bims-instec 2025-01-26 papers

bims-instec

Biomed News

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

Issue of 2025–01–26
fifteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

A Multipotent PROX1+ Tumor Stem/Progenitor Cell Population Emerges During Intestinal Tumorigenesis and Mediates Radioresistance in Colorectal Cancer.
Plasticity in metastatic colorectal cancer.
Necrotizing enterocolitis causes increased ileal goblet cell loss in Wnt2b KO mice.
Protocol for generating liver metastasis microtissues to decipher cellular interactions between metastatic intestinal cancer and liver tissue.
Targeting FABP4/UCP2 axis to overcome cetuximab resistance in obesity-driven CRC with drug-tolerant persister cells.
A constitutive interferon-high immunophenotype defines response to immunotherapy in colorectal cancer.
Omega-3 Docosahexaenoic Acid as a Promising Inducer of Ferroptosis: Dynamics of Action in Prostate and Colorectal Cancer Models.
WFDC3 sensitizes colorectal cancer to chemotherapy by regulating ATM/ATR kinase signaling pathway.
Motif distribution and DNA methylation underlie distinct Cdx2 binding during development and homeostasis.
The role of ferroptosis in colorectal cancer and its potential synergy with immunotherapy.
Consensus molecular subtyping of colorectal carcinoma brain metastases reveals a metabolic signature associated with poor patient survival.
Comprehensive single-cell atlas of colorectal neuroendocrine tumors with liver metastases: unraveling tumor microenvironment heterogeneity between primary lesions and metastases.
Disruption of lipid raft reverses drug resistance in colorectal cancer cells through the phosphatase and tensin homolog/phosphoinositide 3-kinase/protein kinase B pathway and P-glycoprotein.
Impaired oxidative phosphorylation drives primary tumor escape and metastasis.
ACOX1 activates autophagy via the ROS/mTOR pathway to suppress proliferation and migration of colorectal cancer.

Cancer Res. 2025 Jan 22.

A Multipotent PROX1+ Tumor Stem/Progenitor Cell Population Emerges During Intestinal Tumorigenesis and Mediates Radioresistance in Colorectal Cancer.

Pauliina Kallio, Cinzia Bessone, Fatemeh Seyednasrollah, Jefim Brodkin, Marika Lassila, Jenny Högström, Alejandra González-Loyola, Tatiana V Petrova, Caj Haglund, Kari Alitalo.

Colorectal carcinoma (CRC) progression is associated with an increase in PROX1+ tumor cells, which exhibit features of CRC stem cells and contribute to metastasis. Here, we aimed to provide a better understanding to the function of PROX1+ cells in CRC, investigating their progeny and their role in therapy resistance. PROX1+ cells in intestinal adenomas of ApcMin/+ mice expressed intestinal epithelial and CRC stem cell markers, and cells with high PROX1 expression could both self-renew tumor stem/progenitor cells and contribute to differentiated tumor cells. Most PROX1-lineage traced tumor cells were stem/progenitor cells, which can supply cells to multiple intestinal tumor cell lineages, whereas most lineage-traced LGR5+ tumor cells were enterocytes, indicating that PROX1+ and LGR5+ tumor stem cells have distinct differentiation programs. Although the PROX1+ tumor cells proliferated slower than PROX1- cells, irradiation increased the proportion of PROX1+ cells in human CRC cell lines, patient-derived organoids, and tumor xenografts. Furthermore, transcripts related to DNA damage repair (DDR) were enriched in PROX1+ vs. PROX1- cells in adenomas and in CRC tumor cells from patients. Experiments with PROX1 silencing and overexpression indicated that PROX1 expression enhances CRC cell colony formation following irradiation. PROX1 interacted with DDR proteins, including components of non-homologous end-joining (NHEJ) and base excision repair, and inhibition of NHEJ repair led to a decreased proportion of PROX1+ cells following irradiation. In conclusion, PROX1+ cells are irradiation-resistant tumor stem/progenitor cells capable of self-renewal and differentiation. DDR inhibitors could represent a strategy to target the treatment-resistant PROX1+ tumor stem cells.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-1851
Dev Cell. 2025 Jan 20. pii: S1534-5807(24)00757-3. [Epub ahead of print]60(2): 171-173

Plasticity in metastatic colorectal cancer.

Frederick J H Whiting, Trevor A Graham.

Genetic mutations cause colorectal cancer (CRC) initiation, but their contribution to metastasis and therapy resistance is less clear. In a recent issue of Nature, Moorman et al.1 use single-cell transcriptome sequencing to map the changes in cancer cell state (cell phenotypes) that occur through CRC progression.

DOI: https://doi.org/10.1016/j.devcel.2024.12.018
bioRxiv. 2025 Jan 07. pii: 2025.01.07.631715. [Epub ahead of print]

Necrotizing enterocolitis causes increased ileal goblet cell loss in Wnt2b KO mice.

Comfort Adegboye, Chidera Emeonye, Yu-Syuan Wu, Jaedeok Kwon, Luiz Fernando Silva Oliveira, Sathuwarman Raveeniraraj, Amy E O'Connell.

WNT2B is Wnt ligand which is able to support intestinal stem cells (ISC) in culture and support the intestinal epithelium in vivo. We have previously shown that WNT2B is critical for resistance to colitis, but not small intestinal injury, in the adult mouse. WNT2B is thought to coordinate with WNT3 in supporting ISC, and we have also shown that WNT3 expression is low in the early postnatal ileum in mice. Here, we hypothesized that WNT2B may be more critical in the small intestine during early development, and we challenged Wnt2b KO mice and controls with experimental necrotizing enterocolitis (NEC) on postnatal days 5-8. Wnt2b KO mice had similar ileum histology and injury scores to control mice. Molecular analyses showed that Wnt2b KO mice have differences in Lgr5 and Tlr4 expression compared to wild type controls in untreated conditions, but under experimental NEC expression of epithelial markers and inflammatory genes associated with NEC were similar to wild type. Periodic acid Schiff positive cells were lower in the villi of Wnt2b KO mice during NEC, however expression of goblet cell markers was not different compared to wild type mice. We also used an organoid-based NEC model to highlight the epithelium in isolation and also found no impact of WNT2B KO in the setting of NEC. These data further affirm that WNT2B is critical for inflammation responses in the mouse colon, but does not appear to play a major role in the small intestine, no matter the developmental period.

DOI: https://doi.org/10.1101/2025.01.07.631715
STAR Protoc. 2025 Jan 20. pii: S2666-1667(24)00740-8. [Epub ahead of print]6(1): 103575

Protocol for generating liver metastasis microtissues to decipher cellular interactions between metastatic intestinal cancer and liver tissue.

Maria Lamprou, Ana Krotenberg Garcia, Saskia Jacoba Elisabeth Suijkerbuijk.

  Cell competition is a quality control mechanism that promotes elimination of suboptimal cells relative to fitter neighbors. Cancer cells exploit these mechanisms for expansion, but the underlying molecular pathways remain elusive. Here, we present a protocol for generating matrix-free microtissues recapitulating cellular interactions between intestinal cancer and hepatocyte-like cells using microscopy or transcriptomics/proteomics. We describe steps for generating and differentiating liver progenitor organoids and microtissue formation. We then detail procedures for immunofluorescence staining, mounting microtissues, and sorting cells. For complete details on the use and execution of this protocol, please refer to Krotenberg Garcia et al.1.

Keywords:  Cancer; Microscopy; Organoids

DOI:  https://doi.org/10.1016/j.xpro.2024.103575
Transl Oncol. 2025 Jan 16. pii: S1936-5233(25)00005-1. [Epub ahead of print]53 102274

Targeting FABP4/UCP2 axis to overcome cetuximab resistance in obesity-driven CRC with drug-tolerant persister cells.

Yi-Chiao Cheng, Ming-Yao Chen, Vijesh Kumar Yadav, Narpati Wesa Pikatan, Iat-Hang Fong, Kuang-Tai Kuo, Chi-Tai Yeh, Jo-Ting Tsai.

  Colorectal cancer (CRC) is closely linked to obesity, a condition that significantly impacts tumor progression and therapeutic resistance. Although cetuximab, an EGFR-targeting monoclonal antibody, is a cornerstone in metastatic CRC treatment, resistance often emerges, leading to poor outcomes. This study investigated the role of drug-tolerant persister (DTP) cells and their metabolic interactions within the tumor microenvironment (TME) in cetuximab resistance. Using patient-derived organoids and in vivo models, we identified the FABP4/UCP2 axis as a critical mediator of resistance. Organoids derived from cetuximab non-responders revealed upregulated FABP4 and UCP2 expression post-treatment. Coculture experiments with adipocytes showed that FABP4 and UCP2 promote lipid metabolic reprogramming, facilitating cancer cell survival in a dormant state. CRISPR/Cas9 mediated inhibition of FABP4 disrupted this metabolic interaction, sensitising resistant cells to cetuximab. In vivo, the FABP4 inhibitor BMS309403, either alone or in combination with cetuximab, significantly reduced tumor growth in resistant CRC models, highlighting its therapeutic potential. These findings establish the FABP4/UCP2 axis as a pivotal driver of cetuximab resistance in obesity-associated CRC and suggest that targeting this metabolic pathway could improve outcomes in DTP-resistant CRC patients.

Keywords:  Adipocytes; Cetuximab resistance; Colorectal cancer; Drug-tolerant persister cells; FABP4/UCP2 Axis; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.tranon.2025.102274
Cancer Cell. 2025 Jan 13. pii: S1535-6108(24)00483-5. [Epub ahead of print]

A constitutive interferon-high immunophenotype defines response to immunotherapy in colorectal cancer.

Amelia Acha-Sagredo, Pietro Andrei, Kalum Clayton, Emma Taggart, Carlotta Antoniotti, Chloé A Woodman, Hassnae Afrache, Constance Fourny, Maria Armero, Hafsa Kaja Moinudeen, Mary Green, Nisha Bhardwaj, Anna Mikolajczak, Maria Rodriguez-Lopez, Marg Crawford, Emma Connick, Steven Lim, Philip Hobson, Josep Linares, Ekaterina Ignatova, Diana Pelka, Elizabeth C Smyth, Nikolaos Diamantis, Dominika Sosnowska, Martina Carullo, Paolo Ciraci, Francesca Bergamo, Rossana Intini, Emma Nye, Patricia Barral, Michele Mishto, James N Arnold, Sara Lonardi, Chiara Cremolini, Elisa Fontana, Manuel Rodriguez-Justo, Francesca D Ciccarelli.

  Fewer than 50% of metastatic deficient mismatch repair (dMMR) colorectal cancer (CRC) patients respond to immune checkpoint inhibition (ICI). Identifying and expanding this patient population remains a pressing clinical need. Here, we report that an interferon-high immunophenotype locally enriched in cytotoxic lymphocytes and antigen-presenting macrophages is required for response. This immunophenotype is not exclusive to dMMR CRCs but comprises a subset of MMR proficient (pMMR) CRCs. Single-cell spatial analysis and in vitro cell co-cultures indicate that interferon-producing cytotoxic T cells induce overexpression of antigen presentation in adjacent macrophages and tumor cells, including MHC class II invariant chain CD74. dMMR CRCs expressing high levels of CD74 respond to ICI and a subset of CD74 high pMMR CRC patients show better progression free survival when treated with ICI. Therefore, CD74 abundance can identify the constitutive interferon-high immunophenotype determining clinical benefit in CRC, independently of tumor mutational burden or MMR status.

Keywords:  CD74; antigen presentation; colorectal cancer; immunotherapy; interferon; marker of response; patient stratification; spatial transcriptomics; tumor immune microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2024.12.008
Dokl Biochem Biophys. 2025 Jan 22.

Omega-3 Docosahexaenoic Acid as a Promising Inducer of Ferroptosis: Dynamics of Action in Prostate and Colorectal Cancer Models.

D M Olkhovik, M O Silkina, A V Razumovskaya, K V Klycheva, A A Fatkulin, T A Kulagin, S V Nikulin.

  Ferroptosis is an iron-dependent form of programmed cell death (PCD) associated with lipid membrane peroxidation. It has gained attention in cancer research because some tumor cells that are resistant to other forms of PCD are sensitive to ferroptosis. Despite the significant amount of research on ferroptosis, the list of known inducers remains limited, creating opportunities to discover new compounds with clinical potential. Recent studies have shown that long-chain polyunsaturated fatty acids, such as omega-3 docosahexaenoic acid (DHA), can function as ferroptosis inducers. In this study, we examined the kinetics of ferroptosis in prostate and colorectal cancer cells under the influence of erastin and DHA. Differences in the kinetics and mechanisms of action were observed. Moreover, cells resistant to erastin were found to be sensitive to DHA, confirming the potential of further research into its use as an anticancer agent.

Keywords:  colorectal cancer; ferroptosis; omega-3 polyunsaturated fatty acids; prostate cancer

DOI:  https://doi.org/10.1134/S160767292460132X
FASEB J. 2025 Jan 31. 39(2): e70329

WFDC3 sensitizes colorectal cancer to chemotherapy by regulating ATM/ATR kinase signaling pathway.

Xinying Yang, Kai Weng, Pu Xing, Jiangbo Chen, Hao Hao, Tianqi Liu, Tongkun Song, Xiaowen Qiao, Yifan Hou, Jie Chen, Yumeng Ran, Lin Song, Bo Chen, Hong Yang, Zaozao Wang, Jiabo Di, Beihai Jiang, Xiangqian Su.

  Chemoresistance is an ongoing challenge for colorectal cancer (CRC) that significantly compromises the anti-tumor efficacy of current drugs. Identifying effective targets or drugs for overcoming chemoresistance is urgently needed. Our previous study showed that WFDC3 served as a tumor suppressor that hindered CRC metastasis. However, the function of WFDC3 in chemotherapy remains unknown. Here, we found that high WFDC3 expression in CRC patients treated with oxaliplatin was associated with a better prognosis. Concordantly, overexpression of WFDC3 significantly increased sensitivity to oxaliplatin in CRC cells, whereas knocking down WFDC3 led to oxaliplatin resistance. In addition, WFDC3 promoted oxaliplatin-mediated suppression of tumor growth in vivo. Subsequently, we found that WFDC3 could enhance oxaliplatin-induced DNA damage through inhibiting ATM/ATR signaling. WFDC3 knockdown showed the opposite effects. Moreover, a combination treatment of oxaliplatin and inhibitors for ATM or ATR partially reversed chemoresistance to oxaliplatin in CRC cells with low WFDC3 expression. Our results demonstrate that WFDC3 is possibly a biomarker for increasing oxaliplatin sensitivity in CRC by modulating ATM/ATR kinase signaling. Thus, a combination of oxaliplatin with an ATM or ATR inhibitor is a potential treatment option for improving CRC outcome.

Keywords:  ATM; ATR; WFDC3; chemotherapy; colorectal cancer; oxaliplatin

DOI:  https://doi.org/10.1096/fj.202402472R
Nat Commun. 2025 Jan 22. 16(1): 929

Motif distribution and DNA methylation underlie distinct Cdx2 binding during development and homeostasis.

Alireza Lorzadeh, George Ye, Sweta Sharma, Unmesh Jadhav.

Transcription factors guide tissue development by binding to developmental stage-specific targets and establishing an appropriate enhancer landscape. In turn, DNA and chromatin modifications direct the genomic binding of transcription factors. However, how transcription factors navigate chromatin features to selectively bind a small subset of all the possible genomic target loci remains poorly understood. Here we show that Cdx2-a lineage defining transcription factor that binds distinct targets in developing versus adult intestinal epithelial cells-has a preferential affinity for a non-canonical CpG-containing motif in vivo. A higher frequency of this motif at embryonic Cdx2 targets and methylated state of the CpG during development enables selective Cdx2 binding and activation of developmental enhancers and genes. In adult cells, demethylation at these enhancers prevents ectopic Cdx2 binding, instead directing Cdx2 to its canonical motif without a CpG. This shift in Cdx2 binding facilitates Ctcf and Hnf4 recruitment, establishing super-enhancers during development and homeostatic enhancers in adult cells, respectively. Induced DNA methylation in adult mouse epithelium or cultured cells recruits Cdx2 to developmental targets, promoting corecruitment of partner transcription factors. Thus, Cdx2's differential CpG motif preferences enable it to navigate distinct DNA methylation profiles, activating genes specific to appropriate developmental stages.

DOI: https://doi.org/10.1038/s41467-025-56187-0
Front Immunol. 2024 ;15 1526749

The role of ferroptosis in colorectal cancer and its potential synergy with immunotherapy.

Wenhua Xia, Yuanhao Lv, Yan Zou, Zhanting Kang, Zhaoyi Li, Jiaqi Tian, Hongyan Zhou, Wei Su, Jiateng Zhong.

  Colorectal cancer (CRC) is one of the most prevalent and deadly malignancies worldwide. Recently, ferroptosis, a novel form of regulated cell death characterized by iron dependency and lipid peroxidation, has garnered significant attention from researchers. The mechanisms underlying ferroptosis, including intracellular iron levels, lipid peroxidation, and antioxidant system regulation, offer new insights into cancer treatment strategies. This study aims to explore the emerging role of ferroptosis in the context of immunotherapy for CRC, highlighting its potential mechanisms and clinical applications. We employed a comprehensive review of current literature to elucidate the biological mechanisms of ferroptosis, its relationship with CRC, and the interplay between ferroptosis and immunotherapy. Ferroptosis reshapes the tumor microenvironment (TME) by regulating intracellular iron levels, lipid metabolism, and antioxidant systems, significantly enhancing the efficacy of immune checkpoint inhibitors (ICIs). Meanwhile, traditional Chinese medicine therapies promote antitumor immunity by modulating the TME and inducing ferroptosis. Additionally, advances in nanotechnology have facilitated precise therapy by enabling targeted delivery of ferroptosis inducers or immunomodulators, transforming "cold" tumors into "hot" tumors and further boosting ICI efficacy. This study comprehensively reviews the latest developments in ferroptosis, immunotherapy, traditional Chinese medicine, and nanotechnology in CRC, highlighting the importance of ferroptosis-related biomarkers and novel inducers for personalized treatment. In summary, ferroptosis offers a promising strategy to overcome CRC therapy resistance and enhance immunotherapy efficacy, warranting further investigation and translational application.

Keywords:  colorectal cancer; ferroptosis; immune checkpoint inhibitors (ICBs); immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1526749
Mol Oncol. 2025 Jan 17.

Consensus molecular subtyping of colorectal carcinoma brain metastases reveals a metabolic signature associated with poor patient survival.

Barnabas Irmer, Darius Wlochowitz, Carolin Krekeler, Katharina Maria Richter, Suganja Chandrabalan, Michaela Bayerlova, Alexander Wolff, Georg Lenz, Lena-Christin Conradi, Hans-Ulrich Schildhaus, Christine Stadelmann, Veit Rohde, Martin Proescholdt, Gabriela Salinas, Kia Homayounfar, Tanja Kuhlmann, Stephan Hailfinger, Tobias Pukrop, Kerstin Menck, Tim Beissbarth, Annalen Bleckmann.

  The transcriptomic classification of primary colorectal cancer (CRC) into distinct consensus molecular subtypes (CMSs) is a well-described strategy for patient stratification. However, the molecular nature of CRC metastases remains poorly investigated. To this end, this study aimed to identify and compare organotropic CMS frequencies in CRC liver and brain metastases. Compared to reported CMS frequencies in primary CRC, liver metastases from CRC patients were CMS4-enriched and CMS3-depleted, whereas brain metastases mainly clustered as CMS3 and rarely as CMS4. Regarding overall survival rates, CMS4 was the most favorable subtype for patients with hepatic lesions, followed by CMS1 and CMS2. The survival of patients with brain metastases did not correlate with CMS. However, we identified a CMS3-related metabolic gene signature, specifically upregulated in central nervous system (CNS)-infiltrating CRC, as a negative prognostic marker and potential tumor progressor. In summary, subtyping of CRC metastases revealed an organotropic CMS distribution in liver and brain with impact on patient survival. CNS-infiltrating CRC samples were enriched for CMS3 and predictive metabolic biomarkers, suggesting metabolic dysregulation of CRC cells as a prerequisite for metastatic colonization of the brain.

Keywords:  CMS; RNA‐sequencing; biomarker; brain metastasis; colorectal cancer; metabolism

DOI:  https://doi.org/10.1002/1878-0261.13748
Mol Cancer. 2025 Jan 21. 24(1): 28

Comprehensive single-cell atlas of colorectal neuroendocrine tumors with liver metastases: unraveling tumor microenvironment heterogeneity between primary lesions and metastases.

Yiqiao Deng, Qichen Chen, Chengyao Guo, Jinghua Chen, Xin Li, Zhiyu Li, Yefan Zhang, Jianjun Zhao, Jianguo Zhou, Jianqiang Cai, Tao Yan, Xiaobing Wang, Xinyu Bi, Zhen Huang, Hong Zhao.

   BACKGROUND: Colorectal neuroendocrine tumors with liver metastases (CRNELM) are associated with a poorer prognosis compared to their nonmetastatic counterparts. A comprehensive understanding of the tumor microenvironment (TME) heterogeneity between primary lesions (PL) and liver metastases (LM) could provide crucial insights for enhancing clinical management strategies for these patients.
METHODS: We utilized single-cell RNA sequencing to analyze fresh tissue samples from CRNELM patients, aiming to elucidate the variations in TME between PL and LM. Complementary multidimensional validation was achieved through spatial transcriptomics, bulk RNA sequencing, and multiplex immunohistochemistry/immunofluorescence.
RESULTS: Our single-cell RNA sequencing analysis revealed that LM harboured a higher proportion of CD8 + T cells, CD4 + T cells, NK cells, NKT cells, and B cells exhibiting a stress-like phenotype compared to PL. RGS5 + pericytes may play a role in the stress-like phenotype observed in immune cells within LM. MCs in PL (PL_MCs) and LM (LM_MCs) exhibit distinct activation of tumor-associated signaling pathways. Notably, COLEC11 + matrix cancer-associated fibroblasts (COLEC11_mCAFs) were found to be significantly associated with LM_MCs. Cell communication analysis unveiled potential targetable receptor-ligand interactions between COLEC11_mCAFs and LM_MCs. Multidimensional validation confirmed the prominence of the characteristic stress-like phenotypes, including HSPA6_CD8_Tstr, HSPA6_NK, and COLEC11_mCAFs in LM. Moreover, a higher abundance of COLEC11_mCAFs correlated with poorer survival rates in the neuroendocrine tumor patient cohort.
CONCLUSION: Overall, our study provides the first single-cell analysis of the cellular and molecular differences between PL and LM in CRNELM patients. We identified distinct cell subsets and receptor-ligand interactions that may drive TME discrepancies and support metastatic tumor growth. These insights highlight potential therapeutic targets and inform strategies for better managing CRNELM patients.

Keywords:  Colorectal neuroendocrine tumour; Heterogeneity; Liver metastases; Single-cell RNA sequence; Spatial transcriptomics; Tumour microenvironment

DOI:  https://doi.org/10.1186/s12943-025-02231-y
Neoplasma. 2024 Dec;pii: 240422N179. [Epub ahead of print]71(6): 571-580

Disruption of lipid raft reverses drug resistance in colorectal cancer cells through the phosphatase and tensin homolog/phosphoinositide 3-kinase/protein kinase B pathway and P-glycoprotein.

Jing Chen, Wei Zheng, Qian Li, RanRan Xu, TingTing Bai, Chao Pan.

Regarding flotillin knockdown, drug resistance is reversed in colorectal cancer (CRC) cell lines; this is associated with the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, as our previous experimental results indicated. However, the exact mechanism underlying this pathway remains unclear. PI3K inhibitor and activator were added separately to clarify the role of the PI3K pathway in reversing drug resistance. The results showed decreased resistance after inhibiting PI3K activity. Furthermore, the reduced resistance due to flotillin knockdown was restored after adding the PI3K activator. Additional results showed no changes in PI3K molecules. However, p-AKT expression was downregulated. Further results suggested that the phosphatidylinositol (3,4,5)-trisphosphate/phosphatidylinositol 4,5-bisphosphate (PIP3/PIP2) ratio was downregulated, whereas the phosphatase and tensin homolog (PTEN) expression was upregulated. In addition, we also found that P-gp activity inhibition resulted in increased adriamycin accumulation and reversal of resistance, and flotillin knockdown was accompanied by a downregulation of P-gp expression in CRC cells. In conclusion, our study demonstrated that flotillin knockdown could reverse drug resistance in CRC cells by downregulating the PTEN/PI3K/AKT pathway and P-gp.

DOI: https://doi.org/10.4149/neo_2024_240422N179
bioRxiv. 2025 Jan 09. pii: 2025.01.08.631936. [Epub ahead of print]

Impaired oxidative phosphorylation drives primary tumor escape and metastasis.

Emily N Arner, Erin Q Jennings, Daniel R Crooks, Christopher J Ricketts, Melissa M Wolf, Matthew A Cottam, Emilie L Fisher-Gupta, Martin Lang, Nunziata Maio, Yuki Shibata, Evan S Krystofiak, Logan M Vlach, Zaid Hatem, Alexander M Blatt, Darren R Heintzman, Allison E Sewell, Emma S Hathaway, KayLee K Steiner, Xiang Ye, Samuel Schaefer, Zachary A Bacigalupa, W Marston Linehan, Kathryn E Beckermann, Frank M Mason, Kamran Idrees, W Kimryn Rathmell, Jeffrey C Rathmell.

Metastasis causes most cancer deaths and reflects transitions from primary tumor escape to seeding and growth at metastatic sites. Epithelial-to-mesenchymal transition (EMT) is important early in metastasis to enable cancer cells to detach from neighboring cells, become migratory, and escape the primary tumor. While different phases of metastasis expose cells to variable nutrient environments and demands, the metabolic requirements and plasticity of each step are uncertain. Here we show that EMT and primary tumor escape are stimulated by disrupted oxidative metabolism. Using Renal Cell Carcinoma (RCC) patient samples, we identified the mitochondrial electron transport inhibitor NDUFA4L2 as upregulated in cells undergoing EMT. Deletion of NDUFA4L2 enhanced oxidative metabolism and prevented EMT and metastasis while NDUFA4L2 overexpression enhanced these processes. Mechanistically, NDUFA4L2 suppressed oxidative phosphorylation and caused citric acid cycle intermediates to accumulate, which modified chromatin accessibility of EMT-related loci to drive primary tumor escape. The effect of impaired mitochondrial metabolism to drive EMT appeared general, as renal cell carcinoma patient tumors driven by fumarate hydratase mutations with disrupted oxidative phosphorylation were highly metastatic and also had robust EMT. These findings highlight the importance of dynamic shifts in metabolism for cell migration and metastasis, with mitochondrial impairment driving early phases of this process. Understanding mitochondrial dynamics may have important implications in both basic and translational efforts to prevent cancer deaths.

DOI: https://doi.org/10.1101/2025.01.08.631936
Sci Rep. 2025 Jan 23. 15(1): 2992

ACOX1 activates autophagy via the ROS/mTOR pathway to suppress proliferation and migration of colorectal cancer.

Bo Shi, Junjie Chen, Haoran Guo, Xinyu Shi, Qingliang Tai, Guoliang Chen, Huihui Yao, Xiuwei Mi, Runze Zhong, Yang Lu, Yiyuan Zhao, Liang Sun, Diyuan Zhou, Yizhou Yao, Songbing He.

  Acyl-CoA oxidase 1 (ACOX1), a member of the acyl-coenzyme A oxidase family, is considered a crucial regulator whose dysregulation is implicated in the occurrence and progression of various cancers. This study aims to elucidate the impact of ACOX1 in CRC, shedding light on its potential as a therapeutic target. Through analysis of the GEO dataset, it was found that ACOX1 is significantly downregulated in colorectal cancer (CRC), and this lower expression level is associated with a worse prognosis. Additionally, in vitro as well as in vivo, ACOX1 overexpression dramatically reduced the proliferation and metastasis of CRC cells. Mass spectrometry revealed the crucial role of ACOX1 in fatty acid β-oxidation, as its overexpression led to a substantial increase in reactive oxygen species (ROS) derived from fatty acid β-oxidation. Further experiments demonstrated that ACOX1 overexpression, through modulation of fatty acid metabolism, increased ROS levels, reduced the phosphorylation activation of the key autophagy regulator mTOR, enhanced autophagy, and ultimately suppressed the growth and metastasis of CRC. In conclusions, ACOX1 expression is decreased in CRC. ACOX1 may regulate autophagy by reprogramming lipid metabolism to modulate the ROS/mTOR signaling pathway, consequently inhibiting the proliferation and migration of CRC.

Keywords:  ACOX1; Autophagy; Colorectal Cancer; ROS; mTOR

DOI:  https://doi.org/10.1038/s41598-025-87728-8