Characterizing the pan-cancer role of exosomal miRNAs in metastasis across cancers
Exosomal microRNAs (exomiRs) play a critical role in intercellular communication, especially in cancer, where they regulate key cellular processes like proliferation, angiogenesis, and metastasis, highlighting their significance as potential diagnostic and therapeutic targets. Here, we aimed to char...
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Elsevier
2025-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037024004483 |
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| author | Piyush Agrawal Gulden Olgun Arashdeep Singh Vishaka Gopalan Sridhar Hannenhalli |
| author_facet | Piyush Agrawal Gulden Olgun Arashdeep Singh Vishaka Gopalan Sridhar Hannenhalli |
| author_sort | Piyush Agrawal |
| collection | DOAJ |
| description | Exosomal microRNAs (exomiRs) play a critical role in intercellular communication, especially in cancer, where they regulate key cellular processes like proliferation, angiogenesis, and metastasis, highlighting their significance as potential diagnostic and therapeutic targets. Here, we aimed to characterize the role of exomiRs, derived from seven cancer types (four cell lines and three tumors), in influencing the pre-metastatic niche (PMN). In each cancer type we extracted high confidence exomiRs (LogFC >= 2 in exosomes relative to control), their experimentally validated targets, and the enriched pathways among those targets. We then selected the top100 high-confidence targets based on their frequency of appearance in the enriched pathways. We observed significantly higher GC content in exomiRs relative to genomic background. Gene Ontology analysis revealed both general cancer processes, such as wound healing and epithelial cell proliferation, as well as cancer-specific processes, such as “angiogenesis” in the kidney and “ossification” in the lung. ExomiR targets were enriched for cancer-specific tumor suppressor genes and downregulated in PMN formed in lungs compared to normal. Motif analysis showed high inter-cancer similarity among motifs enriched in exomiRs. Our analysis recapitulated exomiRs associated with M2 macrophage differentiation and chemoresistance, such as miR-21 and miR-222–3p, regulating signaling pathways like PTEN/PI3/Akt, NF-kB, etc. Additionally, Cox regression analysis in TCGA indicated that exomiR targets are significantly associated with better overall survival of patients. Lastly, support vector machine model using exomiR targets gene expression classified responders and non-responders to therapy with an AUROC ranging from 0.72 to 0.96, higher than previously reported gene signatures. |
| format | Article |
| id | doaj-art-d733d8b13b15472aa83b6ac3dc2eb505 |
| institution | Kabale University |
| issn | 2001-0370 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj-art-d733d8b13b15472aa83b6ac3dc2eb5052025-01-09T06:13:46ZengElsevierComputational and Structural Biotechnology Journal2001-03702025-01-0127252264Characterizing the pan-cancer role of exosomal miRNAs in metastasis across cancersPiyush Agrawal0Gulden Olgun1Arashdeep Singh2Vishaka Gopalan3Sridhar Hannenhalli4Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD, USA; Corresponding authors.Department of Computer Engineering, Hacettepe University, Ankara 06800, TurkeyCancer Data Science Laboratory, National Cancer Institute, Bethesda, MD, USACancer Data Science Laboratory, National Cancer Institute, Bethesda, MD, USACancer Data Science Laboratory, National Cancer Institute, Bethesda, MD, USA; Corresponding authors.Exosomal microRNAs (exomiRs) play a critical role in intercellular communication, especially in cancer, where they regulate key cellular processes like proliferation, angiogenesis, and metastasis, highlighting their significance as potential diagnostic and therapeutic targets. Here, we aimed to characterize the role of exomiRs, derived from seven cancer types (four cell lines and three tumors), in influencing the pre-metastatic niche (PMN). In each cancer type we extracted high confidence exomiRs (LogFC >= 2 in exosomes relative to control), their experimentally validated targets, and the enriched pathways among those targets. We then selected the top100 high-confidence targets based on their frequency of appearance in the enriched pathways. We observed significantly higher GC content in exomiRs relative to genomic background. Gene Ontology analysis revealed both general cancer processes, such as wound healing and epithelial cell proliferation, as well as cancer-specific processes, such as “angiogenesis” in the kidney and “ossification” in the lung. ExomiR targets were enriched for cancer-specific tumor suppressor genes and downregulated in PMN formed in lungs compared to normal. Motif analysis showed high inter-cancer similarity among motifs enriched in exomiRs. Our analysis recapitulated exomiRs associated with M2 macrophage differentiation and chemoresistance, such as miR-21 and miR-222–3p, regulating signaling pathways like PTEN/PI3/Akt, NF-kB, etc. Additionally, Cox regression analysis in TCGA indicated that exomiR targets are significantly associated with better overall survival of patients. Lastly, support vector machine model using exomiR targets gene expression classified responders and non-responders to therapy with an AUROC ranging from 0.72 to 0.96, higher than previously reported gene signatures.http://www.sciencedirect.com/science/article/pii/S2001037024004483Exosomal miRNACancer metastasisPre-metastatic NicheSurvival AnalysisMachine Learning |
| spellingShingle | Piyush Agrawal Gulden Olgun Arashdeep Singh Vishaka Gopalan Sridhar Hannenhalli Characterizing the pan-cancer role of exosomal miRNAs in metastasis across cancers Computational and Structural Biotechnology Journal Exosomal miRNA Cancer metastasis Pre-metastatic Niche Survival Analysis Machine Learning |
| title | Characterizing the pan-cancer role of exosomal miRNAs in metastasis across cancers |
| title_full | Characterizing the pan-cancer role of exosomal miRNAs in metastasis across cancers |
| title_fullStr | Characterizing the pan-cancer role of exosomal miRNAs in metastasis across cancers |
| title_full_unstemmed | Characterizing the pan-cancer role of exosomal miRNAs in metastasis across cancers |
| title_short | Characterizing the pan-cancer role of exosomal miRNAs in metastasis across cancers |
| title_sort | characterizing the pan cancer role of exosomal mirnas in metastasis across cancers |
| topic | Exosomal miRNA Cancer metastasis Pre-metastatic Niche Survival Analysis Machine Learning |
| url | http://www.sciencedirect.com/science/article/pii/S2001037024004483 |
| work_keys_str_mv | AT piyushagrawal characterizingthepancancerroleofexosomalmirnasinmetastasisacrosscancers AT guldenolgun characterizingthepancancerroleofexosomalmirnasinmetastasisacrosscancers AT arashdeepsingh characterizingthepancancerroleofexosomalmirnasinmetastasisacrosscancers AT vishakagopalan characterizingthepancancerroleofexosomalmirnasinmetastasisacrosscancers AT sridharhannenhalli characterizingthepancancerroleofexosomalmirnasinmetastasisacrosscancers |