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bioRxiv · 10.1101/2023.03.18.533175

Multiomic Analysis of Intercellular Communication through Tumor-Stroma Tunnels in Breast Cancers

Sinha, S.·Callow, B.·Farfel, A.·Roy, S.·Chen, S.·Rajendran, S.·Buschhaus, J.·Luker, K. E.·Ghosh, P.·Luker, G. D.
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Abstract

Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Conditioned media from MSCs failed to recapitulate genes and proteins, some borrowed and others tumor-intrinsic, induced in cancer cells by direct contact. Protein-protein interaction networks revealed the rich connectome between borrowed and intrinsic components. Bioinformatics prioritized one of the borrowed components, CCDC88A/GIV, a multi-modular metastasis-related protein that has recently been implicated in driving a hallmark of cancer, growth signaling autonomy. MSCs transferred GIV protein to ER+ breast cancer cells (that lack GIV) through tunnelling nanotubes via connexin (Cx)43-facilitated intercellular transport. Reinstating GIV alone in GIV-negative breast cancer cells reproduced [~]20% of both the borrowed and the intrinsic gene induction patterns from contact co-cultures; conferred resistance to anti-estrogen drugs; and enhanced tumor dissemination. Findings provide a multiomic insight into MSC[->]tumor cell intercellular transport and validate how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.

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Sinha, S., Callow, B., Farfel, A., Roy, S., Chen, S., Rajendran, S., Buschhaus, J., Luker, K. E., Ghosh, P., Luker, G. D.. 2023-03-21. Multiomic Analysis of Intercellular Communication through Tumor-Stroma Tunnels in Breast Cancers. https://doi.org/10.1101/2023.03.18.533175

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