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Immunosuppressive traits of the hybrid epithelial/mesenchymal phenotype

By Sarthak Sahoo, Sonali Priyadarshini Nayak, Kishore Hari, Prithu Purkait, Susmita Mandal, Akash Kishore, Herbert Levine, Mohit Kumar Jolly

Posted 22 Jun 2021
bioRxiv DOI: 10.1101/2021.06.21.449285

Recent preclinical and clinical data suggests enhanced metastatic fitness of hybrid epithelial/ mesenchymal (E/M) phenotypes, but mechanistic details regarding their survival strategies during metastasis remain unclear. Here, we investigate immune-evasive strategies of hybrid E/M states. We construct and simulate the dynamics of a minimalistic regulatory network encompassing the known associations among regulators of EMT (epithelial-mesenchymal transition) and PD-L1, an established immune-suppressor. Our model simulations, integrated with single-cell and bulk RNA-seq data analysis, elucidate that hybrid E/M cells can have high levels of PD-L1, similar to those seen in cells with a full EMT phenotype, thus obviating the need for cancer cells to undergo a full EMT to be immune-evasive. Specifically, in breast cancer, we show the co-existence of hybrid E/M phenotypes, enhanced resistance to anti-estrogen therapy and increased PD-L1 levels. Our results underscore how the emergent dynamics of interconnected regulatory networks can coordinate different axes of cellular fitness during metastasis.

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