Abstract 1526: Extracellular ATP induces epithelial-mesenchymal transition: A novel model alternative to TGF-beta for inducing and studying cancer metastasis

Abstract

Abstract Cancer metastasis, the spread of cancer to new places in the body, is associated with ~90% of solid tumor related deaths, yet remains one of the least understood processes in cancer. Epithelial-mesenchymal transition (EMT) is one of the first initiating steps that is necessary for cancer metastasis. During EMT, cancer cells lose their cell-cell adhesion and cell polarity, and gain migratory and invasive properties in preparation for metastasis. During this process, cells lose markers and transcription factors associated with the epithelial state, and gain markers and transcription factors associated with the mesenchymal state. TGF-β, a cytokine, has long been known to be an inducer for EMT in cancer. In addition to TGF-β, extracellular ATP (eATP) has recently emerged to be an alternative EMT inducer that has important functions involved in inducing EMT and EMT-related processes such as drug resistance [1]. Intratumoral extracellular ATP levels are to 103 to 104 times higher than those in normal tissues (in the high μM range), suggesting its biological importance. Considering this, we hypothesize that ATP and TGF-β may be redundant and complimentary molecules in the induction of EMT, providing cancer the flexibility to use whatever is present at the time. However, the complex functional relationship between eATP and TGF-β has not previously been investigated. We seek to identify and elucidate the mechanisms and relationships by which ATP and TGF-β induce EMT/metastasis. We have found that, in A549 human non-small cell lung cancer cells, ATP and TGF-β are able to induce comparable amounts of cancer cell migration and invasion using in vitro transwell assays. Total RNAseq and metabolomics studies will be completed to identify the transcriptional and metabolic changes associated with the ATP or TGF-β -activated EMT process. A comparative study of the effects of ATP and TGF-β in the early steps of metastasis have never before been reported, leaving uncertainty in their relationship to each other and their necessity and sufficiency in the EMT process. The elucidation of ATP's mechanisms of action in the processes will significantly enhance our understanding of ATP, cancer, and metastasis, eventually leading to novel and more effective ways of slowing down metastasis and reducing metastasis-related deaths. [1] Cao Y, Wang X, Li Y, Evers M, Zhang H, Chen X. (2019). Extracellular and macropinocytosis internalized ATP work together to induce epithelial-mesenchymal transition and other early metastatic activities in lung cancer. Cancer Cell Int. Citation Format: Maria D. Evers, Jingwen Song, Xiaozhuo Chen. Extracellular ATP induces epithelial-mesenchymal transition: A novel model alternative to TGF-beta for inducing and studying cancer metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1526.