PIK3Cd expression by fibroblasts promotes triple-negative breast cancer progression

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 PIK3Cd (f-PIK3Cd) as a key regulator of progression. Although PIK3Cd 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-PIK3Cd in TNBC cell invasion. Integrated secretomics and transcriptomics analyses revealed a paracrine mechanism via which f-PIK3Cd confers its pro-tumorigenic effects. Inhibition of f-PIK3Cd 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 PIK3Cd in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3Cd 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 PIK3Cd inhibition. Finally, analysis of BC patient cohorts and TCGA datasets identified f-PIK3Cd (protein and mRNA levels) as an independent prognostic factor for overall and disease free survival, highlighting it as a therapeutic target for TNBC.