bims-instec 2025-07-27 papers

bims-instec

Biomed News

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

Issue of 2025–07–27
25 papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

An extracellular matrix niche secreted by epithelial cells drives intestinal organoid formation.
Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradients.
Telocytes deliver essential Wnts directly to murine intestinal stem cells via synapse-like contacts.
Reporter-based screening identifies RAS-RAF mutations as drivers of resistance to active-state RAS inhibitors in colorectal cancer.
BRAFV600E augments WNT signaling in colorectal cancer via aberrant DNA methylation.
High-resolution spatial mapping of cell state and lineage dynamics in vivo with PEtracer.
Subtypes and proliferation patterns of small intestine neuroendocrine tumors revealed by single-cell RNA sequencing.
Glutaminase as a metabolic target of choice to counter acquired resistance to Palbociclib by colorectal cancer cells.
Nutrient sensing and small intestinal enteric neurons.
Predicting colorectal cancer risk in FAP patients using patient-specific organoids.
Rapamycin rescues APC-mutated colon organoid differentiation.
PEAK1 maintains tight junctions in intestinal epithelial cells and resists colitis by inhibiting autophagy-mediated ZO-1 degradation.
Cancer associated fibroblasts-derived lactate induces oxaliplatin treatment resistance by promoting cancer stemness via ANTXR1 lactylation in colorectal cancer.
Neuroendocrine control of intestinal regeneration through the vascular niche in Drosophila.
High-Fat Diet Driven Post-Operative Colon Cancer Recurrence is Dependent upon Genetic Susceptibility to Deoxycholic Acid.
15-Lipoxygenase-dependent radiomitigation by NO●-Donors suppresses ferroptosis in intestinal Epithelium: Multiomics MS imaging and LC-MS evidence.
Ferroptosis-disulfidptosis-related CHMP6 is a clinico-immune target in colorectal cancer.
ADAR1 as a prognostic marker for patients with colorectal cancer and synchronous liver metastasis and a predictor of chemotherapy efficacy.
Hybrid identity and distinct methylation profiles of incomplete intestinal metaplasia in the stomach.
Prognostic impact of the BRAF V600E mutation in patients with MSI-high metastatic colorectal cancer treated with immune checkpoint inhibitors.
SMARCA1-NPFF axis inhibits colorectal cancer metastasis by blocking epithelial-mesenchymal transition and macrophage-dependent immune reprogramming.
Epithelial-mesenchymal transition in colorectal cancer metastasis and progression: molecular mechanisms and therapeutic strategies.
Statins exhibit anti-tumor potential by modulating Wnt/β-catenin signaling in colorectal cancer.
Constructing a novel mitochondrial metabolism-related genes signature to evaluate tumor immune microenvironment and predict survival of colorectal cancer.
The role of microenvironmental pH regulation on colorectal cancer cells - a preliminary study.

Dev Cell. 2025 Jul 16. pii: S1534-5807(25)00404-6. [Epub ahead of print]

An extracellular matrix niche secreted by epithelial cells drives intestinal organoid formation.

Antonius Chrisnandy, Matthias P Lutolf.

  Intestinal organoids have become an important model system in basic and translational research, but their culture typically relies on an ill-defined laminin-rich extracellular matrix (ECM). Using tunable and chemically defined 3D hydrogels, we systematically explored the role of the ECM during murine and human intestinal organoid development. We discovered that without exogenous laminin, stem cells developed into intestinal epithelia with a large proportion of regenerative cells. This population secreted a laminin-rich basement membrane that functioned as a de novo stem cell niche, promoting organoid formation independent of exogenous laminin. We identified ubiquitous expression of laminin chains Lama3, Lamb3, and Lamc2, but Lamb1 and Lamc1 were spatially restricted to the crypt domain. Epithelial-cell-secreted basement membranes extracted from organoids promoted the formation of patterned organoids. Our results highlight the utility of chemically defined matrices for studying ECM biology and pave the way for the replacement of animal-derived matrices in organoid culture.

Keywords:  ECM; basement membrane; epithelium; hydrogels; laminin; niche; organoid; small intestine; stem cells

DOI:  https://doi.org/10.1016/j.devcel.2025.06.026
Nat Commun. 2025 Jul 22. 16(1): 6765

Intestinal tuft cell subtypes represent successive stages of maturation driven by crypt-villus signaling gradients.

Julian R Buissant des Amorie, Max A Betjes, Jochem H Bernink, Joris H Hageman, Veerle E Geurts, Harry Begthel, Dimitrios Laskaris, Maria C Heinz, Ingrid Jordens, Tiba Vinck, Ronja M Houtekamer, Ingrid Verlaan-Klink, Sascha R Brunner, Jacco van Rheenen, Martijn Gloerich, Hans Clevers, Sander J Tans, Jeroen S van Zon, Hugo J G Snippert.

Intestinal tuft cells are epithelial sentinels that trigger host defense upon detection of parasite-derived compounds. While they represent potent targets for immunomodulatory therapies in inflammation-driven intestinal diseases, their functioning and differentiation are poorly understood. Here, we reveal common intermediary transcriptomes among the previously described tuft-1 and tuft-2 subtypes in mouse and human. Tuft cell subtype-specific reporter knock-ins in organoids show that the two subtypes reflect successive post-mitotic maturation stages within the tuft cell lineage. In vitro stimulation with interleukin-4 and 13 is sufficient to fuel the generation of new Nrep+ tuft-1 cells, arising from tuft precursors (tuft-p). Subsequently, changes in crypt-villus signaling gradients, such as BMP, and cholinergic signaling, are required to advance maturation towards Chat+ tuft-2 phenotypes. Functionally, we find chemosensory capacity to increase during maturation. Our tuft subtype-specific reporters and optimized differentiation strategy in organoids provide a platform to study immune-related tuft cell subtypes and their unique chemosensory properties.

DOI: https://doi.org/10.1038/s41467-025-61878-9
Dev Cell. 2025 Jul 19. pii: S1534-5807(25)00438-1. [Epub ahead of print]

Telocytes deliver essential Wnts directly to murine intestinal stem cells via synapse-like contacts.

Gediminas Greicius, Lorenz Mittermeier, Ruanyi Liang, Kristmundur Sigmundsson, Yarn Kit Chan, Pei-Ju Liao, Alexander Ludwig, David M Virshup.

  Spatial and temporal control of Wnt delivery to the intestinal stem cell niche regulates intestinal homeostasis. Telocytes, specialized stromal cells with characteristic long, thin cytoplasmic protrusions, produce essential Wnts for the development and maintenance of this niche. However, how Wnts travel from telocytes to stem cells in the gut remains unclear. Fluorescence and electron microscopy of murine telocytes co-cultured with intestinal organoids identified specialized telocyte extensions that transport and locally secrete Wnts on microvesicles and make intimate contacts with epithelial cells, reminiscent of neuronal contact-based signaling. Investigating the potential role of synapse-forming and plasma membrane-associated platform proteins, we found that depletion of either KANK1 or Liprins from telocytes markedly reduced their filopodia, compromised WNT2 presentation to epithelial cells, and impaired telocyte-dependent organoid growth. Characteristic telocyte structures facilitate Wnt delivery to the intestinal stem cell niche via synapse-like contacts.

Keywords:  Wnt signaling; cytonemes; exovesicle; filopodia; intestinal stem cells; organoids; synapse; telocytes

DOI:  https://doi.org/10.1016/j.devcel.2025.06.040
Sci Signal. 2025 Jul 22. 18(896): eadr3738

Reporter-based screening identifies RAS-RAF mutations as drivers of resistance to active-state RAS inhibitors in colorectal cancer.

Oleksandra Aust, Moritz R T Thiel, Eric Blanc, Mareen Lüthen, Viola Hollek, Rosario Astaburuaga-García, Bertram Klinger, Francisca Böhning, Alexandra Trinks, Dieter Beule, Björn Papke, David Horst, Nils Blüthgen, Christine Sers, Channing J Der, Markus Morkel.

Therapy-induced acquired resistance limits the clinical effectiveness of mutation-specific KRAS inhibitors in colorectal cancer (CRC). Here, we investigated whether broad-spectrum, active-state RAS inhibitors meet similar limitations. We found that KRAS-mutant CRC cell lines were sensitive to the RAS(ON) multiselective RAS inhibitor RMC-7977, given that treatment resulted in RAS-RAF-MEK-ERK pathway inhibition; halted proliferation; and, in some cases, induced apoptosis. RMC-7977 initially reduced the activity of a compartment-specific, dual-color reporter of ERK activity, with reporter reactivation emerging after long-term dose escalation. These drug-resistant cell populations exhibited distinct patterns of phospho-protein abundance, transcriptional activities, and genomic mutations, including a Y71H mutation in KRAS and an S257L mutation in RAF1. Transgenic expression of KRASG13D, Y71H or RAF1S257L in drug-sensitive CRC cells induced resistance to RMC-7977. CRC cells that were resistant to RMC-7977 and harboring RAF1S257L exhibited synergistic sensitivity to concurrent inhibition of RAS and RAF. Our findings demonstrate the power of reporter-assisted screening together with single-cell analyses for dissecting the complex landscape of therapy resistance. The strategy offers opportunities to develop clinically relevant combinatorial treatments to counteract the emergence of resistant cancer cells.

DOI: https://doi.org/10.1126/scisignal.adr3738
iScience. 2025 Jul 18. 28(7): 112708

BRAFV600E augments WNT signaling in colorectal cancer via aberrant DNA methylation.

Layla El Bouazzaoui, Jeroen M Bugter, Emre Küçükköse, André Verheem, Jasmin B Post, Nicola Fenderico, Inne H M Borel Rinkes, Hugo J G Snippert, Madelon M Maurice, Onno Kranenburg.

  The BRAFV600E mutation drives an aggressive subtype of colorectal cancer (CRC). Although WNT signaling activation is a hallmark of CRC, APC mutations are uncommon in BRAF-V600E mutant CRC, and RNF43 mutations are instead suspected to drive WNT pathway activation. Here, we investigated WNT pathway activation in BRAF-V600E mutant CRC using CRISPR-LbCpf1-corrected BRAF (V600E) and RNF43 (P441fs) organoids. BRAFE600V organoids regained dependency on EGF receptor signaling, and lost tumorigenic potential. Under identical growth conditions, correction of BRAFV600E, rather than RNF43P441fs, suppressed WNT target genes and upregulated epithelial differentiation genes and WNT antagonist genes. DNA methylation analysis revealed promoter hypermethylation of WNT antagonist genes and gene body hypermethylation -associated with transcriptional upregulation- of key WNT effectors (LGR5, EPHB2, and TCF4) in BRAFV600E organoids. Demethylation treatment resulted in upregulation of WNT antagonists and reduced WNT target gene expression in BRAFV600E organoids. Our results demonstrate that BRAFV600E enhances WNT pathway activation through modulation of DNA methylation patterns.

Keywords:  Cancer; Cell biology; Epigenetics

DOI:  https://doi.org/10.1016/j.isci.2025.112708
Science. 2025 Jul 24. eadx3800

High-resolution spatial mapping of cell state and lineage dynamics in vivo with PEtracer.

Luke W Koblan, Kathryn E Yost, Pu Zheng, William N Colgan, Matthew G Jones, Dian Yang, Arhan Kumar, Jaspreet Sandhu, Alexandra Schnell, Dawei Sun, Can Ergen, Reuben A Saunders, Xiaowei Zhuang, William E Allen, Nir Yosef, Jonathan S Weissman.

Charting the spatiotemporal dynamics of cell fate determination in development and disease is a long-standing objective in biology. Here we present the design, development, and extensive validation of PEtracer, a prime editing-based, evolving lineage tracing technology compatible with both single-cell sequencing and multimodal imaging methodologies to jointly profile cell state and lineage in dissociated cells or while preserving cellular context in tissues with high spatial resolution. Using PEtracer coupled with MERFISH spatial transcriptomic profiling in a syngeneic mouse model of tumor metastasis, we reconstruct the growth of individually-seeded tumors in vivo and uncover distinct modules of cell-intrinsic and cell-extrinsic factors that coordinate tumor growth. More generally, PEtracer enables systematic characterization of cell state and lineage relationships in intact tissues over biologically-relevant temporal and spatial scales.

DOI: https://doi.org/10.1126/science.adx3800
Elife. 2025 Jul 23. pii: RP101153. [Epub ahead of print]13

Subtypes and proliferation patterns of small intestine neuroendocrine tumors revealed by single-cell RNA sequencing.

Einav Somech, Debdatta Halder, Avishay Spitzer, Chaya Barbolin, Michael Tyler, Reut Halperin, Moshe Biton, Amit Tirosh, Itay Tirosh.

  Neuroendocrine tumors (NETs) occur primarily in the small intestine, lung, and pancreas. Due to their rarity compared to other malignancies in these organs, their complex biology remains poorly understood, including their oncogenesis, tumor composition, and the intriguing phenomena of mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN). Here, we profiled ten low-grade small intestine NET (SiNET) samples as well as one mixed lung tumor by single-cell or single-nuclei RNA-seq. We find that SiNETs are largely separated into two distinct subtypes, in which the neuroendocrine cells upregulate epithelial or neuronal markers, respectively. Surprisingly, in both subtypes, the neuroendocrine cells are largely non-proliferative while higher proliferation is observed in multiple non-malignant cell types. Specifically, B and plasma cells are highly proliferative in the epithelial-like SiNET subtype, potentially reflecting the outcome of high Migration Inhibitory Factor (MIF) expression in those tumors, which may constitute a relevant target. Finally, our analysis of a mixed lung neuroendocrine tumor identifies a population of putative progenitor cells that may give rise to both neuroendocrine and non-neuroendocrine (squamous) cells, potentially explaining the origin of the mixed histology. Taken together, our results provide important insights and hypotheses regarding the biology of neuroendocrine neoplasms.

Keywords:  cancer biology; cell cycle; human; neuroendocrine tumors; single-cell RNA-seq; small intestine; tumor heterogeneity

DOI:  https://doi.org/10.7554/eLife.101153
Oncogene. 2025 Jul 22.

Glutaminase as a metabolic target of choice to counter acquired resistance to Palbociclib by colorectal cancer cells.

Míriam Tarrado-Castellarnau, Carles Foguet, Josep Tarragó-Celada, Marc Palobart, Claudia Hernández-Carro, Jordi Perarnau, Erika Zodda, Ibrahim H Polat, Silvia Marin, Alejandro Suarez-Bonnet, Juan José Lozano, Mariia Yuneva, Timothy M Thomson, Marta Cascante.

Several mechanisms of resistance of cancer cells to cyclin-dependent kinase inhibitors (CDKi) have been identified, including the upregulation of metabolic regulators such as glutaminase. However, whether such resistance mechanisms represent optimal targets has not been determined. Here, we have systematically analyzed metabolic reprogramming in colorectal cancer cells exposed to Palbociclib, a CDKi selectively targeting CDK4/6, or Telaglenastat, a selective glutaminase inhibitor. Through multiple approaches, we show that Palbociclib and Telaglenastat elicit complementary metabolic responses and are thus uniquely suited to counter the metabolic reprogramming induced by the reciprocal drug. As such, while Palbociclib induced reduced tumor growth in vivo, and Telaglenastat did not show a significant effect, the drug combination displayed a strong synergistic effect on tumor growth. Likewise, initial responses to Palbociclib were followed by signs of adaptation and resistance, which were prevented by combining Palbociclib with Telaglenastat. In conclusion, combination with Telaglenastat optimally forestalls acquired resistance to Palbociclib in cancer cells.

DOI: https://doi.org/10.1038/s41388-025-03495-w
Nat Rev Gastroenterol Hepatol. 2025 Jul 24.

Nutrient sensing and small intestinal enteric neurons.

Katrina Ray.

DOI: https://doi.org/10.1038/s41575-025-01105-4
Cancer Gene Ther. 2025 Jul 22.

Predicting colorectal cancer risk in FAP patients using patient-specific organoids.

Aline Habib, Rose Mamistvalov, Mira Malcov, Dalit Ben-Yosef.

Colorectal cancer (CRC), a prevalent global cancer, is mostly sporadic. Familial adenomatous polyposis (FAP), arises from APC germline mutations. We established FAP-human embryonic stem cell lines (FAP1,2,3) with distinct APC mutations and differentiated them into colon organoids to study cancer development. While normal expressing APC lines and FAP3 formed complex organoids, FAP1,2 failed to differentiate. By utilizing CRISPR editing to correct APC mutations in FAP1,2, we succeeded in restoring their ability to form complex organoids expressing colon gene (CDX2). To elucidate the truncated APC proteins' mechanism of action, we used AlphaFold2 algorithm to model their secondary structures. Structural analysis of the normal phenotype organoids (normal and FAP3) revealed 5-6 salt bridges only at the N-terminal oligomerization domain. In contrast, analysis of disease organoids-phenotype (FAP1,2) revealed a production of novel salt bridges, likely act in a dominant-negative manner on full-length APC, disrupting APC function and promoting tumorigenesis. Our study underscores the critical role of germline APC mutations in colon cancer initiation, revealing how specific mutations influence disease severity. By deciphering APC structure-function relationships, we illuminate potential therapies and the molecular underpinnings of APC mutations that precede clinical presentation.

DOI: https://doi.org/10.1038/s41417-025-00923-7
Cancer Gene Ther. 2025 Jul 23.

Rapamycin rescues APC-mutated colon organoid differentiation.

Aline Habib, Rose Mamistvalov, Dalit Ben-Yosef.

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by germline mutations in the adenomatous polyposis coli (APC) gene. This leads to numerous colorectal adenomas and a high risk of colorectal cancer (CRC). Our stem cell-derived colon organoid model revealed that a heterozygous APC mutation is sufficient to induce colorectal cancer formation. We found a link between APC mutation type, organoid maturation and FAP severity. Here, we show that severe germline mutations in hESCs employ diverse mechanisms of carcinogenesis. FAP1-hESCs expressing a truncated 332-amino acid protein exhibited a hyperactivated mTOR pathway, including PTEN inactivation and increased S6K1 and eIF4E activation. This affected oncogenic c-Myc expression and contributed to apoptosis resistance. Rapamycin treatment restored differentiation potential in FAP1 organoids but not FAP2 organoids, which expressed a larger truncated protein without mTOR pathway activation. Our in vitro colon organoids system findings were validated in human patients. Notably, a colon from a FAP1 patient exhibited high expression of mTOR pathway proteins. These findings highlight the potential of rapamycin for personalized therapy in FAP patients with distinct mTOR-mediated APC mutations. Our colon organoid model is valuable for studying CRC and developing new diagnostic, preventive, and therapeutic approaches to prevent or delay tumorigenesis in FAP patients.

DOI: https://doi.org/10.1038/s41417-025-00935-3
Nat Commun. 2025 Jul 24. 16(1): 6777

PEAK1 maintains tight junctions in intestinal epithelial cells and resists colitis by inhibiting autophagy-mediated ZO-1 degradation.

Zaikuan Zhang, Yajun Xie, Qiying Yi, Jianing Liu, Lin Yang, Runzhi Wang, Jing Cai, Xinyi Li, Xiaosong Feng, Shixiang Yao, Zheng Pan, Magdalena Paolino, Qin Zhou.

Tight junctions are crucial for maintaining intestinal barrier homeostasis, but how organisms modulate these junctions remain unclear. Here, we show a role for PEAK1 at cell-cell contact sites, where it interacts with ZO-1 via a conserved region spanning amino acids 714-731. This interaction masks the LC3-interacting region on ZO-1, preventing autophagy-mediated ZO-1 degradation and preserving the integrity of tight junctions in intestinal epithelial cells. Src-mediated phosphorylation of PEAK1 at Y724 promotes the binding between PEAK1 and ZO-1 to stabilize ZO-1 in intestinal epithelial cells. Additionally, PEAK1 binds to CSK to positively regulate Src activity. Loss of PEAK1 in intestinal epithelial cells leads to decreased Src activity and lower ZO-1 protein levels, resulting in disrupted tight junctions, both in vitro and in vivo. In mice, Peak1 deficiency increases intestinal epithelium permeability and exacerbates inflammation in experimentally induced colitis models. Our findings reveal PEAK1's critical role in maintaining tight junction integrity and resistance to intestinal inflammation, extending its known function from promoting tumor cell proliferation and migration to essential physiological processes. These insights refine our understanding of the mechanisms regulating tight junctions and offer potential therapeutic targets for enhancing epithelial barrier function and treating related diseases.

DOI: https://doi.org/10.1038/s41467-025-62107-z
Cancer Lett. 2025 Jul 17. pii: S0304-3835(25)00485-9. [Epub ahead of print]631 217917

Cancer associated fibroblasts-derived lactate induces oxaliplatin treatment resistance by promoting cancer stemness via ANTXR1 lactylation in colorectal cancer.

Jiahua He, Weihao Li, Song Wang, Jin Lan, Xuanlin Hong, Leen Liao, Da Kang, Weifeng Wang, Ruowei Wang, Weili Zhang, Long Yu, Qingjian Ou, Yujing Fang, Xiaojun Wu, Junzhong Lin, Peirong Ding, Chi Zhou, Zhizhong Pan, Jianhong Peng.

  Oxaliplatin is widely used in chemotherapy for patients with advanced colorectal cancer (CRC). However, frequent drug resistance limits its therapeutic efficacy in patients. Here, we found that a subset of cancer associated fibroblasts (CAFs) with activated glycolysis induced CRC resistance to oxaliplatin. Lactate derived from CAFs promoted the transcription of ANTXR1 through histone lactylation and induced ANTXR1 lactylation at lysine 453 residue. The increased expression of ANTXR1 and ANTXR1 K453la in CRC cells was correlated with oxaliplatin resistance in CRC cells and the poor prognosis of CRC patients. Mechanistically, lactylation promoted ANTXR1 stability and activated the RhoC/ROCK1/SMAD5 signal pathway, subsequently contributed to CRC stemness and oxaliplatin resistance. Genetic or pharmacologic inhibition of the lactate shuttle between CAFs and cancer cells improved chemotherapy efficiency in vitro and in cell/patient-derived xenograft models. These findings contribute to a better understanding of oxaliplatin resistance and indicates that inhibition of tumor-stromal interactions might be an attractive strategy for enhancing the efficacy of oxaliplatin.

Keywords:  ANTXR1; Cancer associated fibroblasts; Colorectal cancer; Lactylation; Oxaliplatin

DOI:  https://doi.org/10.1016/j.canlet.2025.217917
Dev Cell. 2025 Jul 16. pii: S1534-5807(25)00432-0. [Epub ahead of print]

Neuroendocrine control of intestinal regeneration through the vascular niche in Drosophila.

André B Medina, Jessica Perochon, Yuanliangzi Tian, Cai T Johnson, Jack Holcombe, Parvathy Ramesh, Sofia Polcowñuk, Yachuan Yu, Julia B Cordero.

  Robust and controlled intestinal regeneration involves reciprocal interactions between the intestinal epithelium and its microenvironment. Here, we identify signaling between enteroendocrine (EE) cells, vasculature-like trachea, and neurons, which drives regional and global stem cell proliferation during adult intestinal regeneration in Drosophila. Reactive oxygen species (ROS) from midgut cells promote production and secretion of diuretic hormone 31 (Dh31), from anterior midgut EE cells. EE and neuronal Dh31 activate tracheal Dh31 receptor, leading to the production of the vascular endothelial growth factor (VEGF)- and platelet-derived-growth-factor (PDGF)-like ligand Pvf1. Pvf1 induces tracheal remodeling and intestinal stem cell (ISC) proliferation through autocrine and paracrine Pvr/mitogen-activated protein kinase (MAPK) signaling, respectively. While EE Dh31 exerts broad control of ISC proliferation throughout the midgut, effects of the neuronal source of the ligand appear restricted to the posterior midgut. Collectively, our work discovered an EE/neuronal/vascular signaling network, controlling global and domain-specific ISC proliferation during adult intestinal regeneration.

Keywords:  Dh31; PDGF/VGEF; enteroendocrine cells; interorgan signaling; intestinal plasticity; intestinal regeneration; neuroendocrine intestinal comparmentalization; neurons; trachea

DOI:  https://doi.org/10.1016/j.devcel.2025.06.036
Cancer Lett. 2025 Jul 22. pii: S0304-3835(25)00512-9. [Epub ahead of print] 217943

High-Fat Diet Driven Post-Operative Colon Cancer Recurrence is Dependent upon Genetic Susceptibility to Deoxycholic Acid.

Ryan Morgan, Mohammad Amin Bayat Tork, Zitong Lin, Claire Wild, Luke R Frietze, Sihao Huang, Meejeon Roh, Andrea Olivas, Colin W Steele, Tao Pan, Benjamin D Shogan.

  The development of postoperative recurrent tumors or metastasis following surgical resection of colorectal cancer remains a major obstacle to colon cancer cure. While a high-fat diet is a risk factor for the development of recurrence, studies that examine the molecular mechanism by which diet drives postoperative tumors have been lacking. Here, using a murine model that mimics postoperative tumor formation, we show that the tumorigenic influence of a high-fat diet strongly depends on the genetic backbone of the primary tumor cells. We identify deoxycholic acid as a major contributor to the promotion of tumor recurrence only when the primary cancer cell has an APC-driving mutation. We investigate the deoxycholic acid effect on the proliferation of organoids and identify the organoid response to deoxycholic acid treatment, including the transcriptome expression and transfer RNA abundance, modification, and charging. The integrated analysis of mRNA and tRNA sequencing results reveals enhanced decoding of codons in proliferation-promoting genes. Our results provide a new understanding of how both diet and tumor genetics together lead to postoperative colorectal cancer recurrence.

Keywords:  Bile Acid; Cancer Genetics; Colorectal Cancer; High-Fat Diet; Protein synthesis; Recurrence

DOI:  https://doi.org/10.1016/j.canlet.2025.217943
Redox Biol. 2025 Jul 21. pii: S2213-2317(25)00290-3. [Epub ahead of print]85 103777

15-Lipoxygenase-dependent radiomitigation by NO●-Donors suppresses ferroptosis in intestinal Epithelium: Multiomics MS imaging and LC-MS evidence.

Yulia Y Tyurina, Hua Tian, Haider H Dar, Mert Akdogan, Ecem Saritas, Vladimir A Tyurin, Louis J Sparvero, Alexander A Kapralov, Galina Shurin, Renee Fisher, Michael W Epperly, Kunal Singh, Yuri L Bunimovich, Joel S Greenberger, Valerian E Kagan, Hülya Bayir.

  Threats of irradiation (IR) exposure increase the need for radiomitigators. An important contributor to radiation injury is ferroptosis, triggered by the disbalanced redox metabolism. We showed that 15-lipoxygenase (15-LOX) catalyzed peroxidation of arachidonoyl-phosphatidyl-ethanolamine is an essential ferroptotic response of ileum to total body IR (TBI). Given that nitric oxide (NO● ) can suppress ferroptosis by inhibiting 15-LOX and by directly scavenging lipid radicals, we tested NO●-donors with optimized half decay times as radiomitigators. Here, we report that diethylenetriamine-NONOate (DETA-NONOate) (with a half decay-time of 20 hr) acted as an effective radiomitigator when administered 24 hr after exposure to TBI (9.25Gy) and markedly prolonged survival of C57BlJ6 mice by - i) decreasing the levels of pro-ferroptotic HOO-PUFA-PE signals, and ii) decreasing the expression of 15-LOX2 - in the ileum on day 4 after TBI. Redox lipidomics LC-MS and two mass spectrometric imaging (MSI) protocols: i) single-cell multi-omics Dual C60/gas cluster ion beam (GCIB) secondary ion mass spectrometry (SIMS), and ii) matrix-assisted laser desorption ionization (MALDI)-MSI, visualized DETA-NONOate's effectiveness in suppressing TBI-induced HOO-PUFA-PE production and preserving intestinal epithelium structural integrity. In vitro, NO● donors were effective in suppressing PUFA-PE peroxidation and ferroptotic death in human intestinal epithelial cells (FHs 74 Int) exposed to radiation (8Gy) plus enzymatic (15-LOX2) pro-ferroptotic stimulation.

Keywords:  GCIB-multiomics/ SIMS imaging of lipids and metabolites; Lipid peroxidation; NO donors; Radiomitigation; Total body Irradiation

DOI:  https://doi.org/10.1016/j.redox.2025.103777
Biol Direct. 2025 Jul 21. 20(1): 88

Ferroptosis-disulfidptosis-related CHMP6 is a clinico-immune target in colorectal cancer.

Yifei Zhu, Huixia Huang, Jiayu Chen, Keji Chen, Yanxi Yao, Yaxian Wang, Yuxue Li, Zhibing Qiu, Dawei Li, Ping Wei.

   BACKGROUND: Ferroptosis and disulfidptosis are newly discovered forms of regulated cell death that play critical roles in cancer progression, metabolism, and immune evasion. However, their interplay and combined influence on colorectal cancer (CRC) progression remain insufficiently understood.
METHODS: We developed a ferroptosis-disulfidptosis-related gene (FDRG) score using machine-learning algorithms to analyze gene modifications associated with these pathways in CRC, utilizing data from the TCGA and GEO databases. The model was externally validated, and associations with clinical outcomes, immune infiltration, mutational landscapes, immunotherapy responses, and drug sensitivity were explored. Key genes were further investigated through bioinformatics and in vitro experiments.
RESULTS: We constructed an 8-gene risk model with strong prognostic value, stratifying CRC patients into high- and low-risk groups with significant differences in clinical characteristics, immune cell infiltration, and therapeutic responses. Among these genes, CHMP6 was identified as a previously uncharacterized tumor suppressor in CRC. Beyond its inhibitory effect on tumor cell proliferation, migration, and invasion, CHMP6 was found to play a critical role in modulating anti-tumor immunity. Our findings established CHMP6 as a dual-function tumor suppressor that not only restrains tumor progression but also enhances immune-mediated tumor control.
CONCLUSIONS: The FDRG score is a robust tool for predicting CRC prognosis, tumor microenvironment dynamics, and response to immunotherapy. CHMP6 emerged as a promising tumor suppressor and potential therapeutic target, offering new insights into CRC treatment strategies.

Keywords:  CHMP6; Colorectal cancer; Disulfidptosis; Drug sensitivity; Ferroptosis; Immunotherapy; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13062-025-00676-1
Sci Rep. 2025 Jul 23. 15(1): 26752

ADAR1 as a prognostic marker for patients with colorectal cancer and synchronous liver metastasis and a predictor of chemotherapy efficacy.

Kaori Nitta, Kunitoshi Shigeyasu, Yoshitaka Kondo, Hibiki Umeda, Toshiaki Takahashi, Kazuya Moriwake, Kazuhiro Yoshida, Sho Takeda, Yuki Matsumi, Hiroyuki Kishimoto, Tomokazu Fuji, Kazuya Yasui, Kosei Takagi, Masashi Kayano, Shunsuke Nakamura, Hiroyuki Michiue, Hideki Yamamoto, Nobuhiko Kanaya, Yuhei Kondo, Eiki Miyake, Yusuke Yoshida, Ryohei Shoji, Yoshihiko Kakiuchi, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara.

  RNA editing by adenosine deaminase acting on RNA (ADAR) enzymes plays a role in cancer progression. However, its clinical significance in metastatic colorectal cancer (CRC) remains unclear. This study aimed to evaluate whether ADAR1 expression predicts prognosis and treatment response in colorectal cancer (CRC) with synchronous liver metastasis. This study included 40 patients with stage IV CRC and synchronous liver metastases. ADAR1 expression in tumor tissues was evaluated using immunohistochemistry. Expression levels were quantified using the immunoreactive score, and associations with clinicopathological features, overall survival (OS), and chemotherapy response were examined. High ADAR1 expression was significantly associated with multiple liver metastases (P = 0.0206), lymph node metastasis (P = 0.0241), and reduced response to chemotherapy (P = 0.0224). Significantly shorter OS was observed in patients with high ADAR1 expression in the nucleus (P = 0.0458). ADAR1 expression was an independent prognostic factor comparable to the presence of extrahepatic metastases. Low ADAR1 expression was correlated with a higher likelihood of achieving a response to chemotherapy. ADAR1 expression can reflect tumor aggressiveness and chemotherapy resistance in patients with CRC and synchronous liver metastasis. ADAR1 has considerable potential as a dual-purpose biomarker for stratifying patients based on prognosis and optimizing treatment intensity.

Keywords:  Biomarker; Chemotherapy; Colorectal cancer; Liver metastasis; RNA editing

DOI:  https://doi.org/10.1038/s41598-025-11918-7
Gut. 2025 Jul 21. pii: gutjnl-2025-335793. [Epub ahead of print]

Hybrid identity and distinct methylation profiles of incomplete intestinal metaplasia in the stomach.

Hyesung Kim, Junseong Kim, In Ho Jeong, Eunsun Park, Mira Yoo, Seokho Yoon, Donghyun Lee, Jaekyung Myung, Eunyoung Choi, Jim Goldenring, Bogun Jang.

   BACKGROUND: Gastric intestinal metaplasia (GIM), particularly the incomplete subtype (Inc IM), is strongly associated with increased gastric cancer (GC) risk. However, its role as a true precursor lesion remains uncertain.
OBJECTIVE: We aimed to delineate the molecular identity, differentiation potential and oncogenic relevance of Inc IM.
METHODS: Spatial transcriptomics using a custom lineage-enriched panel was applied to profile GIM and GC tissues. Subtype-specific GIM organoid models were developed for DNA methylation and chromatin accessibility profiling. Single-cell RNA sequencing was performed to evaluate differentiation capacity.
RESULTS: Spatial transcriptomics revealed that Inc IM potentially originates from the deep antral gland cells and harbours a hybrid transcriptomic signature incorporating gastric, small intestinal and large intestinal lineages across both differentiated and stem/progenitor compartments. DNA methylation profiling of subtype-specific organoids showed that Inc IM exhibits extensive intergenic hypermethylation, resembling native antral mucosa. In contrast, complete subtype was marked by promoter hypermethylation of tumour suppressor genes and displayed a more fully intestinalised epigenetic profile. Organoid models recapitulated subtype-specific traits and demonstrated lineage plasticity. Spatial mapping of GC samples revealed an enrichment of Inc IM-like cells, particularly within microsatellite stable tumours. Approximately 76% of the GCs analysed were linked to GIM, while the remaining (24%) appeared to be associated with deep antral differentiation.
CONCLUSIONS: Inc IM represents a phenotypically unstable and epigenetically deregulated metaplastic state with dual-lineage potential and molecular resemblance to GC. These findings establish Inc IM as a true precursor to GC and underscore the importance of active surveillance and early intervention strategies.

Keywords:  EPIGENETICS; GASTRIC CANCER; GASTRIC METAPLASIA; GASTRIC PRE-CANCER; ORGANOIDS

DOI:  https://doi.org/10.1136/gutjnl-2025-335793
Eur J Cancer. 2025 Jul 12. pii: S0959-8049(25)00427-7. [Epub ahead of print]227 115645

Prognostic impact of the BRAF V600E mutation in patients with MSI-high metastatic colorectal cancer treated with immune checkpoint inhibitors.

Claire Gallois, Margherita Ambrosini, Sara Lonardi, Emily Alouani, Rosine Guimbaud, Michael J Overman, Frank Sinicrope, Thibault Mazard, Marie Decraecker, Javier Ros, Elena Elez, Simon Pernot, Chiara Cremolini, Alice Boilève, Pauline Parent, Priya Jayachandran, Marie Dutherage, Mathilde Mercier, Clémence Flecchia, Marwan Fakih, Francesco Sclafani, Filippo Pietrantonio, Julien Taieb, David Tougeron.

   INTRODUCTION: The prognostic impact of the BRAF V600E mutation in patients with deficient mismatch repair (dMMR)/microsatellite instability (MSI) metastatic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICI) is poorly understood.
MATERIAL AND METHODS: This retrospective international study included patients with dMMR/MSI mCRC treated with ICI all lines between 2014 and 2023, and available BRAF mutation status.
RESULTS: Of 909 patients included, 345 (38 %) had BRAF V600E dMMR/MSI mCRC. In multivariable analysis, BRAFm was not associated with a shorter progression-free survival (PFS) and overall survival (OS) from ICI start compared to BRAFwt patients (median PFS: 25.0 vs 41.5 months, adjusted hazard ratio (adjHR)= 0.97, p = 0.8 and OS: 55.1 months vs not reached adjHR= 0.98, p = 0.9). However, in patients treated with ICI in first line, the rate of secondary resistance, defined as the progression after the first 6 months of treatment, was higher in BRAFm patients (20 % vs 11 %, p = 0.02). In patients with disease control for 6 months in 1st line, the PFS and OS from this point onwards were significantly shorter in BRAFm patients (adjHR for PFS 2.09, p = 0.03 and adjHR for OS 2.80, p = 0.019). The poor prognostic value of the BRAF mutation was no longer observed in patients treated with anti-PD1 and anti-CTLA4 combination.
CONCLUSIONS: In patients with dMMR/MSI mCRC, the BRAF V600E mutation is not associated with a shorter PFS/OS on ICI treatment in the overall population across all lines. However, specifically in patients treated in the first-line setting, our results suggest that the BRAF mutation is associated with a higher rate of secondary resistance, suggesting that a combination of PD1 and CTLA4 inhibitors upfront may be of particular interest in these patients.

Keywords:  BRAF mutation; Colorectal cancer; Microsatellite instability, immune checkpoint inhibitor

DOI:  https://doi.org/10.1016/j.ejca.2025.115645
Cancer Lett. 2025 Jul 18. pii: S0304-3835(25)00502-6. [Epub ahead of print]631 217933

SMARCA1-NPFF axis inhibits colorectal cancer metastasis by blocking epithelial-mesenchymal transition and macrophage-dependent immune reprogramming.

Haojia Wang, Shuya Du, Songtao Ji, Ge Miao, Jianing Yu, Mingzhen Zhou, Yuanci Zhang, Xuemei Li, Wanqi Ma, Ang Li, Xiaohua Yang, Yun Zhou, Junshu Wang, Xiaoyu Huang, Xin Wang, Zhenxiong Liu, Xue Bai, Yuanyuan Lu, Xiaodi Zhao.

  Dysregulation of chromatin remodeling represents an essential driving factor for cancer development and progression. Our previous work demonstrated that increased inclusion of exon 13 during alternative splicing functionally inactivates SMARCA1, the catalytic subunit of the ISWI chromatin remodeling complex, to promote colorectal cancer (CRC) metastasis, but the precise mechanism underlying SMARCA1-mediated metastasis suppression remains elusive. In this study, through ATAC-seq and RNA-seq analyses, we established an inverse correlation between SMARCA1 activity and neuropeptide FF (NPFF) transcriptional output in CRC cell lines and clinical specimens. Ectopic NPFF expression significantly enhanced CRC cell migration, invasion and metastatic potential, effectively counteracting the antimetastatic function mediated by SMARCA1. Mechanistically, SMARCA1 attenuates NPFF transcription by impairing the DNA-binding capacity of the ETS-family transcription factor SPIB at the NPFF promoter. SMARCA1-deficient CRC cells exhibit increased NPFF secretion, which drives epithelial‒mesenchymal transition (EMT) through autocrine activation of the JAK2/STAT5 signaling axis, subsequently increasing the expression of EMT-related transcription factors. Notably, the oncogenic activity of NPFF was also dependent on immune microenvironment modulation, as NPFF orchestrated the polarization of tumor-associated macrophages toward the M2-like phenotype while upregulating protumorigenic genes, which encode growth factors, chemokines, and matrix metalloproteinases, in macrophages. Our study reveals the SMARCA1-NPFF axis as a dual regulator of metastatic progression and immune microenvironment reprogramming in CRC, identifying the NPFF as a novel therapeutic vulnerability factor for the management of metastatic CRC.

Keywords:  Chromatin remodeling factors; Colorectal cancer; Epithelial-mesenchymal transition; Immune microenvironment; Neuropeptide FF

DOI:  https://doi.org/10.1016/j.canlet.2025.217933
Cell Death Discov. 2025 Jul 22. 11(1): 336

Epithelial-mesenchymal transition in colorectal cancer metastasis and progression: molecular mechanisms and therapeutic strategies.

Fangfang Nie, Xue Sun, Jizhuo Sun, Jingdong Zhang, Yuanhe Wang.

Colorectal cancer (CRC) continues to be a major contributor to cancer-associated death, with metastatic disease posing substantial therapeutic challenges. The epithelial-mesenchymal transition (EMT) orchestrates the transformation of polarized epithelial cells into motile mesenchymal phenotypes, characterized by enhanced migratory capacity and invasive properties. EMT is central to CRC metastasis and progression, particularly concerning its contribution to invasion, internal infiltration, and colonization. Beyond metastasis, EMT facilitates cancer cells' adaptation to diverse microenvironments, gain of stem cell-like characteristics, metabolic reprogramming, and evasion of therapeutic interventions. EMT signatures are emerging as potential prognostic biomarkers, offering valuable insights for real-time disease surveillance and personalized therapeutic strategies. Targeting EMT presents a promising therapeutic avenue to improve drug sensitivity and counteract resistance in CRC. This review systematically examines the molecular mechanisms regulating EMT in CRC, including key transcription factors; post-translational and epigenetic modifications; non-coding RNAs; and pivotal signaling pathways. Additionally, we evaluate the clinical implications of EMT in CRC progression and metastasis and critically assess emerging therapeutic strategies targeting EMT. This study lays the groundwork for developing more efficient interventions to mitigate metastasis and enhance treatment outcomes and patient survival by elucidating the intricate molecular networks that govern EMT and its contributions to CRC pathology.

DOI: https://doi.org/10.1038/s41420-025-02593-8
Oncotarget. 2025 Jul 21. 16 562-581

Statins exhibit anti-tumor potential by modulating Wnt/β-catenin signaling in colorectal cancer.

Sneha Tripathi, Ekta Gupta, Rutika Naik, Satyajeet Khare, Rafeeq Mir, Siddhesh Kamat, Sanjeev Galande.

  Colorectal cancer remains the second leading cause of cancer-related deaths worldwide, highlighting the urgent need for more effective therapies and a deeper understanding of its molecular basis. Drug repurposing has gained traction as a viable strategy to target dysregulated oncogenic pathways. Statins, commonly prescribed for lowering cholesterol, have recently shown potential anti-cancer effects. In this study, we explore how statin treatment influences lipid metabolism, gene expression, and proteomic profiles in colorectal cancer models. Our findings provide direct evidence that statins selectively modulate key components of the Wnt/β-catenin signaling pathway, a major driver of adenoma formation, including members of the special AT-rich sequence-binding (SATB) protein family. We show that statin treatment downregulates SATB1, a known promoter of tumorigenesis in the context of Wnt activation, while simultaneously upregulating SATB2, which plays an opposing role. This reciprocal regulation shifts cellular phenotypes between epithelial and mesenchymal states in 3D spheroid models. Together, these results highlight the therapeutic potential of statins in colorectal cancer and support their consideration in drug repurposing approaches.

Keywords:  SATB1; Wnt/β-catenin signaling; colorectal cancer; statins; tumor-suppressive phenotype

DOI:  https://doi.org/10.18632/oncotarget.28755
Front Med (Lausanne). 2025 ;12 1618471

Constructing a novel mitochondrial metabolism-related genes signature to evaluate tumor immune microenvironment and predict survival of colorectal cancer.

Hou Wang, Kai Zhang, Guang Ning.

   Background: Colorectal cancer (CRC) is a highly lethal gastrointestinal malignancy with substantial global health implications. Although mitochondrial metabolism genes play a crucial role in CRC development, their prognostic significance remains unclear.
Methods: This study systematically analyzed the expression and prognostic value of mitochondrial metabolism-related genes in CRC patients, establishing a risk model using data from TCGA and GEO databases. We also investigated the tumor microenvironment (TME), immune cell infiltration, tumor mutation burden, microsatellite instability (MSI), and drug sensitivity. Core mitochondrial metabolism-related gene, TMEM86B was identified and its functions validated through cell-based assays and in vivo mouse models.
Results: Fifteen mitochondrial metabolism-related genes were identified, including HSD3B7, ORC1, GPSM2, NDUFA4L2, CHDH, LARS2, TMEM86B, FABP4, TNFAIP8L3, HMGCL, GDE1, ACOX1, ARV1, HDC, and GSR. The nomogram, which incorporates independent prognostic genes TMEM86B, TNFAIP8L3, HDC, and key clinical features pTNM stage (pathological Tumor-Node-Metastasis), age, was created to predict patient outcomes. Notable differences in immune cell infiltration were observed between risk groups. The risk score was associated with TME genes and immune checkpoints, indicating an immunosuppressive environment in high-risk groups. Furthermore, TIDE analysis revealed that integrating the risk score with immune score, stromal score, or microsatellite status improved the prediction of immunotherapy response across different CRC patient subgroups. Core mitochondrial metabolism-related gene, TMEM86B promotes colorectal cancer progression by enhancing cell proliferation, migration, and invasion, and its downregulation significantly inhibits tumor growth both in vitro and in vivo.
Conclusion: Our findings indicate that the risk model associated with mitochondrial metabolism may serve as a dependable prognostic indicator, facilitating tailored therapeutic strategies for CRC patients. TMEM86B promotes colorectal cancer progression, and its downregulation inhibits tumor growth in vitro and in vivo.

Keywords:  colorectal cancer; drug susceptibility; immunotherapy; mitochondrial metabolism; prognostic biomarker; tumor microenvironment

DOI:  https://doi.org/10.3389/fmed.2025.1618471
J Physiol Pharmacol. 2025 Jun;76(3):

The role of microenvironmental pH regulation on colorectal cancer cells - a preliminary study.

J Basak, M Wlodarczyk, K Marynczak, J Wlodarczyk, L Dziki.

The pH gradient inversion is one of the characteristic features of cancer cells. The acidic environment outside the tumor and the alkaline inside cancer cells significantly affect its growth and ability to metastasize and reduce the effectiveness of therapy. In this study, we examined the effect of the alkaline pH on the viability of colorectal cancer (CRC) cells Caco-2 and Ht-29, and normal human fibroblasts BJ-CRL-2522 as a control cell line. Moreover, we analyzed the expression level of 3 genes at different pH: pro-apoptotic BAX, proliferation marker MKI67, and pH-sensitive receptor GPR4 using the RT-qpCR method. We demonstrated increased Ht-29 cell viability at alkaline pH, with simultaneous morphological changes, and decreased Caco-2 cell viability at pH above 9. The expression of BAX, GPR4 was upregulated in Ht-29 and BJ cells cultured at alkaline pH, whereas in Caco-2 cells the expression was significantly different between conditions. MKI67 expression was slightly increased in HT-29 and BJ, while decreased in Caco-2 cells. Our study shed new light on the cellular processes occurring under the influence of alkalization, but it is difficult to assess what role alkalization may play in the potential therapy of CRC, therefore, further studies are necessary.

DOI: https://doi.org/10.26402/jpp.2025.3.10