Agrawal Piyush, Olgun Gulden, Singh Arashdeep, Gopalan Vishaka, Hannenhalli Sridhar
Department of Medical Research, SRM Medical College Hospital & Research Centre, SRMIST, Kattankulathur, Chennai, Tamil Nadu, India.
Department of Computer Engineering, Hacettepe University, 06800, Ankara, Turkey.
bioRxiv. 2024 Aug 21:2024.08.20.608894. doi: 10.1101/2024.08.20.608894.
Exosomal microRNAs (exomiRs), transported via exosomes, play a pivotal role in intercellular communication. In cancer, exomiRs influence tumor progression by regulating key cellular processes such as proliferation, angiogenesis, and metastasis. Their role in mediating communication between cancer cells and the tumor microenvironment highlights their significance as potential diagnostic and therapeutic targets.
In this study, we aimed to characterize the role of exomiRs in influencing the pre-metastatic niche (PMN). Across 7 tumor types, including 4 cell lines and three tumors, we extracted high confidence exomiRs (Log FC >= 2 in exosomes relative to control) and their targets (experimentally identified and targeted by at least 2 exomiRs). Subsequently, we identified enriched pathways and selected the top 100 high-confidence exomiR targets based on the frequency of their appearance in the enriched pathways. These top 100 targets were consistently used throughout the analysis.
Cancer cell line and tumor derived ExomiRs have significantly higher GC content relative to genomic background. Pathway enriched among the top exomiR targets included general cancer-associated processes such as "wound healing" and "regulation of epithelial cell proliferation", as well as cancer-specific processes, such as "regulation of angiogenesis in kidney" (KIRC), "ossification" in lung (LUAD), and "positive regulation of cytokine production" in pancreatic cancer (PAAD). Similarly, 'Pathways in cancer' and 'MicroRNAs in cancer' ranked among the top 10 enriched KEGG pathways in all cancer types. ExomiR targets were not only enriched for cancer-specific tumor suppressor genes (TSG) but are also downregulated in pre-metastatic niche formed in lungs compared to normal lung. Motif analysis shows high similarity among motifs identified from exomiRs across cancer types. Our analysis recapitulates exomiRs associated with M2 macrophage differentiation and chemoresistance such as miR-21 and miR-222-3p, regulating signaling pathways such as PTEN/PI3/Akt, NF-κB, etc. Cox regression indicated that exomiR targets are significantly associated with overall survival of patients in TCGA. Lastly, a Support Vector Machine (SVM) model using exomiR target gene expression classified responders and non-responders to neoadjuvant chemotherapy with an AUROC of 0.96 (in LUAD), higher than other previously reported gene signatures.
Our study characterizes the pivotal role of exomiRs in shaping the PMN in diverse cancers, underscoring their diagnostic and therapeutic potential.
通过外泌体运输的外泌体微小RNA（外泌体miRNA）在细胞间通讯中起关键作用。在癌症中，外泌体miRNA通过调节增殖、血管生成和转移等关键细胞过程影响肿瘤进展。它们在介导癌细胞与肿瘤微环境之间通讯的作用凸显了其作为潜在诊断和治疗靶点的重要性。
在本研究中，我们旨在阐明外泌体miRNA在影响前转移微环境（PMN）中的作用。在包括4种细胞系和3种肿瘤的7种肿瘤类型中，我们提取了高可信度的外泌体miRNA（相对于对照，外泌体中Log FC >= 2）及其靶标（通过实验鉴定且至少由2种外泌体miRNA靶向）。随后，我们鉴定了富集的通路，并根据其在富集通路中出现的频率选择了前100个高可信度的外泌体miRNA靶标。在整个分析过程中始终使用这前100个靶标。
癌细胞系和肿瘤来源的外泌体miRNA相对于基因组背景具有显著更高的GC含量。外泌体miRNA前靶标中富集的通路包括一般癌症相关过程，如“伤口愈合”和“上皮细胞增殖的调节”，以及癌症特异性过程，如肾透明细胞癌（KIRC）中的“肾血管生成的调节”、肺腺癌（LUAD）中的“骨化”和胰腺癌（PAAD）中的“细胞因子产生的正调节”。同样，“癌症中的通路”和“癌症中的微小RNA”在所有癌症类型的前10个富集的KEGG通路中名列前茅。外泌体miRNA靶标不仅富集了癌症特异性肿瘤抑制基因（TSG），而且与正常肺相比，在肺中形成的前转移微环境中也下调。基序分析表明，从不同癌症类型的外泌体miRNA鉴定出的基序之间具有高度相似性。我们的分析概括了与M2巨噬细胞分化和化疗耐药相关的外泌体miRNA，如miR-21和miR-222-3p，它们调节PTEN/PI3/Akt、NF-κB等信号通路。Cox回归表明，外泌体miRNA靶标与TCGA中患者的总生存期显著相关。最后，使用外泌体miRNA靶基因表达的支持向量机（SVM）模型对新辅助化疗的反应者和无反应者进行分类，在肺腺癌中的曲线下面积（AUROC）为0.96，高于其他先前报道的基因特征。
我们的研究阐明了外泌体miRNA在多种癌症中塑造前转移微环境的关键作用，强调了它们的诊断和治疗潜力。
