PT - JOURNAL ARTICLE AU - Teresa Gagliano AU - Kalpit Shah AU - Sofia Gargani AU - Liyan Lao AU - Mansour Alsaleem AU - Jianing Chen AU - Vasileios Ntafis AU - Penghan Huang AU - Angeliki Ditsiou AU - Viviana Vella AU - Kritika Yadav AU - Kamila Bienkowska AU - Giulia Bresciani AU - Kai Kang AU - Leping Li AU - Philip Carter AU - Graeme Benstead-Hum AU - Timothy O’Hanlon AU - Michael Dean AU - Frances M.G. Pearl AU - Soo-Chin Lee AU - Emad A Rakha AU - Andrew R Green AU - Dimitris L. Kontoyiannis AU - Erwei Song AU - Justin Stebbing AU - Georgios Giamas TI - Global kinome silencing combined with 3D invasion screening of the tumor microenvironment identifies fibroblast-expressed PIK3Cδ involvement in triple-negative breast cancer progression AID - 10.1101/822049 DP - 2019 Jan 01 TA - bioRxiv PG - 822049 4099 - http://biorxiv.org/content/early/2019/11/02/822049.short 4100 - http://biorxiv.org/content/early/2019/11/02/822049.full AB - As there is growing evidence for the tumor microenvironment’s (TME) role in tumorigenesis, we sought to investigate 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 has been mainly described in leucocytes, we detected high expression in primary fibroblasts derived from TNBC patients, while PIK3Cδ was undetectable in cancer epithelial cell lines. Genetic and pharmacologic gain- and loss-of functions experiments verified the contribution of f-PIK3Cδ in TNBC cell invasion. By employing an integrated secretomics and transcriptomics analysis, we 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 subsequently 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, in addition to 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.