026-01464-x
JCI Insight. 2026 Mar 23. pii: e179533. [Epub ahead of print]11(6):

Dietary palmitic acid inhibits colorectal cancer progression through enhancing bisecting GlcNAc.

Lei Lei, Juan Tang, Yuejiao Lv, Bingyi Jia, Wenqing Cai, Shuangshuang Sheng, Keying Li, Zhiwen Shi, Ning Fan, Zengqi Tan, Xiang Li, Feng Guan.

  Glycosylation changes are pivotal in colorectal cancer (CRC) development. The role of bisecting GlcNAc, a specific N-glycosylation type catalyzed by glycosyltransferase MGAT3, in CRC progression remains elusive. Previous studies indicated that dietary interventions can be beneficial for patients with certain congenital disorders of glycosylation. However, the impact of dietary fatty acids, such as palmitic acid (PA), on glycosylation regulation remains largely unclear. Here, we observed markedly decreased levels of bisecting GlcNAc and MGAT3 in colonic tissues of CRC patients. Downregulation of bisecting GlcNAc in CRC cells increased cell proliferation, migration, and invasion, while decreasing apoptosis. Moreover, a PA-rich diet inhibited CRC carcinogenesis in azoxymethane/dextran sodium sulfate-induced CRC mice by elevating bisecting GlcNAc levels. However, in Mgat3fl/fl Villin-Cre mice the inhibitory effects of the PA-rich diet were abolished. Intact glycopeptide analysis revealed that PA enhanced the bisecting GlcNAc modification on desmoglein 2 (DSG2). Additionally, DSG2 was identified to inhibit CRC carcinogenesis through the EGFR/AKT signaling pathway. In conclusion, dietary PA suppresses CRC carcinogenesis by regulating bisecting GlcNAc modification on DSG2, providing a direct mechanistic link between dietary fatty acids and CRC.

Keywords:  Colorectal cancer; Gastroenterology; Oncology

DOI:  https://doi.org/10.1172/jci.insight.179533