bims-instec 2025-10-19 papers

bims-instec

Biomed News

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

Issue of 2025–10–19
seventeen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Generation of Intestinal Epithelial Monolayers From Single-Cell Dissociated Organoids.
Cancer-associated fibroblasts enhance colorectal cancer lymphatic metastasis via CLEC11A/LGR5-mediated WNT pathway activation.
Activation of a FOXO3-induced cell cycle arrest regulates ferroptosis.
Invasin-functionalized PIC hydrogels enable long-term 3D culture of epithelial organoids.
Tumor-infiltrating bacteria disrupt cancer epithelial cell interactions and induce cell-cycle arrest.
Decellularized Extracellular Matrix Scaffolds to Engineer the Dormant Landscape of Microscopic Colorectal Cancer Liver Metastasis.
Mathematical Modeling Quantifies "Just-Right" APC Inactivation for Colorectal Cancer Initiation.
CPT1A facilitated ferroptosis by forming feedback loop with Nrf2 via PI3K/AKT pathway in colorectal cancer.
Integrative multi-omics analysis uncovers a novel FOSL2-COL8A1-EMT regulatory axis driving colorectal cancer progression.
MM-129 Counteracts 5-Fluorouracil-Induced Cellular Senescence in Colon Cancer via SIRT1/STAT3 Signaling Pathway.
Exploiting metabolic cell death for cancer therapy.
CPT2 inhibition enhances selective autophagy and proliferation in colorectal cancer via GPAT4-dependent glycerophospholipid biosynthesis.
Spatial metabolic gradients in the liver and small intestine.
C6orf223 promotes colorectal cancer growth and metastasis by facilitating PRMT5-MEP50 multiprotein complex assembling.
ALKBH8-mediated codon-specific translation promotes colorectal tumorigenesis.
Claudin-7 deficiency induces metabolic reprogramming of neutrophils in the colorectal cancer microenvironment.
Targeting FADS1-mediated lipid metabolism and signaling: a novel therapeutic strategy for precision oncology in colorectal and esophageal cancers.

Bio Protoc. 2025 Oct 05. 15(19): e5474

Generation of Intestinal Epithelial Monolayers From Single-Cell Dissociated Organoids.

Neta Felsenthal, Danijela Matic Vignjevic.

  Intestinal organoids are generated from intestinal epithelial stem cells, forming 3D mini-guts that are often used as an in vitro model to evaluate and manipulate the regenerative capacities of intestinal epithelial stem cells. Plating 3D organoids on different substrates transforms organoids into 2D monolayers, which self-organize to form crypt-like regions (which contain stem cells and transit amplifying cells) and villus-like regions (which contain differentiated cells). This "open lumen" organization facilitates multiple biochemical and biomechanical studies that are otherwise complex in 3D organoids, such as drug applications to the cell's apical side or precise control over substrate protein composition or substrate stiffness. Here, we describe a protocol to generate homogenous intestinal monolayers from single-cell intestinal organoid suspension, resulting in de novo crypt formation. Our protocol results in higher viability of intestinal cells, allowing successful monolayer formation. Key features • This protocol requires preexisting experience in culturing mouse intestinal organoids. • This protocol requires preexisting experience in generating polyacrylamide (PAA) gels for culturing 2D monolayers. • This protocol generates intestinal monolayers that can be subjected to additional analysis, e.g., drug treatment, immunofluorescent staining, single-molecule fluorescent in-situ hybridization (smFISH), or live imaging.

Keywords:  Accumax; Crypts; Monolayers; Mouse; Organoids; Single-cell intestinal epithelial monolayers; Small intestine; Villus-like

DOI:  https://doi.org/10.21769/BioProtoc.5474
J Clin Invest. 2025 Oct 15. pii: e194243. [Epub ahead of print]135(20):

Cancer-associated fibroblasts enhance colorectal cancer lymphatic metastasis via CLEC11A/LGR5-mediated WNT pathway activation.

Chuhan Zhang, Teng Pan, Yuyuan Zhang, Yushuai Wu, Anning Zuo, Shutong Liu, Yuhao Ba, Benyu Liu, Shuaixi Yang, Yukang Chen, Hui Xu, Peng Luo, Quan Cheng, Siyuan Weng, Long Liu, Xing Zhou, Jingyuan Ning, Xinwei Han, Jinhai Deng, Zaoqu Liu.

  Hypoxia in the tumor microenvironment promotes lymphatic metastasis, yet the role of cancer-associated fibroblasts (CAFs) in this process remains insufficiently elucidated in colorectal cancer (CRC). In this study, we developed a large language model-based cellular hypoxia-predicting classifier to identify hypoxic CAFs (HCAFs) at single-cell resolution. Our findings revealed that HCAFs enhance CRC lymphatic metastasis by secreting CLEC11A, a protein that binds to the LGR5 receptor on tumor cells, subsequently activating the WNT/β-catenin signaling pathway. This promotes epithelial-mesenchymal transition and lymphangiogenesis, facilitating the spread of tumor cells via the lymphatic system. Furthermore, we demonstrate that the hypoxia-induced transcription factor HIF1A regulates the conversion of normoxic CAFs to HCAFs, driving CLEC11A expression and promoting metastasis. In vivo and vitro experiments confirmed the pro-metastatic role of CLEC11A in CRC, with its inhibition reducing lymphatic metastasis. This effect was markedly reversed by targeting the LGR5 receptor on tumor cells or inhibiting the WNT/β-catenin pathway, further elucidating the underlying mechanisms of CLEC11A-driven metastasis. These findings underscore the potential of targeting the CLEC11A-LGR5 axis to prevent lymphatic dissemination in CRC. Our study highlights the role of HCAFs in CRC progression and reveals mechanisms of lymphatic metastasis for intervention.

Keywords:  Bioinformatics; Colorectal cancer; Gastroenterology; Machine learning; Oncology

DOI:  https://doi.org/10.1172/JCI194243
Cell Death Discov. 2025 Oct 16. 11(1): 465

Activation of a FOXO3-induced cell cycle arrest regulates ferroptosis.

Huanjie Huang, Matthias van Sligtenhorst, Alida M M Smits, Can Gulersonmez, Edwin Stigter, Tobias B Dansen, Boudewijn M T Burgering.

FOXO transcription factors act downstream of PI3K signaling, and FOXO transcriptional activity is inhibited through nuclear exclusion by PKB/AKT-mediated phosphorylation. Many studies have shown FOXO to contribute to organismal homeostasis by mitigating (extra)cellular stress to prevent cell death (reviewed in [1]). Here we show that FOXO3 activation protects cells from ferroptosis, an iron-dependent form of non-apoptotic cell death. In untransformed hTERT-RPE-1 cells, FOXO3 activation reduces ferroptosis in a multilayered manner. First, FOXO3 mediates protection from ferroptosis in part through a p27-induced G1 cell cycle arrest. Second, FOXO3 activation reduces cellular H2O2 levels, thereby limiting substrate availability for the Fenton reaction, which fuels hydroxyl radical formation for lipid peroxidation. Third, FOXO3 activation lowers cellular iron content by reducing TFR1 expression, which, combined with the lowering of cellular H2O2 levels, likely further reduces the formation of hydroxyl radicals through the Fenton reaction. Finally, FOXO3 activation reduces expression of long-chain-fatty-acid-CoA ligase 4 (ACSL4) and Peroxisomal targeting signal 1 receptor (PEX5), proteins involved in lipid metabolism and protection against ferroptosis. Taken together, we show that FOXO3 activation results in protection from ferroptosis, adding to the repertoire of FOXO-controlled cell protection programs.

DOI: https://doi.org/10.1038/s41420-025-02760-x
Proc Natl Acad Sci U S A. 2025 Oct 21. 122(42): e2507500122

Invasin-functionalized PIC hydrogels enable long-term 3D culture of epithelial organoids.

Joost J A P M Wijnakker, Sangho Lim, Robin Schreurs, João Ferreira Faria, Jeroen Korving, Harry Begthel, Kirti K Iyer, Paul H J Kouwer, Hans Clevers.

  Tissue stem cell (TSC)-derived epithelial organoids are typically cultured in Matrigel [T. Sato et al., Nature 459, 262-265 (2009)], an extracellular matrix-like hydrogel produced from Engelbreth-Holm-Swarm sarcoma cells. This tumor is grown in the mouse abdomen [R. W. Orkin et al., J. Exp. Med. 145, 204-220 (1977)]. Previously, we demonstrated that the Yersinia membrane protein Invasin, coated on transwells, replaces Matrigel by activating β1-integrins, allowing long-term expansion of primary epithelial cells as 2D organoid sheets [J. J. A. P. M. Wijnakker et al., Proc. Natl. Acad. Sci. U.S.A. 122, e2420595121 (2025)]. Here, we functionalize a synthetic polyisocyanide (PIC) hydrogel with the integrin-activating domain of Invasin (INV). PIC hydrogels are soluble at 4 °C and form a gel at 37 °C [P. H. J. Kouwer et al., Nature 493, 651-655 (2013)]. When INV is covalently linked to PIC, the resulting hydrogel supports multipassage 3D growth of human intestinal and airway organoids. Self-renewal, polarization, and differentiation are maintained. The 3D swelling assay for cystic fibrosis drug testing (S. F. Boj et al., J. Vis. Exp. (2017), 10.3791/55159] was validated using PIC-INV. With PIC-INV hydrogels, we establish a fully defined and animal-free system for 3D TSC-derived organoid culture.

Keywords:  Invasin; PIC; biomaterials; organoid; stem cells

DOI:  https://doi.org/10.1073/pnas.2507500122
Cancer Cell. 2025 Oct 16. pii: S1535-6108(25)00402-7. [Epub ahead of print]

Tumor-infiltrating bacteria disrupt cancer epithelial cell interactions and induce cell-cycle arrest.

Jorge Luis Galeano Niño, Falk Ponath, Victor A Ajisafe, Clara R Becker, Andrew G Kempchinsky, Martha A Zepeda-Rivera, Javier A Gomez, Hanrui Wu, Jessica G Terrazas, Heather Bouzek, Elizabeth Cromwell, Pritha Chanana, Matthew Wong, Ashish Damania, Michael G White, Y Nancy You, Scott Kopetz, Nadim J Ajami, Jennifer A Wargo, Christopher D Johnston, Susan Bullman.

  Tumor-infiltrating bacteria are increasingly recognized as modulators of cancer progression and therapy resistance. We describe a mechanism by which extracellular intratumoral bacteria, including Fusobacterium, modulate cancer epithelial cell behavior. Spatial imaging and single-cell spatial transcriptomics show that these bacteria predominantly localize extracellularly within tumor microniches of colorectal and oral cancers, characterized by reduced cell density, transcriptional activity, and proliferation. In vitro, Fusobacterium nucleatum disrupts epithelial contacts, inducing G0-G1 arrest and transcriptional quiescence. This state confers 5-fluorouracil resistance and remodels the tumor microenvironment. Findings were validated by live-cell imaging, spatial profiling, mouse models, and a 52-patient colorectal cancer cohort. Transcriptomics reveals downregulation of cell cycle, transcription, and antigen presentation genes in bacteria-enriched regions, consistent with a quiescent, immune-evasive phenotype. In an independent rectal cancer cohort, high Fusobacterium burden correlates with reduced therapy response. These results link extracellular bacteria to cancer cell quiescence and chemoresistance, highlighting microbial-tumor interactions as therapeutic targets.

Keywords:  Fusobacterium; cancer progression; cell-cycle arrest; chemoresistance; colorectal cancer; epithelial cell-to-cell contacts; host-pathogen interactions; intratumoral bacteria; live-cell confocal imaging; spatial single-cell transcriptomics; tumor microenvironment; tumor-infiltrating bacteria

DOI:  https://doi.org/10.1016/j.ccell.2025.09.010
Adv Healthc Mater. 2025 Oct 13. e01791

Decellularized Extracellular Matrix Scaffolds to Engineer the Dormant Landscape of Microscopic Colorectal Cancer Liver Metastasis.

Sabrina N VandenHeuvel, Lucia L Nash, Abigail J Clevenger, Claudia A Collier, Oscar R Benavides, Sanjana Roy, Brinlee Goggans, Aelita Salikhova, Anvitha Tharakesh, Svasti Haricharan, Amber N Stratman, Scott Kopetz, Alex J Walsh, Shreya A Raghavan.

  Recurrent liver-metastatic colorectal cancer contributes to high mortality. Recurrence occurs when dormant, microscopic residual disease survives initial treatment to escape dormancy. In their dormant, microscopic state within the liver, these metastatic lesions are undetectable by clinical diagnostic imaging until they form overt, chemoresistant metastases. Therefore, understanding the molecular mechanisms underlying dormancy in colorectal cancer liver metastases is a significant knowledge gap, motivating the engineering of nuanced in vitro models of disease. The current work presents an engineered model of liver-metastatic colorectal cancer dormancy. Decellularized extracellular matrix (dECM) scaffolds are used to provide microscopic colorectal cancer cell clusters with a biomimetic, 3D liver-specific architecture to colonize. Combined with nutrient deprivation and low dose chemotherapy, liver dECM significantly promotes dormancy, which manifests as slowed proliferation, nutrient/chemo-dependent G1/S and ECM-driven G2/M cell cycle arrest, diminished tumorigenicity, and robust chemotherapy resistance. The engineered dormancy signature is reversible, mimicking dormancy escape. The dECM-based model of engineered dormant colorectal cancer liver metastasis is crucial for advancing knowledge of dormancy induction and reversal, to improve therapeutics and patient survival.

Keywords:  colorectal cancer; dormancy; extracellular matrix; in vitro; liver metastasis

DOI:  https://doi.org/10.1002/adhm.202501791
Cancer Res. 2025 Oct 15.

Mathematical Modeling Quantifies "Just-Right" APC Inactivation for Colorectal Cancer Initiation.

Meritxell Brunet Guasch, Nathalie A Feeley, Ignacio Soriano, Steve Thorn, Ian P M Tomlinson, Michael D Nicholson, Tibor Antal.

Dysregulation of the tumor suppressor gene APC is a canonical step in colorectal cancer development by promoting activation of the WNT/β-catenin pathway. Curiously, most colorectal tumors carry biallelic mutations that result in only partial loss of APC function, suggesting that a "just-right" level of APC inactivation, and hence WNT signaling, provides the optimal conditions for tumorigenesis. Mutational processes act variably across the APC gene, which could contribute to the bias against complete APC inactivation. Here, we proposed a mathematical model to quantify the tumorigenic effect of biallelic APC genotypes, controlling for somatic mutational processes. Analysis of sequence data from >2500 colorectal cancers showed that APC genotypes resulting in partial protein function confer about 50 times higher probability of progressing to cancer compared to complete APC inactivation. The optimal inactivation level varied with anatomical location and additional mutations of WNT pathway regulators. Assessment of the regulatory effects of secondary alterations in WNT drivers in combination with APC in vivo provided evidence that AMER1 mutations increase WNT activity in tumors with suboptimal APC genotypes. The fitness landscape of APC inactivation was consistent across microsatellite unstable and POLE-deficient colorectal cancers and tumors in patients with familial adenomatous polyposis. Together, these findings suggest a general "just-right" optimum for APC inactivation and WNT signaling, pointing to WNT hyperactivation as a potential vulnerability in cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0445
Apoptosis. 2025 Oct 16.

CPT1A facilitated ferroptosis by forming feedback loop with Nrf2 via PI3K/AKT pathway in colorectal cancer.

Xiao-Huan Li, Feng Lv, Si-Qi Li, Hao-Wei Deng, Li-Ping Tang, Ke-Zhi Li, Li-Ye Xie, Bang-Li Hu, Shu-Fang Ning.

  Carnitine palmitoyltransferase 1A (CPT1A) has been implicated in the development of colorectal cancer (CRC), yet its role in ferroptosis remains to be fully understood. In this study, we found that CPT1A expression was associated with metastasis of CRC by gene datasets analysis and immunohistochemical staining of clinical samples, and it was upregulated in CRC cells compared with normal colon cell. The CCK-8, Transwell, and wound healing assays demonstrated that overexpression of CPT1A enhanced the viability, invasion, and migratory capacity of CRC cells. CPT1A expression was reduced following induction of ferroptosis in CRC cells, and this downregulation could be reversed by a ferroptosis inhibitor. Moreover, CPT1A overexpression inhibited ferroptosis in CRC cells. Nrf2, a well-known negative regulator of ferroptosis, was found to colocalize with CPT1A in CRC cells. Molecular docking, Co-IP assay and Ch-IP assay further confirmed an interaction between CPT1A and Nrf2. Notably, Nrf2 overexpression upregulated CPT1A expression, whereas Nrf2 knockdown produced the opposite effect. CPT1A overexpression led to activation of PI3K/AKT pathway in CRC cells. Inactivation of the PI3K/AKT pathway by the inhibitor partially reversed the anti-ferroptosis effect of CPT1A overexpression. Furthermore, inhibition of PI3K/AKT pathway suppressed Nrf2 expression, and reduce nuclear translocation of Nrf2, whereas activation of this pathway enhanced Nrf2 expression and nuclear translocation. In vivo experiments corroborated these findings, showing that CPT1A overexpression promoted Nrf2 expression, suppress ferroptosis, facilitated tumor growth, inactivated PI3K/AKT pathway. Taken together, our data suggest that CPT1A associates with metastasis of CRC, and inhibits ferroptosis through a regulatory feedback loop involving Nrf2 and PI3K/AKT pathway.

Keywords:  CPT1A; Colorectal cancer; Feedback loop; Ferroptosis

DOI:  https://doi.org/10.1007/s10495-025-02171-4
Biochem Biophys Res Commun. 2025 Oct 10. pii: S0006-291X(25)01508-6. [Epub ahead of print]787 152792

Integrative multi-omics analysis uncovers a novel FOSL2-COL8A1-EMT regulatory axis driving colorectal cancer progression.

Xingyu Zhang, Teng Yu, Xiuming Li, Xun Zou, Yizhuo Song, Lin Liu, Xiaozhu Shen, Shunfang Liu, Bin Liu.

  Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with metastasis and therapeutic resistance driven in part by activation of epithelial-mesenchymal transition (EMT). However, the upstream regulatory networks sustaining EMT programs in CRC are not fully understood. Here, through an integrative multi-omics strategy combining cross-cohort transcriptomic analysis, machine learning-based feature prioritization, and functional validation, we identify COL8A1, a nonfibrillar type VIII collagen, as a critical EMT effector and oncogenic regulator in CRC. COL8A1 was consistently overexpressed across independent CRC datasets and correlated with advanced tumor stage, poor patient survival, and strong enrichment of EMT-related transcriptional programs. Mechanistically, we demonstrate that FOSL2, an AP-1 family transcription factor, directly binds to a conserved high-affinity motif within the COL8A1 promoter and transcriptionally activates its expression. FOSL2 and COL8A1 exhibit strong co-expression at both mRNA and protein levels in CRC specimens, and FOSL2 silencing suppresses COL8A1 expression. Functionally, COL8A1 promotes mesenchymal phenotypes, enhances CRC cell migration and invasion in vitro, and promotes tumor growth in vivo. Collectively, our findings uncover a previously unrecognized FOSL2-COL8A1-EMT regulatory axis that fuels CRC progression and metastasis, providing novel mechanistic insights into EMT maintenance and nominating COL8A1 as a promising prognostic biomarker and therapeutic target for advanced colorectal cancer.

Keywords:  COL8A1; Colorectal cancer; Epithelial-mesenchymal transition (EMT); FOSL2; Transcriptional regulation; Tumor progression

DOI:  https://doi.org/10.1016/j.bbrc.2025.152792
Cells. 2025 Sep 24. pii: 1498. [Epub ahead of print]14(19):

MM-129 Counteracts 5-Fluorouracil-Induced Cellular Senescence in Colon Cancer via SIRT1/STAT3 Signaling Pathway.

Hubert Klepacki, Beata Sieklucka, Joanna Kalafut, Krystyna Kowalczuk, Arkadiusz Surazynski, Mariusz Mojzych, Anna Pryczynicz, Dariusz Pawlak, Natascia Tiso, Justyna Magdalena Hermanowicz.

  Cellular senescence plays a critical role in tumorigenesis and is recognized as a hallmark of colorectal cancer (CRC). Emerging evidence suggests that 5-fluorouracil (5-FU)-induced senescence may contribute to chemoresistance and tumor recurrence. Here, we investigated the effect of 5-FU on colon cancer cell senescence and whether MM-129 (pyrazolo[4,3-e]tetrazolo[4,5-b][1,2,4]triazine sulfonamide) can antagonize this activity. Senescence was identified by the expression of senescence-associated β-galactosidase (SA-β-gal) and cyclin-dependent kinase inhibitor 1A (p21) using qPCR, microscopy, flow cytometry, and immunohistochemistry. We also measured interleukin 6 (IL-6) and tumor necrosis factor (TNF-α) as key SASP cytokines, along with E-cadherin (CDH1), a marker of epithelial integrity. The SIRT1/STAT3 pathway was evaluated to elucidate the mechanism of MM-129's action. MM-129 counteracted 5-FU-induced senescence in colon cancer models, reducing p21 levels in zebrafish xenografts and the number of SA-β-gal-positive cells in vitro and in tumor tissues from DLD-1 and HT-29 mouse xenografts. MM-129 also inhibited senescence-associated responses by suppressing SASP cytokines (IL-6, TNF-α) and restoring E-cadherin (CDH1), and it modulated the SIRT1/STAT3 axis, which may underlie the observed senotherapeutic effects. In conclusion, MM-129 represents a novel senotherapeutic candidate. By modulating the SIRT1/STAT3 axis, it may suppress the SASP and weaken pro-survival signaling, thereby facilitating selective clearance of senescent cells. Integrating senotherapeutics with conventional cancer therapies may enhance efficacy and open new avenues for translational research.

Keywords:  5-fluorouracil; MM-129; SIRT1/STAT3 signaling; cellular senescence; chemoresistance; colorectal cancer; senescence-associated secretory phenotype; senotherapeutic agent

DOI:  https://doi.org/10.3390/cells14191498
Nat Rev Cancer. 2025 Oct 15.

Exploiting metabolic cell death for cancer therapy.

Chao Mao, Dadi Jiang, Albert C Koong, Boyi Gan.

Resistance to cell death is a hallmark of cancer, driving tumour progression and limiting therapeutic efficacy. Metabolic cell death pathways have been identified as unique vulnerabilities in cancer, with ferroptosis being the most extensively studied, alongside the more recently discovered pathways of cuproptosis and disulfidptosis - each triggered by distinct metabolic perturbations. In this Review, we examine the molecular mechanisms and regulatory networks that govern these forms of metabolic cell death in cancer cells. We further examine the potential crosstalk between these pathways and discuss how insights gained and challenges encountered from extensive studies on ferroptosis can guide future research and therapeutic strategies targeting cuproptosis and disulfidptosis in cancer treatment. We highlight the complexity and dual roles of metabolic cell death in cancer and offer our perspective on how to leverage these cell death processes to develop innovative, targeted cancer therapies.

DOI: https://doi.org/10.1038/s41568-025-00879-8
Commun Biol. 2025 Oct 17. 8(1): 1480

CPT2 inhibition enhances selective autophagy and proliferation in colorectal cancer via GPAT4-dependent glycerophospholipid biosynthesis.

Kuo Li, Hongyan Wang, Chan Li, Mingming Xiao, Yuan Luo, Shikai Shen, Guosheng Li, Yuan Fu, Wenbin Chen, Ruofan Shao, Wanlin Cui, Hongfu Wei, Jingyang Zhao, Mengfei Liu, Juan Li.

Metabolic reprogramming is one of the hallmark events in colorectal cancer. Tumor cells adapt to microenvironmental changes by regulating energy and biomaterial metabolism. This study identifys abnormal lipid accumulation and significant downregulation of fatty acid metabolism in colorectal cancer. The core gene of this pathway, CPT2, critically impacts colorectal cancer patient survival and regulates tumor cell proliferation both in vitro and in vivo. Metabolite analysis demonstrates that CPT2 knockdown induced accumulation of glycerophospholipids, primarily phosphatidylcholine and phosphatidylethanolamine, driven by enhanced long-chain fatty acid-dependent glycerophospholipid biosynthesis mediated by GPAT4. Transcriptomic analysis and subsequent experiments reveal that glycerophospholipid accumulation, as key components of vesicles and autophagosomes, promoted autophagosome maturation and elongation, thereby activating selective autophagy (lipophagy) in colorectal cancer cells and accelerating tumor progression. These findings enhance understanding of tumor metabolic characteristics and identify novel diagnostic and therapeutic targets for colorectal cancer.

DOI: https://doi.org/10.1038/s42003-025-08877-0
Nature. 2025 Oct 15.

Spatial metabolic gradients in the liver and small intestine.

Laith Z Samarah, Clover Zheng, Xi Xing, Won Dong Lee, Amichay Afriat, Uthsav Chitra, Michael R MacArthur, Wenyun Lu, Connor S R Jankowski, Cong Ma, Craig J Hunter, Michael Neinast, Daniel R Weilandt, Benjamin J Raphael, Joshua D Rabinowitz.

The properties of mammalian cells depend on their location within organs. Gene expression in the liver varies between periportal and pericentral hepatocytes1-3, and in the intestine from crypts to villus tips4,5. A key element of tissue spatial organization is probably metabolic, but direct assessments of spatial metabolism remain limited. Here we map spatial metabolic gradients in the mouse liver and intestine. We develop an integrated experimental-computational workflow using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS), isotope tracing and deep-learning artificial intelligence. Most measured metabolites (>90%) showed significant spatial concentration gradients in the liver lobules and intestinal villi. In the liver, tricarboxylic acid (TCA)-cycle metabolites and their isotope labelling from both glutamine and lactate localized periportally. Energy-stress metabolites, including adenosine monophosphate (AMP), also localized periportally, consistent with a high periportal energy demand. In the intestine, the TCA intermediates malate (tip) and citrate (crypt) showed opposite spatial patterns, aligning with higher glutamine catabolism in tips and lactate oxidation in crypts based on isotope tracing. Finally, we mapped the fate of the obesogenic dietary sugar fructose. In the intestine, oral fructose was catabolized faster in the villus bottom than in the tips. In the liver, fructose-derived carbon accumulated pericentrally as fructose-1-phosphate and triggered pericentral adenosine triphosphate (ATP) depletion. Thus, we both provide foundational knowledge regarding intestine and liver metabolic organization and identify fructose-induced focal derangements in liver metabolism.

DOI: https://doi.org/10.1038/s41586-025-09616-5
J Clin Invest. 2025 Oct 15. pii: e186052. [Epub ahead of print]135(20):

C6orf223 promotes colorectal cancer growth and metastasis by facilitating PRMT5-MEP50 multiprotein complex assembling.

Yufeng Qiao, Zhenzhen Wu, Peng Wang, Yiliang Jin, Furong Bai, Fei Zhang, Yunhe An, Meiying Xue, Han Feng, Yong Zhang, Yaxin Hou, Junfeng Du, Huiyun Cai, Guizhi Shi, Bing Zhou, Pu Gao, Jizhong Lou, Peng Zhang, Kelong Fan, Jinbo Liu, Pengcheng Bu.

  Protein arginine methyltransferase 5 (PRMT5) complexes with methylosome protein 50 (MEP50) play crucial roles in tumor progress. However, the regulatory mechanism of governing the PRMT5-MEP50 hetero-octameric complex remains unclear. Here, we demonstrate that C6orf223, to our knowledge an uncharacterized protein, facilitates PRMT5-MEP50 multiprotein complex assembling, thereby promoting colorectal cancer (CRC) growth and metastasis. C6orf223 forms dimers through disulfide bonds, with its N-terminal arginine-enriched region binding to the C-terminal negatively charged groove of PRMT5, thus stabilizing PRMT5-MEP50 multiprotein and enhancing PRMT5 methyltransferase activity. Consequently, PRMT5-mediated H4R3me2s substantially decreases the expression of the tumor suppressor GATA5, leading to the upregulation of multiple oncogenic target genes including WWTR1, FGFR1, and CLU. Targeting C6orf223 using siRNAs encapsulated in ferritin protein shells effectively suppresses CRC tumor growth and metastasis. Collectively, our findings characterize the role of C6orf223 in facilitating PRMT5-MEP50 hetero-octameric complex assembling and suggest that C6orf223 could serve as a potential therapeutic target for CRC.

Keywords:  Cell biology; Colorectal cancer; Oncology

DOI:  https://doi.org/10.1172/JCI186052
Nat Commun. 2025 Oct 13. 16(1): 9075

ALKBH8-mediated codon-specific translation promotes colorectal tumorigenesis.

Yu Qian, Canlan Wu, Saisai Wei, Sujun Yan, Junxuan Peng, Lei Yu, Yunyi Gao, Jingyu Hou, Wentao Yu, Zhanghui Chen, Jun Zhang, Xiangwei Gao.

Reprogramming gene expression at the translational level drives intestinal tumorigenesis. Codon decoding during translation elongation relies on tRNA modifications, while their pathological relevance in colorectal cancer remains to be elucidated. Here, we show that AlkB homolog 8 (ALKBH8), a uridine 34 (U34) tRNA methyltransferase, is a direct target of Wnt/β-catenin and is upregulated in colorectal cancer. Genetic ablation of ALKBH8 inhibits the development of intestinal tumors in Apcmin/+, azoxymethane/dextran sulfate sodium (AOM/DSS), and xenograft models. Loss of ALKBH8 induces ribosome pausing at adenine-ending codons, impairing the translation elongation of mRNAs enriched with these codons. Specifically, ALKBH8 regulates the translation of KRAS proto-oncogene in a codon-dependent manner. Rescue experiments demonstrate that the methyltransferase activity of ALKBH8 is required for its translation-promoting function. Together, our findings reveal ALKBH8-dependent mRNA translation as a critical mediator of intestinal tumorigenesis, underscoring its potential as a promising target for colorectal cancer therapy.

DOI: https://doi.org/10.1038/s41467-025-64144-0
Cell Death Dis. 2025 Oct 16. 16(1): 728

Claudin-7 deficiency induces metabolic reprogramming of neutrophils in the colorectal cancer microenvironment.

Xiaoqing Liang, Dajin Yuan, Songyun Zhao, Jianbo Zhou, Kun Wang, Xiaoli Liu, Yin Liu, Huimin Li, Mengdi Hao, Wenbin Huang, Wenjie Li, Lei Ding.

Neutrophils are integral components of the bone marrow and stromal cell network. They express the immune checkpoint molecule PD-L1 and can induce T cell exhaustion, thereby promoting immunosuppression. In this study, we investigated whether tumor-derived Cldn7 deficiency could recruit polymorphonuclear neutrophils (PMNs), induce their metabolic reprogramming, and consequently drive their transition toward a pro-tumor phenotype, leading to the establishment of an immunosuppressive tumor microenvironment (TME). Using single-cell RNA sequencing, clinical sample validation, and both in vivo and in vitro experiments, we found that Cldn7 deficiency in colorectal cancer (CRC) results in a tumor microenvironment characterized by significantly increased infiltration of CD11b⁺ Ly6G⁺ neutrophils. This is accompanied by neutrophil metabolic reprogramming that facilitates their phenotypic shift toward a tumor-promoting state, which in turn suppresses the cytotoxic function of CD8⁺ T cells and contributes to the formation of an immunosuppressive TME, thereby accelerating CRC progression. Mechanistically, Cldn7 deficiency indirectly activates the NF-κB signaling pathway, leading to elevated secretion of chemokines such as CXCL1 that are responsible for PMN recruitment. Inhibition of the NF-κB/CXCL1 axis reduces PMN infiltration, decreases PD-L1 expression on neutrophils, suppresses neutrophil glycolysis and histone lactylation, reverses the exhausted phenotype of CD8⁺ T cells, thereby mitigating the immunosuppressive microenvironment. Furthermore, overexpression of Cldn7 enhances the efficacy of immune checkpoint blockade (ICB) therapy.Collectively, our findings indicate that Cldn7 deficiency not only contributes to immune evasion and malignant progression in CRC but also plays a critical role in immune modulation. Targeting PMN metabolic reprogramming and immunosuppressive function associated with Cldn7 loss may offer a promising strategy to improve the therapeutic efficacy of immunotherapy in CRC.

DOI: https://doi.org/10.1038/s41419-025-08064-3
Cell Death Discov. 2025 Oct 16. 11(1): 460

Targeting FADS1-mediated lipid metabolism and signaling: a novel therapeutic strategy for precision oncology in colorectal and esophageal cancers.

Jingxuan Lian, Xiaohui Duan, Wenjie Chen, Xinhong Zhang, Ming Lu, Zheshen Lin, Zhentian Wu, Litian Ma, Rong Liang.

Gastrointestinal (GI) cancers exhibit aberrant lipid metabolism, yet the causal mechanisms remain elusive. Here, we integrated Mendelian randomization (MR) and multi-omics data to dissect metabolic drivers of 20 GI diseases. Focusing on colorectal (CC) and esophageal cancer (EC), we identified five metabolites (e.g., 1,2-di-palmitoyl-sn-glycero-3-phosphocholine) and arachidonic acid ethyl ester as causal drivers. Summary-data-based MR and colocalization analysis (PP.H4 > 0.75) revealed FADS1 as a master regulator of these metabolites, with genetic variants exhibiting tissue-specific lipidomic effects. Functional validation using FADS1-knockout cell lines and mouse models demonstrated that FADS1 inhibition suppresses tumor cell proliferation, migration, and invasion while promoting apoptosis. In vivo, FADS1 deletion reduced chemically induced CC/EC tumor burden by 62-75%, accompanied by decreased Ki-67/MMP-9 expression and inflammatory infiltration. Mechanistically, FADS1 ablation disrupted lipid metabolism (reduced linoleic acid and arachidonic acid) and attenuated PI3K/AKT and MAPK signaling. Multi-omics integration further corroborated FADS1-mediated epigenetic regulation (e.g., mQTL-driven DNA methylation). This study establishes FADS1 as a pivotal orchestrator of GI carcinogenesis via metabolic reprogramming and signaling dysregulation, offering a compelling therapeutic target for precision oncology in CC and EC. Regulatory mechanisms of FADS1 in CC and EC.

DOI: https://doi.org/10.1038/s41420-025-02768-3