bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–02–09
sixteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Acidosis overrides molecular heterogeneity to shape therapeutically targetable metabolic phenotypes in colon cancers.
  2. PRMT5 Maintains Homeostasis of the Intestinal Epithelium by Modulating Cell Proliferation and Survival.
  3. Dynamic Reprogramming of Stromal Pdgfra-expressing cells during WNT-Mediated Transformation of the Intestinal Epithelium.
  4. Adaptive Plasticity Tumor Cells Modulate MAPK-Targeting Therapy Response in Colorectal Cancer.
  5. BRAF mutant appendiceal adenocarcinoma differs from colorectal cancer but responds to BRAF-targeted therapy.
  6. Oncofetal reprogramming induces phenotypic heterogeneity in colorectal cancer.
  7. HMGA1 acts as an epigenetic gatekeeper of ASCL2 and Wnt signaling during colon tumorigenesis.
  8. Dual independent mechanisms underlying gut epithelial remodeling upon sugar substitute consumption.
  9. Pioneer factor GATA6 promotes colorectal cancer through 3D genome regulation.
  10. The E2F4 transcriptional repressor is a key mechanistic regulator of colon cancer resistance to irinotecan (CPT-11).
  11. PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma.
  12. Tumor "age" in early-onset colorectal cancer.
  13. HMGA1 is a crucial mediator of colon tumorigenesis driven by the loss of APC.
  14. Ferroptosis Plays a Pivotal Role in Activating and Modulating Specific Intracellular Signaling Pathways Integrated into the Therapeutic Management of Colorectal Cancer.
  15. ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3.
  16. TRIM21-mediated PRMT1 degradation attenuates colorectal cancer malignant progression.
  1. Cancer Lett. 2025 Feb 01. pii: S0304-3835(25)00076-X. [Epub ahead of print] 217512
    Acidosis overrides molecular heterogeneity to shape therapeutically targetable metabolic phenotypes in colon cancers.
    Elena Richiardone, Maria Virginia Giolito, Rim Al Roumi, Jérôme Ambroise, Romain Boidot, Bernhard Drotleff, Bart Ghesquière, Barbara Lupo, Livio Trusolino, Alberto Bardelli, Sabrina Arena, Olivier Feron, Cyril Corbet.
      Colorectal cancer (CRC) represents a prototypical example of a cancer type for which inter- and intra-tumor heterogeneities remain major challenges for the clinical management of patients. Besides genotype-mediated phenotypic alterations, tumor microenvironment (TME) conditions are increasingly recognized to promote intrinsic diversity and phenotypic plasticity and sustain disease progression. In particular, acidosis is a common hallmark of solid tumors, including CRC, and it is known to induce aggressive cancer cell phenotypes. In this study, we report that long-term adaptation to acidic pH conditions is associated with common metabolic alterations, including a glycolysis-to-respiration switch and a higher reliance on the activity of phosphoglycerate dehydrogenase (PHGDH), in CRC cells initially displaying molecularly heterogeneous backgrounds. Pharmacological inhibition of PHGDH activity or mitochondrial respiration induces greater growth-inhibitory effects in acidosis-exposed CRC cells in 2D and 3D culture conditions, and in patient-derived CRC organoids. These data pave the way for drugs targeting the acidic tumor compartment as a "one-size-fits-all" therapeutic approach to delay CRC progression.
    Keywords:  Colon cancer; PHGDH; acidosis; metabolism; microenvironment; mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.canlet.2025.217512
  2. Adv Sci (Weinh). 2025 Feb 03. e2415559
    PRMT5 Maintains Homeostasis of the Intestinal Epithelium by Modulating Cell Proliferation and Survival.
    Leilei Li, Zhe Zhang, Xu Wang, Haiyong Zhao, Liansheng Liu, Yanhui Xiao, Shan Hua, Ye-Guang Chen.
      Intestinal homeostasis is sustained by self-renewal of intestinal stem cells, which continuously divide and produce proliferative transit-amplifying (TA) and progenitor cells. Protein arginine methyltransferases 5 (PRMT5) plays a crucial role in regulating homeostasis of various mammalian tissues. However, its function in intestinal homeostasis remains elusive. In this study, conditional knockout of Prmt5 in the mouse intestinal epithelium leads to a reduction in stem cell population, suppression of cell proliferation, and increased cell apoptosis within the intestinal crypts, accompanied with shortened gut length, decreased mouse body weight, and eventual animal mortality. Additionally, Prmt5 deletion or its enzymatic inhibition in intestinal organoids in vitro also shows resembling cellular phenotypes. Methylome profiling identifies 90 potential Prmt5 substrates, which are involved in RNA-related biological processes and cell division. Consistently, Prmt5 depletion in intestinal organoids leads to aberrant alternative splicing in a subset of genes related to the mitotic cell cycle. Furthermore, Prmt5 loss triggers p53-mediated apoptosis in the intestinal epithelium. Collectively, the findings uncover an indispensable role of PRMT5 in promoting cell proliferation and survival, as well as maintaining stem cells in the gut epithelium.
    Keywords:  cell proliferation and survival; intestinal homeostasis; protein arginine methylation; protein arginine methyltransferases 5; stem cells
    DOI:  https://doi.org/10.1002/advs.202415559
  3. bioRxiv. 2025 Jan 25. pii: 2025.01.22.634326. [Epub ahead of print]
    Dynamic Reprogramming of Stromal Pdgfra-expressing cells during WNT-Mediated Transformation of the Intestinal Epithelium.
    O Pellon-Cardenas, P Rout, S Hassan, E Fokas, He Ping, I Patel, J Patel, O Plotsker, A Wu, R Kumar, M Akther, A Logerfo, S Wu, D E Wagner, D Boffelli, K D Walton, E Manieri, K Tong, J R Spence, N J Bessman, R A Shivdasani, M P Verzi.
      Stromal fibroblasts regulate critical signaling gradients along the intestinal crypt-villus axis 1 and provide a niche that supports adjacent epithelial stem cells. Here we report that Pdgfra -expressing fibroblasts secrete ligands that promote a regenerative-like state in the intestinal mucosa during early WNT-mediated tumorigenesis. Using a mouse model of WNT-driven oncogenesis and single-cell RNA sequencing (RNA-seq) of mesenchyme cell populations, we revealed a dynamic reprogramming of Pdgfra + fibroblasts that facilitates WNT-mediated tissue transformation. Functional assays of potential mediators of cell-to-cell communication between these fibroblasts and the oncogenic epithelium revealed that TGFB signaling is notably induced in Pdgfra + fibroblasts in the presence of oncogenic epithelium, and TGFB was essential to sustain regenerative-like growth of organoids ex vivo . Genetic reduction of Cdx2 in the β-catenin mutant epithelium elevated the fetal-like/regenerative transcriptome and accelerated WNT-dependent onset of oncogenic transformation of the tissue in vivo . These results demonstrate that Pdgfra + fibroblasts are activated during WNT-driven oncogenesis to promote a regenerative state in the epithelium that precedes and facilitates formation of tumors.
    DOI:  https://doi.org/10.1101/2025.01.22.634326
  4. bioRxiv. 2025 Jan 24. pii: 2025.01.22.634215. [Epub ahead of print]
    Adaptive Plasticity Tumor Cells Modulate MAPK-Targeting Therapy Response in Colorectal Cancer.
    Oscar E Villarreal, Yixin Xu, Ha Tran, Annette Machado, Dionne Prescod, Amanda Anderson, Rosalba Minelli, Mike Peoples, Alejandro Hernandez Martinez, Hey Min Lee, Chi Wut Wong, Natalie Fowlkes, Preeti Kanikarla, Alexey Sorokin, Jumanah Alshenaifi, Olu Coker, Kangyu Lin, Chris Bristow, Andrea Viale, John Paul Shen, Christine Parseghian, Joseph R Marszalek, Ryan Corcoran, Scott Kopetz.
      MAPK pathway inhibitors (MAPKi) are increasingly used in the treatment of advanced colorectal cancer, but often produce short-lived responses in patients. Although acquired resistance by de novo mutations in tumors have been found to reduce response in some patients, additional mechanisms underlying the limited response durability of MAPK targeting therapy remain unknown. Here, we denote new contributory tumor biology and provide insight on the impact of tumor plasticity on therapy response. Analysis of MAPKi treated patients revealed activation of stemness programs and increased ASCL2 expression, which are associated with poor outcomes. Greater ASCL2 with MAPKi treatment was also seen in patient-derived CRC models, independent of driver mutations. We find ASCL2 denotes a distinct cell population, arising from phenotypic plasticity, with a proliferative, stem-like phenotype, and decreased sensitivity to MAPKi therapy, which were named adaptive plasticity tumor (APT) cells. MAPK pathway suppression induces the APT phenotype in cells, resulting in APT cell enrichment in tumors and limiting therapy response in preclinical and clinical data. APT cell depletion improved MAPKi treatment efficacy and extended MAPKi response durability in mice. These findings uncover a cellular program that mitigates the impact of MAPKi therapies and highlights the importance of addressing tumor plasticity to improve clinical outcomes.
    DOI:  https://doi.org/10.1101/2025.01.22.634215
  5. NPJ Precis Oncol. 2025 Feb 05. 9(1): 38
    BRAF mutant appendiceal adenocarcinoma differs from colorectal cancer but responds to BRAF-targeted therapy.
    Vinay K Pattalachinti, Emaan Haque, Mahmoud Yousef, Abdelrahman Yousef, Saikat Chowdhury, Michael Overman, Christine M Parseghian, Van K Morris, Bryan Kee, Ryan W Huey, Kanwal Raghav, Colin M Court, John Paul Shen.
      Appendiceal Adenocarcinoma (AA) is a rare gastrointestinal cancer with no FDA-approved targeted therapies. Here, we retrospectively compare BRAF-mutant AA and colorectal cancer (CRC). BRAF mutation is rare in AA (3%). Unlike CRC, BRAFV600E AA is not associated with poor prognosis, female sex, microsatellite instability, mucinous histology, or poor differentiation. In both cancers, BRAFV600E but not atypical BRAF mutations are mutually exclusive with other Ras-activating mutations. BRAFV600E + EGFR inhibition shows efficacy in BRAFV600E AA (disease control rate = 80%, median progression-free survival = 7.1 months).
    DOI:  https://doi.org/10.1038/s41698-025-00821-z
  6. Nat Genet. 2025 Feb 07.
    Oncofetal reprogramming induces phenotypic heterogeneity in colorectal cancer.
      
    DOI:  https://doi.org/10.1038/s41588-025-02092-7
  7. J Clin Invest. 2025 Feb 03. pii: e184442. [Epub ahead of print]135(3):
    HMGA1 acts as an epigenetic gatekeeper of ASCL2 and Wnt signaling during colon tumorigenesis.
    Li Z Luo, Jung-Hyun Kim, Iliana Herrera, Shaoguang Wu, Xinqun Wu, Seong-Sik Park, Juyoung Cho, Leslie Cope, Lingling Xian, Bailey E West, Julian Calderon-Espinosa, Joseph Kim, Zanshé Thompson, Isha Maloo, Tatianna Larman, Karen L Reddy, Ying Feng, Eric R Fearon, Cynthia L Sears, Linda Resar.
      Mutated tumor cells undergo changes in chromatin accessibility and gene expression, resulting in aberrant proliferation and differentiation, although how this occurs is unclear. HMGA1 chromatin regulators are abundant in stem cells and oncogenic in diverse tissues; however, their role in colon tumorigenesis is only beginning to emerge. Here, we uncover a previously unknown epigenetic program whereby HMGA1 amplifies Wnt signaling during colon tumorigenesis driven by inflammatory microbiota and/or Adenomatous polyposis coli (Apc) inactivation. Mechanistically, HMGA1 "opens" chromatin to upregulate the stem cell regulator, Ascl2, and downstream Wnt effectors, promoting stem and Paneth-like cell states while depleting differentiated enterocytes. Loss of just one Hmga1 allele within colon epithelium restrains tumorigenesis and Wnt signaling driven by mutant Apc and inflammatory microbiota. However, HMGA1 deficiency has minimal effects in colon epithelium under homeostatic conditions. In human colon cancer cells, HMGA1 directly induces ASCL2 by recruiting activating histone marks. Silencing HMGA1 disrupts oncogenic properties, whereas reexpression of ASCL2 partially rescues these phenotypes. Further, HMGA1 and ASCL2 are coexpressed and upregulated in human colorectal cancer. Together, our results establish HMGA1 as an epigenetic gatekeeper of Wnt signals and cell state under conditions of APC inactivation, illuminating HMGA1 as a potential therapeutic target in colon cancer.
    Keywords:  Colorectal cancer; Epigenetics; Oncology; Transcription
    DOI:  https://doi.org/10.1172/JCI184442
  8. FASEB J. 2025 Feb 15. 39(3): e70374
    Dual independent mechanisms underlying gut epithelial remodeling upon sugar substitute consumption.
    Dong Woo Seo, Kyung Tae Hong, Jung Hoon Lee, Jun-Seok Lee, Yong Taek Jeong.
      Intestinal epithelial cells (IECs) are dynamically regulated by luminal contents, including dietary ingredients, food additives, and microbiota-derived metabolites. Although sugar substitutes are commonly used as food additives for their sweet taste and lower calorie content, there is limited experimental evidence regarding their potential to drive gut remodeling. In this study, we designed experimental models for short-term consumption of erythritol, a natural sugar alcohol widely used as a sugar substitute, and investigated its effects on gut remodeling and the underlying mechanisms. Our findings indicate that erythritol consumption induces hyperplasia in tuft cells (TCs) and goblet cells (GCs), as well as enhances the activity of intestinal stem cells-increases in expression levels of leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5), the key intestinal stem cell marker, in the number of proliferating stem cells, and facilitation of their differentiation into villi cells-while maintaining the number of Lgr5+ intestinal stem cells. Notably, the enhanced stem cell activity was observed even in Trpm5 knockout mice, suggesting that it is mechanistically independent of TC hyperplasia. Instead, we demonstrated the functional involvement of the gut microbiota, as antibiotic treatment abolished this effect, and fecal material transfer from erythritol-consumed mice replicated the enhancement of stem cell activity in recipient mice. Furthermore, we identified acetate as the metabolite responsible for enhancing stem cell activity. These findings suggest the functional decoupling of TC hyperplasia and the enhancement of stem cell activity, providing a potential therapeutic avenue for gut epithelial diseases.
    Keywords:  erythritol; intestine; short‐chain fatty acids; stem cell; sugar substitute
    DOI:  https://doi.org/10.1096/fj.202402105RR
  9. Sci Adv. 2025 Feb 07. 11(6): eads4985
    Pioneer factor GATA6 promotes colorectal cancer through 3D genome regulation.
    Huijue Lyu, Xintong Chen, Yang Cheng, Te Zhang, Ping Wang, Josiah Hiu-Yuen Wong, Juan Wang, Lena Stasiak, Leyu Sun, Guangyu Yang, Lu Wang, Feng Yue.
      Colorectal cancer (CRC) is one of the most lethal and prevalent malignancies. While the overexpression of pioneer factor GATA6 in CRC has been linked with metastasis, its role in genome-wide gene expression dysregulation remains unclear. Through studies of primary human CRC tissues and analysis of the TCGA data, we found that GATA6 preferentially binds at CRC-specific active enhancers, with enrichment at enhancer-promoter loop anchors. GATA6 protein also physically interacts with CTCF, suggesting its critical role in 3D genome organization. The ablation of GATA6 through AID and CRISPR systems severely impaired cancer cell clonogenicity and proliferation. Mechanistically, GATA6 knockout induced global loss of CRC-specific open chromatins and extensive alterations of critical enhancer-promoter interactions for CRC oncogenes. Last, we showed that GATA6 knockout greatly reduced tumor growth and improved survival in mice. Together, we revealed a previously unidentified mechanism by which GATA6 contributes to the pathogenesis of colorectal cancer.
    DOI:  https://doi.org/10.1126/sciadv.ads4985
  10. bioRxiv. 2025 Jan 24. pii: 2025.01.22.633435. [Epub ahead of print]
    The E2F4 transcriptional repressor is a key mechanistic regulator of colon cancer resistance to irinotecan (CPT-11).
    Junichi Matsubara, Yong Fuga Li, Sanjay Koul, Junko Mukohyama, Luis E Valencia Salazar, Taichi Isobe, Dalong Qian, Michael F Clarke, Debashis Sahoo, Russ B Altman, Piero Dalerba.
      Background.Colorectal carcinomas (CRCs) are seldom eradicated by cytotoxic chemotherapy. Cancer cells with stem-like functional properties, often referred to as "cancer stem cells" (CSCs), display preferential resistance to several anti-tumor agents used in cancer chemotherapy, but the molecular mechanisms underpinning their selective survival remain only partially understood. Methods. In this study, we used Transcription Factor Target Genes (TFTG) enrichment analysis to identify transcriptional regulators (activators or repressors) that undergo preferential activation by chemotherapy in CRC cells with a "bottom-of-the-crypt" phenotype (EPCAM + /CD44 + /CD166 + ; CSC-enriched) as compared to CRC cells with a "top-of-the-crypt" phenotype (EPCAM + /CD44 neg /CD166 neg ; CSC-depleted). The two cell populations were purified in parallel by fluorescence-activated cell sorting (FACS) from a patient-derived xenograft (PDX) line representative of a moderately differentiated human CRC, following in vivo chemotherapy with irinotecan (CPT-11). The transcriptional regulators identified as differentially activated were tested for differential expression in normal vs. cancer tissues, and in cell populations enriched in stem/progenitor cell-types as compared to differentiated lineages (goblet cells, enterocytes) in the mouse colon epithelium. Finally, the top candidate was tested for mechanistic contribution to drug-resistance by selective down-regulation using short-hairpin RNAs (shRNAs). Results. Our analysis identified E2F4 and TFDP1, two core components of the DREAM transcriptional repression complex, as transcriptional modulators preferentially activated by irinotecan in EPCAM + /CD44 + /CD166 + as compared to EPCAM + /CD44 neg /CD166 neg cancer cells. The expression levels of both genes ( E2F4 , TFDP1 ) were found up-regulated in CRCs as compared to human normal colon tissues, and in a sub-population of mouse colon epithelial cells enriched in stem/progenitor elements (Epcam + /Cd44 + /Cd66a low /Kit neg ) as compared to other sub-populations enriched in either goblet cells (Epcam + /Cd44 + /Cd66a low /Kit + ) or enterocytes (Epcam + /Cd44 neg /Cd66a high ). Most importantly, E2F4 down-regulation using shRNAs dramatically enhanced the sensitivity of human CRCs to in vivo treatment with irinotecan , across three independent PDX models. Conclusions. Our data identified E2F4 and the DREAM repressor complex as critical regulators of human CRC resistance to irinotecan , and as candidate targets for the development of chemo-sensitizing agents.
    DOI:  https://doi.org/10.1101/2025.01.22.633435
  11. Nat Commun. 2025 Feb 01. 16(1): 1237
    PPARα-mediated lipid metabolism reprogramming supports anti-EGFR therapy resistance in head and neck squamous cell carcinoma.
    Valentin Van den Bossche, Julie Vignau, Engy Vigneron, Isabella Rizzi, Hannah Zaryouh, An Wouters, Jérôme Ambroise, Steven Van Laere, Simon Beyaert, Raphaël Helaers, Cédric van Marcke, Lionel Mignion, Elise Y Lepicard, Bénédicte F Jordan, Céline Guilbaud, Olivier Lowyck, Hajar Dahou, Antonella Mendola, Manon Desgres, Léo Aubert, Isabelle Gerin, Guido T Bommer, Romain Boidot, Perrine Vermonden, Aurélien Warnant, Yvan Larondelle, Jean-Pascal Machiels, Olivier Feron, Sandra Schmitz, Cyril Corbet.
      Anti-epidermal growth factor receptor (EGFR) therapy (cetuximab) shows a limited clinical benefit for patients with locally advanced or recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), due to the frequent occurrence of secondary resistance mechanisms. Here we report that cetuximab-resistant HNSCC cells display a peroxisome proliferator-activated receptor alpha (PPARα)-mediated lipid metabolism reprogramming, with increased fatty acid uptake and oxidation capacities, while glycolysis is not modified. This metabolic shift makes cetuximab-resistant HNSCC cells particularly sensitive to a pharmacological inhibition of either carnitine palmitoyltransferase 1A (CPT1A) or PPARα in 3D spheroids and tumor xenografts in mice. Importantly, the PPARα-related gene signature, in human clinical datasets, correlates with lower response to anti-EGFR therapy and poor survival in HNSCC patients, thereby validating its clinical relevance. This study points out lipid metabolism rewiring as a non-genetic resistance-causing mechanism in HNSCC that may be therapeutically targeted to overcome acquired resistance to anti-EGFR therapy.
    DOI:  https://doi.org/10.1038/s41467-025-56675-3
  12. Cell. 2025 Feb 06. pii: S0092-8674(24)01416-8. [Epub ahead of print]188(3): 589-593
    Tumor "age" in early-onset colorectal cancer.
    Gianluca Mauri, Giorgio Patelli, Giovanni Crisafulli, Salvatore Siena, Alberto Bardelli.
      The incidence of early-onset colorectal cancer (EO-CRC) is surging, and by 2030, one-third of all CRCs will occur before the commonly recommended screening age of 50 years. The time required for EO-CRC to reach the metastatic stage is unknown, yet this knowledge is critical to tailor early-diagnosis screening strategies. Here, we discuss how defining a key biological feature of EO-CRC may be central to protecting young adults from an alarming and probably unprecedented tumor epidemic.
    DOI:  https://doi.org/10.1016/j.cell.2024.12.003
  13. J Clin Invest. 2025 Feb 03. pii: e187442. [Epub ahead of print]135(3):
    HMGA1 is a crucial mediator of colon tumorigenesis driven by the loss of APC.
    Yuxiang Wang, Mikayla Ybarra, Zhenghe Wang.
      Colorectal cancer is the second leading cause of cancer death in the United States. The adenomatous polyposis coli (APC) pathway plays a critical role in colorectal tumorigenesis, but the mechanism is not fully understood. In this issue of the JCI, Luo and colleagues used genetically engineered mouse models to show that high mobility group A (HMGA1) is a critical mediator in the development of colon tumors driven by the loss of the Apc gene. HMGA1 activated the transcription of Achaete-Scute Family BHLH Transcription Factor 2 (ASCL2), which regulated intestinal stemness and promoted colon tumorigenesis.
    DOI:  https://doi.org/10.1172/JCI187442
  14. Int J Mol Cell Med. 2024 ;13(4): 374-386
    Ferroptosis Plays a Pivotal Role in Activating and Modulating Specific Intracellular Signaling Pathways Integrated into the Therapeutic Management of Colorectal Cancer.
    Marzieh Monemi, Hanan Hassan Ahmed, Radhwan Abdul Kareem, Waam Mohammed Taher, Mariem Alwan, Mahmood Jasem Jawad, Atheer Khdyair Hamad, Samaneh Moradi.
      It is expected that the amount of recently diagnosed colon cancer cases will increase to around 3.2 million yearly until 2040. Although early diagnostic procedures and management approaches have been improved, colorectal cancer (CRC) treatment remains challenging. There is an urgent need to discover new therapeutic agents to enhance therapeutic strategies. Ferroptosis is distinguished as a mode of regulated cell death considered by iron-dependent lipid peroxidation. Contemporary investigations suggest that induction of ferroptosis in CRC can effectively target neoplastic cells that are resistant to alternative forms of cell death. This review has summarized recent scientific work on the implications of ferroptosis in CRC treatment and highlights its underlying molecular and biological mechanisms. While investigating its therapeutic potential, it shows the importance of diverse modulators of ferroptosis, including the 7-membered solute carrier family 11 or xCT (SLC7A11), reactive oxygen species (ROS), glutathione (GSH), and iron in the context of CRC. Recent research has identified specific pathways and compounds that can induce ferroptosis in CRC, such as apatinib and elesclimol, which are involved in pivotal signaling cascades. Attenuation of proteins such as splicing factor, arginine/serine 9 (SFRS9), and Tp53-induced glycolysis and apoptosis regulator (TIGAR) may increase the sensitivity of CRC cells to ferroptosis, thus suggesting promising therapeutic avenues. Compounds including IMCA and β-elemene have shown efficacy in inducing ferroptosis while minimizing toxicity to normal tissues, thereby demonstrating their potential as therapeutic agents for CRC. Participating ferroptosis stimulator drugs with current treatment regimens, such as cetuximab and aspirin, may offer better treatment outcomes for CRC patients, especially those presenting resistance to conventional therapies.
    Keywords:  Colorectal cancer; epidemiology; screening tests; treatment approaches
    DOI:  https://doi.org/10.22088/IJMCM.BUMS.13.4.374
  15. Nat Commun. 2025 Feb 06. 16(1): 1406
    ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3.
    Shiyang Wang, Xi Wu, Wenxin Bi, Jiuzhi Xu, Liyuan Hou, Guilin Li, Yuwei Pan, Hanfu Zhang, Mengzhen Li, Sujuan Du, Mingxin Zhang, Di Liu, Shuiling Jin, Xiaojing Shi, Yuhua Tian, Jianwei Shuai, Maksim V Plikus, Moshi Song, Zhaocai Zhou, Lu Yu, Cong Lv, Zhengquan Yu.
      Aberrant release of mitochondrial reactive oxygen species (mtROS) in response to cellular stress is well known for promoting cancer progression. However, precise molecular mechanism by which mtROS contribute to epithelial cancer progression remains only partially understood. Here, using colorectal cancer (CRC) models, we show that upon sensing excessive mtROS, phosphatase PGAM5, which normally localizes to the mitochondria, undergoes aberrant cleavage by presenilin-associated rhomboid-like protein (PARL), becoming released into the cytoplasm. Cytosolic PGAM5 then directly binds to and dephosphorylates MST3 kinase. This, in turn, prevents STK25-mediated LATS1/2 phosphorylation, leading to YAP activation and CRC progression. Importantly, depletion of MST3 reciprocally promotes accumulation of cytosolic PGAM5 by inducing mitochondrial damage. Taken together, these findings demonstrate how mtROS promotes CRC progression by activating YAP via a post-transcriptional positive feedback loop between PGAM5 and MST3, both of which can serve as potential targets for developing next-generation anti-colon cancer therapeutics.
    DOI:  https://doi.org/10.1038/s41467-025-56444-2
  16. Cell Death Dis. 2025 Jan 31. 16(1): 56
    TRIM21-mediated PRMT1 degradation attenuates colorectal cancer malignant progression.
    Menghan Cao, Zhiying Shao, Xingyou Qian, Miaolei Chen, Chuyin Deng, Xintian Chen, Tingting Tang, Kaixu Zhang, Sufang Chu, Junnian Zheng, Jin Bai, Zhongwei Li.
      Tripartite motif-containing 21 (TRIM21) plays a crucial role in antiviral responses and autoimmune diseases. While the impact of TRIM21 on cancer has been studied in various tumors, its role in colorectal cancer (CRC) remains unclear. In this study, we found that TRIM21 expression is reduced in primary CRC tissues. Low levels of TRIM21 in CRC are associated with unfavorable clinicopathological characteristics and shorter survival. Furthermore, we demonstrate that TRIM21 suppresses the proliferation, tumorigenesis, migration, and metastasis of CRC cells by promoting the ubiquitination-mediated degradation of PRMT1. These findings suggest that TRIM21 holds potential as a valuable predictive biomarker for assessing the prognosis of CRC patients.
    DOI:  https://doi.org/10.1038/s41419-025-07383-9
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