A multi-tiered map of EMT defines major transition points and identifies vulnerabilities
Paul, I.; Bolzan, D.; Youssef, A.; Gagnon, K. A.; Hook, H.; Karemore, G.; Oliphant, M. U.; Lin, W.; Liu, Q.; Phanse, S.; White, C.; Padhorny, D.; Kotelnikov, S.; Andrieu, G.; Chen, C. S.; Hu, P.; Denis, G. V.; Kozakov, D.; Raught, B.; Siggers, T.; Wuchty, S.; Muthuswamy, S.; Emili, A.
Show abstract
Epithelial to mesenchymal transition (EMT) is a complex cellular program proceeding through a hybrid E/M state linked to cancer-associated stemness, migration and chemoresistance. Deeper molecular understanding of this dynamic physiological landscape is needed to define events which regulate the transition and entry into and exit from the E/M state. Here, we quantified >60,000 molecules across ten time points and twelve omic layers in human mammary epithelial cells undergoing TGF{beta}-induced EMT. Deep proteomic profiles of whole cells, nuclei, extracellular vesicles, secretome, membrane and phosphoproteome defined state-specific signatures and major transition points. Parallel metabolomics showed metabolic reprogramming preceded changes in other layers, while single-cell RNA sequencing identified transcription factors controlling entry into E/M. Covariance analysis exposed unexpected discordance between the molecular layers. Integrative causal modeling revealed co-dependencies governing entry into E/M that were verified experimentally using combinatorial inhibition. Overall, this dataset provides an unprecedented resource on TGF{beta} signaling, EMT and cancer.
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