Platelet PI3Kβ regulates breast cancer metastasis

Graff, R. C.; Haimowitz, A.; Aguilan, J.; Levine, A.; Zhang, J.; Yuan, W.; Roose-Girma, M.; Seshagiri, S.; Porcelli, S. A.; Gamble, M. J.; Sidoli, S.; Bresnick, A. R.; Backer, J.

doi:10.1101/2024.09.10.612261

bioRxiv · 10.1101/2024.09.10.612261

Platelet PI3Kβ regulates breast cancer metastasis

Graff, R. C.·Haimowitz, A.·Aguilan, J.·Levine, A.·Zhang, J.·Yuan, W.·Roose-Girma, M.·Seshagiri, S.·Porcelli, S. A.·Gamble, M. J.·Sidoli, S.·Bresnick, A. R.·Backer, J.

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Abstract

Platelets promote tumor metastasis by several mechanisms. Platelet-tumor cell interactions induce the release of platelet cytokines, chemokines, and other factors that promote tumor cell epithelial-mesenchymal transition and invasion, granulocyte recruitment to circulating tumor cells (CTCs), and adhesion of CTCs to the endothelium, assisting in their extravasation at metastatic sites. Previous studies have shown that platelet activation in the context of thrombus formation requires the Class IA PI 3-kinase PI3K{beta}. We now define a role for platelet PI3K{beta} in breast cancer metastasis. Platelet PI3K{beta} is essential for platelet-stimulated tumor cell invasion through Matrigel. Consistent with this finding, in vitro platelet-tumor cell binding and tumor cell-stimulated platelet activation are reduced in platelets isolated from PI3K{beta} mutant mice. RNAseq and proteomic analysis of human breast epithelial cells co-cultured with platelets revealed that platelet PI3K{beta} regulates the expression of EMT and metastasis-associated genes in these cells. The EMT and metastasis-associated proteins PAI-1 and IL-8 were specifically downregulated in co-cultures with PI3K{beta} mutant platelets. PI3K{beta} mutant platelets are impaired in their ability to stimulate YAP and Smad2 signaling in tumor cells, two pathways regulating PAI-1 expression. Finally, we show that mice expressing mutant PI3K{beta} show reduced spontaneous metastasis, and platelets isolated from these mice are less able to stimulate experimental metastasis in WT mice. Taken together, these data support a role for platelet PI3K{beta} in promoting breast cancer metastasis and highlight platelet PI3K{beta} as a potential therapeutic target. SignificanceWe demonstrate that platelet PI3K{beta} regulates metastasis, broadening the potential use of PI3K{beta}-selective inhibitors as novel agents to treat metastasis.

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Graff, R. C., Haimowitz, A., Aguilan, J., Levine, A., Zhang, J., Yuan, W., Roose-Girma, M., Seshagiri, S., Porcelli, S. A., Gamble, M. J., Sidoli, S., Bresnick, A. R., Backer, J.. 2024-09-14. Platelet PI3Kβ regulates breast cancer metastasis. https://doi.org/10.1101/2024.09.10.612261

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