Stromal NRG1 in luminal breast cancer defines pro-fibrotic and migratory cancer-associated fibroblasts

Berdiel, M.; Maia, A.; Hristova, Z.; Borgoni, S.; Vetter, M.; Burmester, S.; Becki, C.; Abnaof, K.; Binenbaum, I.; Bethmann, D.; Chatziioannou, A.; Hasmann, M.; Thomssen, C.; Espinet, E.; Wiemann, S.

doi:10.1101/2020.04.06.026971

bioRxiv · 10.1101/2020.04.06.026971

Stromal NRG1 in luminal breast cancer defines pro-fibrotic and migratory cancer-associated fibroblasts

Berdiel, M.·Maia, A.·Hristova, Z.·Borgoni, S.·Vetter, M.·Burmester, S.·Becki, C.·Abnaof, K.·Binenbaum, I.·Bethmann, D.·Chatziioannou, A.·Hasmann, M.·Thomssen, C.·Espinet, E.·Wiemann, S.

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Abstract

HER3 is highly expressed in luminal breast cancer subtypes. Its activation by NRG1 promotes activation of AKT and ERK1/2, contributing to tumour progression and therapy resistance. HER3-targeting agents that block this activation, are currently under phase 1/2 clinical studies, and although they have shown favorable tolerability, their activity as a single agent has proven to be limited. Here we show that phosphorylation and activation of HER3 in luminal breast cancer cells occurs in a paracrine manner and is mediated by NRG1 expressed by cancer-associated fibroblasts (CAFs). Moreover, we uncover an autocrine role of NRG1 in CAFs. This occurs independently of HER3 and results in the induction of a strong migratory and pro-fibrotic phenotype, describing a subset of CAFs with elevated expression of NRG1 and an associated transcriptomic profile that determines their functional properties. Finally, we identified Hyaluronan Synthase 2 (HAS2), a targetable molecule strongly correlated with NRG1, as an attractive player supporting NRG1 - autocrine signaling in CAFs.

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Berdiel, M., Maia, A., Hristova, Z., Borgoni, S., Vetter, M., Burmester, S., Becki, C., Abnaof, K., Binenbaum, I., Bethmann, D., Chatziioannou, A., Hasmann, M., Thomssen, C., Espinet, E., Wiemann, S.. 2020-04-06. Stromal NRG1 in luminal breast cancer defines pro-fibrotic and migratory cancer-associated fibroblasts. https://doi.org/10.1101/2020.04.06.026971

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