PIK3Cδ 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., Chen, J., Ntafis, V., Ditsiou, A., Vella, V., Yadav, K., Bienkowska, K., Bresciani, G., Kang, K., Li, L., Carter, P., Benstead-Hum, G., O'hanlon, T., Dean, M., Pearl, F. M. G., …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: PIK3Cδ; 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