PIK3C? expression by fibroblasts promotes triple-negative breast cancer progression

Huang, Penghan; Gagliano, Teresa; Shah, Kalpit; Gargani, Sofia; Lao, Liyan; Alsaleem, Mansour; Chen, Jianing; Ntafis, Vasileios; Ditsiou, Angeliki; Vella, Viviana; Yadav, Kritika; Bienkowska, Kamila; Bresciani, Giulia; Kang, Kai; Li, Leping; Carter, Philip; Benstead-Hum, Graeme; O'hanlon, Timothy; Dean, Michael; Pearl, Frances M G; Lee, Soo Chin; Rakha, Emad A.; Green, Andrew R; Kontoyiannis, Dimitris L; Song, Erwei; Stebbing, Justin; Giamas, Georgios

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.

Citation

Huang, P., Gagliano, T., Shah, K., Gargani, S., Lao, L., Alsaleem, M., …Giamas, G. (2020). PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression. Journal of Clinical Investigation, 130(6), 3188-3204. https://doi.org/10.1172/jci128313

• Journal Article Type: Article
• Acceptance Date: Feb 28, 2020
• Online Publication Date: Mar 10, 2020
• Publication Date: 2020-06
• Deposit Date: Feb 28, 2020
• Publicly Available Date: Mar 20, 2020
• Journal: Journal of Clinical Investigation
• Print ISSN: 0021-9738
• Publisher: American Society for Clinical Investigation
• Peer Reviewed: Peer Reviewed
• Volume: 130
• Issue: 6
• Pages: 3188-3204
• DOI: https://doi.org/10.1172/jci128313
• Keywords: PIK3C?; triple negative breast cancer; secretome, RNA sequencing, CAF, TME
• Public URL: https://nottingham-repository.worktribe.com/output/4050059
• Publisher URL: https://www.jci.org/articles/view/128313