Gagliano, Teresa, Shah, Kalpit, Gargani, Sofia, Lao, Liyan, Alsaleem, Mansour, Chen, Jianing, Ntafis, Vasileios, Huang, Penghan, Ditsiou, Angeliki, Vella, Viviana, Yadav, Kritika, Bienkowska, Kamila, Benstead-Hum, Graeme, Pearl, Frances M G, Giamas, Georgios and others, (2020) PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression. Journal of Clinical Investigation. ISSN 0021-9738

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Abstract

As there is growing evidence for the tumor microenvironment’s (TME) role in tumorigenesis, we investigated the role of fibroblast-expressed kinases in triple negative breast cancer (TNBC). Using a high-throughput kinome screen combined with 3D invasion assays, we identified fibroblast-expressed PIK3Cδ (f-PIK3Cδ) as a key regulator of progression. Although PIK3Cδ was expressed in primary fibroblasts derived from TNBC patients, it was undetectable in breast cancer cell lines. Genetic and pharmacologic gain- and loss-of functions experiments verified the contribution of f-PIK3Cδ in TNBC cell invasion. Integrated secretomics and transcriptomics analyses revealed a paracrine mechanism via which f-PIK3Cδ confers its pro-tumorigenic effects. Inhibition of f-PIK3Cδ promoted the secretion of factors, including PLGF and BDNF, which led to upregulation of NR4A1 in TNBC cells where it acts as a tumor suppressor. Inhibition of PIK3Cδ in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3Cδ in cancer progression. Similar results were observed in the MMTV-PyMT transgenic BC mouse model, along with a decrease on tumor metastasis emphasizing the potential immune-independent effects of PIK3Cδ inhibition. Finally, analysis of BC patient cohorts and TCGA datasets identified f-PIK3Cδ (protein and mRNA levels) as an independent prognostic factor for overall and disease free survival, highlighting it as a therapeutic target for TNBC.

Item Type:	Article
Keywords:	PIK3Cδ; fibroblasts; triple-negative breast cancer; tumor microenvironment
Schools and Departments:	School of Life Sciences > Biochemistry
Subjects:	R Medicine R Medicine > R Medicine (General)
Depositing User:	Georgios Giamas
Date Deposited:	17 Mar 2020 08:52
Last Modified:	17 Mar 2020 08:52
URI:	http://sro.sussex.ac.uk/id/eprint/90450

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