bims-instec 2025-04-20 papers

bims-instec

Biomed News

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

Issue of 2025–04–20
seventeen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Tcf4 regulates secretory cell fate decisions in the small intestine and colon tumors: insights from transcriptomic, histological, and microbiome analyses.
Peritoneal resident macrophages constitute an immunosuppressive environment in peritoneal metastasized colorectal cancer.
THBS2-producing matrix CAFs promote colorectal cancer progression and link to poor prognosis via the CD47-MAPK axis.
Targeting PLK1-CBX8-GPX4 axis overcomes BRAF/EGFR inhibitor resistance in BRAFV600E colorectal cancer via ferroptosis.
Therapeutic Targeting of the Pentose Phosphate Pathway in Colorectal Cancer Using 6-Aminonicotinamide and 5-Fluorouracil.
Peroxisomal membrane protein PMP70 confers drug resistance in colorectal cancer.
Rap2B drives tumorigenesis and progression of colorectal cancer through intestinal cytoskeleton remodeling.
Colorectal cancer progression to metastasis is associated with dynamic genome-wide biphasic 5-hydroxymethylcytosine accumulation.
Colorectal cancer peritoneal metastasis is promoted by tissue-specific fibroblasts that can arise in response to various local disorders.
FADS2 inhibits colorectal cancer cell proliferation by regulating ferroptosis through SLC7A11/GPX4.
Hypoxia-induced Wnt5a-secreting fibroblasts promote colon cancer progression.
Early-onset colorectal cancer: Hollyoaks tackles taboos and raises awareness.
Cholesterol-targeting Wnt-β-catenin signaling inhibitors for colorectal cancer.
ADAR1-high tumor-associated macrophages induce drug resistance and are therapeutic targets in colorectal cancer.
Cuproptosis-related gene ACAD8 inhibits the metastatic ability of colorectal cancer by inducing cuproptosis.
ARID3A inhibits colorectal cancer cell stemness and drug-resistance by targeting a multitude of stemness-associated genes.
GLUT1 inhibition by BAY-876 induces metabolic changes and cell death in human colorectal cancer cells.

Stem Cell Res Ther. 2025 Apr 12. 16(1): 170

Tcf4 regulates secretory cell fate decisions in the small intestine and colon tumors: insights from transcriptomic, histological, and microbiome analyses.

Lucie Janeckova, Monika Stastna, Dusan Hrckulak, Linda Berkova, Jan Kubovciak, Jakub Onhajzer, Vitezslav Kriz, Stela Dostalikova, Tereza Mullerova, Katerina Vecerkova, Marketa Tenglerova, Stepan Coufal, Klara Kostovcikova, Richard S Blumberg, Dominik Filipp, Konrad Basler, Tomas Valenta, Michal Kolar, Vladimir Korinek.

   BACKGROUND: The canonical Wnt signaling pathway controls the continuous renewal of the intestinal epithelium and the specification of epithelial cell lineages. Tcf4, a nuclear mediator of Wnt signaling, is essential for the differentiation and maintenance of Paneth cells in the small intestine. Its deficiency is associated with reduced expression of key α-defensins, highlighting its role in host-microbe interactions. However, the exact function of Tcf4 in specifying the secretory lineage and its contribution to antimicrobial peptide production remain incompletely understood. Remarkably, α-defensin expression has also been detected in human colon adenomas, where aberrant Wnt signaling is a hallmark. This raises important questions: What is the role of these Paneth-like cells in tumor biology, and how does Tcf4 influence their identity and function?
METHODS: We investigated cell specification in small intestinal crypts and colon tumors using conditional Tcf7l2 deletion, cell type-specific Cre recombinases, and reporter alleles in mice. Transcriptomic (single-cell and bulk RNA sequencing) and histological analyses were performed and complemented by microbiome profiling, antibiotic treatment, and intestinal organoids to functionally validate the main findings.
RESULTS: The inactivation of Tcf4 depletes Paneth cells and antimicrobial peptides, disrupting the gut microbiota balance. In secretory progenitors, loss of Tcf4 shifts differentiation toward goblet cells. In the small intestine, alternative secretory progenitors produce Wnt ligands to support stem cells and epithelial renewal in the absence of Paneth cells. In colon tumors, Paneth-like cells form a tumor cell population, express Wnt ligands, and require Tcf4 for their identity. Loss of Tcf4 redirects their differentiation toward goblet cells.
CONCLUSIONS: Tcf4 controls the balance between Paneth and goblet cells and is essential for antimicrobial peptide production in the small intestine. In colon adenomas, Paneth-like tumor cells drive antimicrobial gene expression and provide Wnt3 ligands, which may have implications for cancer therapy.

Keywords:  Antimicrobial peptides; Colorectal cancer; Intestinal cell lineage; Intestinal crypt; Paneth cells; Single-cell transcriptomics

DOI:  https://doi.org/10.1186/s13287-025-04280-y
Nat Commun. 2025 Apr 17. 16(1): 3669

Peritoneal resident macrophages constitute an immunosuppressive environment in peritoneal metastasized colorectal cancer.

J Saris, A Y F Li Yim, S Bootsma, K J Lenos, R Franco Fernandez, H N Khan, J Verhoeff, D Poel, N M Mrzlikar, L Xiong, M P Schijven, N C T van Grieken, O Kranenburg, M E Wildenberg, A Logiantara, C Jongerius, J J Garcia Vallejo, S S Gisbertz, S Derks, J B Tuynman, G R A M D'Haens, L Vermeulen, J Grootjans.

Patients with peritoneal metastasized colorectal cancer (PM-CRC) have a dismal prognosis. We hypothesized that an immunosuppressive environment in the peritoneal cavity underlies poor prognosis. We define the composition of the human peritoneal immune system (PerIS) using single-cell technologies in 18 patients with- and without PM-CRC, as well as in matched peritoneal metastases (n = 8). Here we show that the PerIS contains abundant immunosuppressive C1Q+VSIG4+ and SPP1+VSIG4+ peritoneal-resident macrophages (PRMs), as well as monocyte-like cavity macrophages (mono-CMs), which share features with tumor-associated macrophages, even in homeostasis. In PM-CRC, expression of immunosuppressive cytokines IL10 and VEGF increases, while simultaneously expression of antigen-presenting molecules decreases in PRMs. These intratumoral suppressive PRMs originate from the PerIS, and intraperitoneal depletion of PRMs in vivo using anti-CSF1R combined with anti-PD1 significantly reduces tumor burden and improves survival. Thus, PRMs define a metastatic site-specific immunosuppressive niche, and targeting PRMs is a promising treatment strategy for PM-CRC.

DOI: https://doi.org/10.1038/s41467-025-58999-6
Cell Rep. 2025 Apr 11. pii: S2211-1247(25)00326-2. [Epub ahead of print]44(4): 115555

THBS2-producing matrix CAFs promote colorectal cancer progression and link to poor prognosis via the CD47-MAPK axis.

Zaoqu Liu, Yuhao Ba, Dan Shan, Xing Zhou, Anning Zuo, Yuyuan Zhang, Hui Xu, Shutong Liu, Benyu Liu, Yanan Zhao, Siyuan Weng, Ruizhi Wang, Jinhai Deng, Peng Luo, Quan Cheng, Xin Hu, Shuaixi Yang, Fubing Wang, Xinwei Han.

  Cancer-associated fibroblasts (CAFs) display significant functional and molecular heterogeneity within the tumor microenvironment, playing diverse roles in cancer progression. Employing single-cell RNA sequencing data of colorectal cancer (CRC), we identified a subset of matrix CAFs (mCAFs) as a critical subtype that secretes THBS2, a molecule linked to advanced cancer stages and poor prognosis. Spatial transcriptomics and multiplex immunohistochemistry revealed clear spatial colocalization between THBS2-producing mCAFs and tumor cells. Mechanically, CAF-secreted THBS2 binds to CD47 on tumor cells, triggering the MAPK/ERK5 signaling pathway, which enhances tumor progression. The tumor-promoting role of THBS2 was further validated using fibroblast-specific THBS2 knockout mice, patient-derived organoids, and xenografts. Moreover, the transcription factor CREB3L1 was identified as a regulator of the transformation of normal fibroblasts into THBS2-producing mCAFs. These findings underscore the pivotal role of THBS2 in CRC progression and highlight the therapeutic potential of targeting the THBS2-CD47 axis and CREB3L1 in CRC.

Keywords:  CAFs; CP: Cancer; THBS2; colorectal cancer; mCAF; prognosis

DOI:  https://doi.org/10.1016/j.celrep.2025.115555
Nat Commun. 2025 Apr 16. 16(1): 3605

Targeting PLK1-CBX8-GPX4 axis overcomes BRAF/EGFR inhibitor resistance in BRAFV600E colorectal cancer via ferroptosis.

Zhan Zhao, Jiashuai He, Shenghui Qiu, Lu Wang, Shuchen Huangfu, Yangzhi Hu, Qing Wu, Yabing Yang, Xiaobo Li, Maohua Huang, Shijin Liu, Hanyang Guan, Zuyang Chen, Xiangwei Zhang, Yiran Zhang, Hui Ding, Xiaoxu Zhao, Guandi Xiao, Yunlong Pan, Tongzheng Liu, Yanping Wu, Jinghua Pan.

Metastatic BRAFV600E colorectal cancer (CRC) confers poor prognosis and represents a therapeutic bottleneck. To identify resistance mechanisms of the mitogen-activated protein kinase (MAPK) pathway in BRAFV600E CRC, we perform genome-wide CRISPR-Cas9 screening and discover that targeting glutathione peroxidase 4 (GPX4) overcomes resistance to BRAF inhibitor (BRAFi) combined with or without epidermal growth factor receptor inhibitor (EGFRi) in BRAFV600E CRC. Specifically, BRAFi ± EGFRi upregulates GPX4 expression, which antagonizes therapy-induced ferroptosis. Moreover, polo-like kinase 1 (PLK1) substrate activation promotes PLK1 translocation to the nucleus, activating chromobox protein homolog 8 (CBX8) phosphorylation at Ser265 to drives GPX4 expression. Targeting PLK1 enhances BRAFi ± EGFRi inhibition and triggers ferroptosis in vitro, vivo, organoid, and patient-derived xenograft model. Collectively, we demonstrate a PLK1-CBX8-GPX4 signaling axis that relays the ferroptosis mechanism of therapeutic resistance and propose a clinically actionable strategy to overcome BRAFi ± EGFRi resistance in BRAFV600E CRC.

DOI: https://doi.org/10.1038/s41467-025-58992-z
Mol Carcinog. 2025 Apr 16.

Therapeutic Targeting of the Pentose Phosphate Pathway in Colorectal Cancer Using 6-Aminonicotinamide and 5-Fluorouracil.

Israa Ahmad Cheikh, Berthe Hayar, Noorhan Ghanem, Lara Al Saleh, Chirine El-Baba, Sadaf Al-Hadeethi, Riyad El-Khoury, Julnar Usta, Nadine Darwiche.

  Colorectal cancer (CRC) is a significant global health concern with rising incidence and mortality rates. 5-Fluorouracil (5-FU) is the standard chemotherapy for CRC but is often constrained by resistance and toxicity, highlighting the need for more efficient treatments. The pentose phosphate pathway (PPP), a glucose metabolic shunt, is significantly upregulated in CRC to support nucleotide synthesis and redox balance. Therefore, we hypothesized that targeting the PPP decreases CRC cell growth, reduces tumor progression, and improves 5-FU therapy. Consequently, we investigated the anti-tumor activities, cell death mechanism, and mode of action of the PPP inhibitor, 6-aminonicotinamide (6-AN), and 5-FU alone or in combination against CRC. We used human CRC cell lines with different p53 and 5-FU resistance statuses and a CRC xenograft model. Our findings show that 6-AN reduced the viability of human CRC cells independently of their p53 and 5-FU resistance profile, with its effect further enhanced in combination with 5-FU. The 6-AN/5-FU combination treatment synergized by reducing the total dehydrogenase activity of the PPP, inducing oxidative stress, and promoting senescence in CRC cells. Furthermore, 6-AN treatment significantly decreased tumor growth in a CRC xenograft mouse model. However, combining 6-AN with 5-FU did not reduce tumor volume significantly, highlighting the complexities of translating in vitro findings to animal models. These results suggest that interfering with the PPP activity suppresses CRC cell growth and may reduce 5-FU resistance. This study underscores targeting cancer metabolism as a novel therapeutic strategy to minimize drug resistance and to improve CRC therapeutic outcomes.

Keywords:  5‐fluorouracil; 6‐aminonicotinamide; cancer therapy; colorectal cancer; pentose phosphate pathway

DOI:  https://doi.org/10.1002/mc.23920
Cell Death Dis. 2025 Apr 14. 16(1): 293

Peroxisomal membrane protein PMP70 confers drug resistance in colorectal cancer.

Jinwen Yin, Yu Shao, Fengxing Huang, Yuntian Hong, Wanhui Wei, Congqing Jiang, Qiu Zhao, Lan Liu.

Metabolic reprogramming is a key contributor to cancer therapeutic resistance. Peroxisomes are highly metabolic organelles essential for lipid metabolism and reactive oxygen species (ROS) turnover. Recent studies pointed out that targeting peroxisomal genes could be a promising strategy for treating therapy-resistant cells. However, the role of peroxisomes in CRC chemoresistance remains largely unexplored. This study aimed to investigate the function of peroxisomes in CRC chemoresistance and uncover the underlying mechanisms. Our results showed that the protein level of peroxisome marker PMP70 was strongly correlated with oxaliplatin (LOHP)-treated tumor recurrence in CRC. LOHP was confirmed to induce pexophagy in CRC cells, whereas LOHP-resistant cells maintained stable peroxisome levels and resisted this selective autophagy. Moreover, depletion of PMP70 significantly reduced the viability of resistant CRC cells in response to LOHP, both in vitro and in vivo. Mechanistically, PMP70 acted as a potential protector against excessive lipid peroxidation (LPO) in PMP70High and LOHP-resistant CRC cells. Additionally, PMP70-depleted cells exhibited an altered metabolic profile, characterized by reduced neutral lipids, fewer lipid droplets (LDs), and cell cycle arrest, indicating that PMP70 downregulation resulted in metabolic impairment. In conclusion, our study unveiled the pivotal role of PMP70-mediated peroxisomal functions in conferring chemoresistance, particularly in the context of LOHP resistance in CRC.

DOI: https://doi.org/10.1038/s41419-025-07572-6
Cell Death Dis. 2025 Apr 13. 16(1): 290

Rap2B drives tumorigenesis and progression of colorectal cancer through intestinal cytoskeleton remodeling.

Jiehui Di, Zhongjun Zhao, Mingyi Xia, Keyu Gao, Keli Chai, Bao Zhu, Wanping Sun, Yanping Zhang, Junnian Zheng, Yong Liu.

Ras family protein plays a key role in transducing signals involved in cytoskeletal remodeling and cell adhesion, which are particularly important in the development of colorectal cancer (CRC). While Rap2B, a member of the Ras superfamily, has been linked to cancer malignancy in vitro, its exact role in tumorigenesis remains unclear. In this study, we demonstrated that intestine-specific knockout of Rap2B suppresses the initiation and progression of CRC. Mechanistically, Rap2B interacts with plectin and enhances its expression, which in turn inhibits plectin-mediated F-actin assembly. Deletion of Rap2B resulted in a remodeling of the intestinal cytoskeleton, leading to reduced tumorigenesis and diminished metastatic potential. Clinically, there is a positive correlation between the expression levels of Rap2B and plectin in human CRC tissues, and higher levels of Rap2B and plectin predicting poorer clinical outcome in CRC patients. These findings underscore a critical role of Rap2B in CRC progression and highlight its potential as a therapeutic target.

DOI: https://doi.org/10.1038/s41419-025-07627-8
BMC Biol. 2025 Apr 16. 23(1): 100

Colorectal cancer progression to metastasis is associated with dynamic genome-wide biphasic 5-hydroxymethylcytosine accumulation.

Ben Murcott, Floris Honig, Dominic Oliver Halliwell, Yuan Tian, James Lawrence Robson, Piotr Manasterski, Jennifer Pinnell, Thérèse Dix-Peek, Santiago Uribe-Lewis, Ashraf E K Ibrahim, Julia Sero, David Gurevich, Nikolas Nikolaou, Adele Murrell.

   BACKGROUND: Colorectal cancer (CRC) progression from adenoma to adenocarcinoma is associated with global reduction in 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). DNA hypomethylation continues upon liver metastasis. Here we examine 5hmC changes upon progression to liver metastasis.
RESULTS: 5hmC is increased in metastatic liver tissue relative to the primary colon tumour and expression of TET2 and TET3 is negatively correlated with risk for metastasis in patients with CRC. Genes associated with increased 5-hydroxymethylcytosine show KEGG enrichment for adherens junctions, cytoskeleton and cell migration around a core cadherin (CDH2) network. Overall, the 5-hydroxymethylcyosine profile in the liver metastasis is similar to normal colon appearing to recover at many loci where it was originally present in normal colon and then spreading to adjacent sites. The underlying sequences at the recover and spread regions are enriched for SALL4, ZNF770, ZNF121 and PAX5 transcription factor binding sites. Finally, we show in a zebrafish migration assay using SW480 CRISPR-engineered TET knockout and rescue cells that reduced TET expression leads to a reduced migration frequency.
CONCLUSIONS: Together these results suggest a biphasic trajectory for 5-hydroxymethyation dynamics that has bearing on potential therapeutic interventions aimed at manipulating 5-hydroxymethylcytosine levels.

Keywords:  5-Hydroxymethylcytosine; Colorectal cancer progression to metastasis; Epigenetics; Ten-eleven-translocation (TET); Zebrafish assay

DOI:  https://doi.org/10.1186/s12915-025-02205-y
Cancer Lett. 2025 Apr 12. pii: S0304-3835(25)00252-6. [Epub ahead of print] 217686

Colorectal cancer peritoneal metastasis is promoted by tissue-specific fibroblasts that can arise in response to various local disorders.

Cristiano Ramos, Natalie Walterskirchen, Viktoria Knöbl, Chiara Zotter, Catharina Müller, Vasileios Gerakopoulos, Anna Rauch, Lena Falk, Monika Sachet, Edoardo D'Angelo, Marco Agostini, Dietmar Pils, Stefanie Aust, Michael Grusch, Rebecca Herzog, Klaus Kratochwill, Solange Le Blanc, Kristiaan J Lenos, Louis Vermeulen, Stefan Riss, Thomas Bachleitner-Hofmann, Oliver Strobel, Helmut Dolznig, Michael Bergmann, Christine Brostjan, Lukas W Unger, Rudolf Oehler.

  Peritoneal membrane injury induces the activation of local fibroblasts and tissue remodelling, which ultimately can progress to fibrosis. Metastasis of colorectal cancer (CRC) to the abdominal cavity results in such peritoneal damage. Patients with colorectal cancer peritoneal metastasis (CPM) have a particularly poor prognosis, and CPM tumours are characterised by a high infiltration of fibroblasts. Here, we characterised the molecular and functional features of these fibroblasts, and investigated their interaction with other cells in the peritoneal microenvironment. Primary fibroblasts were isolated from 89 patients with different malignant and benign disorders of the peritoneum. We performed comprehensive analyses of single-cell and transcriptome profiling, secretome characterization, and functional enzymatic activity. We were able to identify a peritoneum-specific fibroblast population that increases in response to different types of damage-inducing peritoneal pathologies, including metastasis. These fibroblasts are characterised by the IGFBP2-dependent expression of CD38, which mediates extracellular non-canonical adenosinergic activity and contributes to the suppression of macrophages and T cells. Importantly, peritoneal fibroblasts promoted the growth and invasiveness of tumour cells in a xenograft mouse model of peritoneal metastasis, highlighting their pro-tumorigenic role. Their specific gene signature was associated with poor prognosis in a dataset of 51 patients suffering from colorectal peritoneal metastasis. This study revealed that the CPM is infiltrated by a peritoneal fibroblast subtype, which is absent in healthy tissue, but also observed in benign peritoneal diseases. Given the limited therapeutic options for these patients, these pro-tumorigenic peritoneal fibroblasts could represent an attractive target for inhibiting the peritoneal spread of tumour cells.

Keywords:  CD38; Cancer associated fibroblasts; Colorectal cancer; IGFBP2; Peritoneal environment; Peritoneal metastasis; Tumour immunology

DOI:  https://doi.org/10.1016/j.canlet.2025.217686
Mol Biol Rep. 2025 Apr 15. 52(1): 394

FADS2 inhibits colorectal cancer cell proliferation by regulating ferroptosis through SLC7A11/GPX4.

Qinghui Yang, Hao Zhang, Jing Luo, Hongmei Yu, Xiaodi Yang, Chen Wang.

   BACKGROUND: Colorectal cancer (CRC) is a leading factor in cancer mortality globally. Ferroptosis, a regulated cell death described via lipid peroxidation, is crucial in cancer biology. This study explores the link between ferroptosis, FADS2, and CRC, focusing on the prognostic significance and therapeutic potential of targeting FADS2.
METHODS: The differential expression analysis of the Cancer Genome Atlas-colon adenocarcinoma (TCGA-COAD) and GSE36400 datasets was conducted to determine key ferroptosis-related genes, followed by functional enrichment analysis. Prognosis-related genes were assessed utilizing Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression. Genetic variation analysis and immune analysis were employed to evaluate the clinical significance of FADS2. The impacts of FADS2 knockdown on CRC cell migration, proliferation, invasion, and ferroptosis were evaluated by in vitro cell experiments.
RESULTS: 64 key ferroptosis-related genes in CRC were highly enriched in pathways such as glutathione metabolism and peroxisome. Eleven prognosis-associated genes were identified, with TP53 showing the highest mutation frequency. High FADS2 expression was linked to poorer prognosis and higher immune cell infiltration. FADS2 knockdown significantly decreased glutathione (GSH) levels, SLC7A11, and GPX4 expression, increased malondialdehyde (MDA) levels, indicating the promotion of ferroptosis. Functional tests revealed knockdown FADS2 repressed CRC cell proliferation, migration, and invasion. SLC7A11 or GPX4 overexpression partially rescued the effects of FADS2 knockdown. Additionally, FADS2 knockdown enhances the chemosensitivity of CRC cells to oxaliplatin.
CONCLUSION: FADS2 is essential for encouraging CRC cell proliferation and tumor growth by preventing ferroptosis. Targeting FADS2 may enhance ferroptosis and suppress CRC progression, offering a possible course of treatment for CRC patients. The knockdown of FADS2 enhances the chemosensitivity of CRC cells to oxaliplatin, providing valuable insights for future clinical applications.

Keywords:   FADS2 ; Cell proliferation; Colorectal cancer; Ferroptosis; Prognosis

DOI:  https://doi.org/10.1007/s11033-025-10395-5
Nat Commun. 2025 Apr 17. 16(1): 3653

Hypoxia-induced Wnt5a-secreting fibroblasts promote colon cancer progression.

Akikazu Harada, Yoshiaki Yasumizu, Takeshi Harada, Katsumi Fumoto, Akira Sato, Natsumi Maehara, Ryota Sada, Shinji Matsumoto, Takashi Nishina, Kiyoshi Takeda, Eiichi Morii, Hisako Kayama, Akira Kikuchi.

Wnt5a, a representative Wnt ligand that activates the β-catenin-independent pathway, has been shown to promote tumorigenesis. However, it is unclear where Wnt5a is produced and how it affects colon cancer aggressiveness. In this study, we demonstrate that Wnt5a is expressed in fibroblasts near the luminal side of the tumor, and its depletion suppresses mouse colon cancer formation. To characterize the specific fibroblast subtype, a meta-analysis of human and mouse colon fibroblast single-cell RNA-seq data is performed. The results show that Wnt5a is expressed in hypoxia-induced inflammatory fibroblast (InfFib), accompanied by the activation of HIF2. Moreover, Wnt5a maintains InfFib through the suppression of angiogenesis mediated by soluble VEGF receptor1 (Flt1) secretion from endothelial cells, thereby inducing further hypoxia. InfFib also produces epiregulin, which promotes colon cancer growth. Here, we show that Wnt5a acts on endothelial cells, inducing a hypoxic environment that maintains InfFib, thereby contributing to colon cancer progression through InfFib.

DOI: https://doi.org/10.1038/s41467-025-58748-9
Lancet Gastroenterol Hepatol. 2025 May;pii: S2468-1253(25)00107-4. [Epub ahead of print]10(5): 417

Early-onset colorectal cancer: Hollyoaks tackles taboos and raises awareness.

Joe Moody.

DOI: https://doi.org/10.1016/S2468-1253(25)00107-4
Nat Chem Biol. 2025 Apr 16.

Cholesterol-targeting Wnt-β-catenin signaling inhibitors for colorectal cancer.

Ashutosh Sharma, Julian Zalejski, Shruti Vijay Bendre, Simona Kavrokova, Hale Siir Hasdemir, Defne Gorgun Ozgulbas, Jiachen Sun, Koralege C Pathmasiri, Ruicheng Shi, Ahmed Aloulou, Kyli Berkley, Charles F Delisle, Young Wang, Erin Weisser, Pawanthi Buweneka, Dominick Pierre-Jacques, Sayandeb Mukherjee, Diana A Abbasi, Daesung Lee, Bo Wang, Vladimir Gevorgyan, Stephanie M Cologna, Emad Tajkhorshid, Erik R Nelson, Wonhwa Cho.

Most persons with colorectal cancer (CRC) carry adenomatous polyposis coli (APC) truncation leading to aberrant Wnt-β-catenin signaling; however, effective targeted therapy for them is lacking as the mechanism by which APC truncation drives CRC remains elusive. Here, we report that the cholesterol level in the inner leaflet of the plasma membrane (IPM) is elevated in all tested APC-truncated CRC cells, driving Wnt-independent formation of Wnt signalosomes through Dishevelled (Dvl)-cholesterol interaction. Cholesterol-Dvl interaction inhibitors potently blocked β-catenin signaling in APC-truncated CRC cells and suppressed their viability. Because of low IPM cholesterol level and low Dvl expression and dependence, normal cells including primary colon epithelial cells were not sensitive to these inhibitors. In vivo testing with a xenograft mouse model showed that our inhibitors effectively suppressed truncated APC-driven tumors without causing intestinal toxicity. Collectively, these results suggest that the most common type of CRC could be effectively and safely treated by blocking the cholesterol-Dvl-β-catenin signaling axis.

DOI: https://doi.org/10.1038/s41589-025-01870-y
Mol Cancer. 2025 Apr 16. 24(1): 116

ADAR1-high tumor-associated macrophages induce drug resistance and are therapeutic targets in colorectal cancer.

Hibiki Umeda, Kunitoshi Shigeyasu, Toshiaki Takahashi, Kazuya Moriwake, Yoshitaka Kondo, Kazuhiro Yoshida, Sho Takeda, Shuya Yano, Yuki Matsumi, Hiroyuki Kishimoto, Tomokazu Fuji, Kazuya Yasui, Hideki Yamamoto, Kosei Takagi, Masashi Kayano, Hiroyuki Michiue, Keiichiro Nakamura, Yoshiko Mori, Fuminori Teraishi, Hiroshi Tazawa, Yuzo Umeda, Shunsuke Kagawa, Ajay Goel, Toshiyoshi Fujiwara.

   BACKGROUND: Colorectal cancer (CRC) is considered the third most common type of cancer worldwide. Tumor-associated macrophages (TAMs) have been shown to promote drug resistance. Adenosine-to-inosine RNA-editing, as regulated by adenosine deaminase acting on RNA (ADAR), is a process that induces the posttranscriptional modification of critical oncogenes. The aim of this study is to determine whether the signals from cancer cells would induce RNA-editing in macrophages.
METHODS: The effects of RNA-editing on phenotypes in macrophages were analyzed using clinical samples and in vitro and in vivo models.
RESULTS: The intensity of the RNA-editing enzyme ADAR1 (Adenosine deaminase acting on RNA 1) in cancer and mononuclear cells indicated a strong positive correlation between the nucleus and cytoplasm. The ADAR1-positive mononuclear cells were positive for CD68 and CD163, a marker for M2 macrophages. Cancer cells transport pro-inflammatory cytokines or ADAR1 protein directly to macrophages via the exosomes, promoting RNA-editing in AZIN1 (Antizyme Inhibitor 1) and GLI1 (Glioma-Associated Oncogene Homolog 1) and resulting in M2 macrophage polarization. GLI1 RNA-editing in the macrophages induced by cancer cells promotes the secretion of SPP1, which is supplied to the cancer cells. This activates the NFκB pathway in cancer cells, promoting oxaliplatin resistance. When the JAK inhibitors were administered, oncogenic RNA-editing in the macrophages was suppressed. This altered the macrophage polarization from M2 to M1 and decreased oxaliplatin resistance in cancer cells.
CONCLUSIONS: This study revealed that ADAR1-high TAMs are crucial in regulating drug resistance in CRC and that targeting ADAR1 in TAMs could be a promising treatment approach for overcoming drug resistance in CRC.

Keywords:  Biomarker; Chemoresistance; Colorectal cancer; Macrophage; RNA-editing

DOI:  https://doi.org/10.1186/s12943-025-02312-y
Front Immunol. 2025 ;16 1560322

Cuproptosis-related gene ACAD8 inhibits the metastatic ability of colorectal cancer by inducing cuproptosis.

HuiE Zhuang, Yizhen Chen, Sifu Huang.

   Background: Distant metastasis of colorectal cancer (CRC) significantly impacts patient prognosis. Cuproptosis is a new form of copper ion-dependent cell death. However, whether cuproptosis-related genes (CRGs) play a role in the metastatic potential of CRC remains unclear. This study focuses on CRGs-ACAD8 to explore its role and mechanism in metastatic CRC (mCRC).
Methods: Clinical sample data from TCGA, GEO, and Fujian Provincial Hospital patients were integrated to analyze ACAD8 expression and its association with the diagnosis and prognosis of CRC. Small interfering RNA, immunohistochemistry, colony formation, wound-healing assays and so on were used to evaluate the biological functions of ACAD8. Bioinformatics was applied to investigate its relationships with immune infiltration, chemotherapy sensitivity, and signaling pathways.
Results: ACAD8 expression was significantly reduced in mCRC and demonstrated excellent diagnostic performance. Patients with high ACAD8 expression had significantly better survival. ACAD8 was closely associated with immune cell infiltration, and enhanced chemotherapy sensitivity. Pathway enrichment analysis suggested that ACAD8 might inhibit the metastasis of CRC by regulating pathways such as response to metal ions and tight junction organization. Finally, experiments confirmed a positive correlation between copper levels and ACAD8 mRNA expression, with CuCl2 upregulating ACAD8 expression. Knockdown of ACAD8 induced cuproptosis. CuCl2 inhibited the proliferation, stemness, and migratory abilities of CRC cells, while si ACAD8 attenuated these effects. Moreover, CuCl2 enhanced the sensitivity of CRC cells to oxaliplatin and 5-fluorouracil, whereas si ACAD8 diminished this chemosensitizing effect.
Conclusion: As a novel tumor suppressor, low expression of CRGs-ACAD8 is associated with the metastasis of CRC. ACAD8 holds potential diagnostic and prognostic value and may contribute to the precise treatment of CRC by regulating immune infiltration and chemotherapy sensitivity.

Keywords:  ACAD8; colorectal cancer; cuproptosis; distant metastasis; immunotherapy

DOI:  https://doi.org/10.3389/fimmu.2025.1560322
Life Sci. 2025 Apr 16. pii: S0024-3205(25)00277-2. [Epub ahead of print] 123642

ARID3A inhibits colorectal cancer cell stemness and drug-resistance by targeting a multitude of stemness-associated genes.

Tamal Kanti Gope, Debankur Pal, Amit Kumar Srivastava, Bilash Chatterjee, Subhankar Bose, Rupasri Ain.

   AIMS: ARID3A is highly expressed in CRC patients. However, the functional role of ARID3A in CRC remains unexplored. We sought to demonstrate ARID3A function in CRC.
MATERIALS AND METHODS: ARID3A was knocked-down using lentiviruses harboring shRNA. CRC patients' tissue cDNA array was used to assess expression of ARID3A. Effect of ARID3A on CSC-associated genes was analysed using real-time PCR array. Western-blot analysis and ChIP assay were used to validate the role of ARID3A. Paclitaxel-resistant CSC-enriched cell population was used to assess correlation between ARID3A, stemness and drug resistance potential. Ex vivo findings were corroborated on preclinical mouse model.
KEY FINDINGS: ARID3A expression was significantly higher throughout CRC stages than normal individuals. ARID3A expression was significantly higher in the aggressive CRC cell line HCT116 compared to HT29, which expressed higher levels of CD44, CD133, and EpCAM, suggesting a reciprocal relationship between ARID3A expression and CRC stemness. Real-time PCR-based stem cell array using ARID3A-knockdown HCT116 cells showed upregulation of 9 cancer stem cell (CSC)-associated genes. ChIP-assay verified binding of ARID3A on transcriptionally active promoter regions of CSC associated genes. ARID3A depletion led to enhanced proliferation, anchorage-independent growth, and ABCG2 upregulation in HCT116 cells. In paclitaxel-resistant HCT116 cells, ARID3A expression was dampened, whereas, CD44 and CD133 increased. ARID3A knockdown accelerated tumor growth and promoted larger tumor formation in nude-mouse xenograft model. Ki67, CD44 and CD133 were highly upregulated in knockdown tumors.
SIGNIFICANCE: This study demonstrated that ARID3A inhibits CRC stemness, anchorage-independent growth, self-renewal, anti-cancer drug resistance of CRC cells and tumor growth in vivo.

Keywords:  CD133; CRC; Cancer stem cell; Drug-resistance; Paclitaxel; Xenograft

DOI:  https://doi.org/10.1016/j.lfs.2025.123642
BMC Cancer. 2025 Apr 17. 25(1): 716

GLUT1 inhibition by BAY-876 induces metabolic changes and cell death in human colorectal cancer cells.

Masato Hayashi, Keishi Nakamura, Shinichi Harada, Mariko Tanaka, Akiko Kobayashi, Hiroto Saito, Toshikatsu Tsuji, Daisuke Yamamoto, Hideki Moriyama, Jun Kinoshita, Noriyuki Inaki.

   BACKGROUND: Glucose transporter 1 (GLUT1) is known to play a crucial role in glucose uptake in malignant tumors. GLUT1 inhibitors reportedly exhibit anti-tumor effects by suppressing cancer cell proliferation. BAY-876, a selective GLUT1 inhibitor, has been shown to inhibit tumor growth in ovarian and breast cancers. In this study, we investigated the anti-proliferative effects of BAY-876 treatment in human colorectal cancer (CRC) cell lines.
METHODS: We investigated the metabolic changes and effects on proliferation from BAY-876 treatment in HCT116, DLD1, COLO205, LoVo, and Caco-2 cells in vitro. Additionally, a mouse xenograft model was established using HCT116 cells to examine the tumor-inhibitory effects of BAY-876 treatment in vivo.
RESULTS: BAY-876 treatment inhibited cell proliferation in HCT116, DLD1, COLO205, and LoVo cells. Reduced GLUT1 protein expression levels were observed through western blot analysis. Flux analysis indicated enhanced mitochondrial respiration, accompanied by increased reactive oxygen species levels and apoptosis rates. Tumor-inhibitory effects were also observed in the xenograft model, with the BAY-876-treated groups showing GLUT1 suppression.
CONCLUSIONS: BAY-876 treatment induced metabolic changes and inhibited cell proliferation in human CRC cell lines. Using BAY-876 is a potential novel approach for treating CRC.

Keywords:  Apoptosis; BAY-876; Colorectal cancer; Glucose transporter 1

DOI:  https://doi.org/10.1186/s12885-025-14141-9