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PIK3Cd expression by fibroblasts promotes triple-negative breast cancer progression
journal contribution
posted on 2023-06-09, 20:51 authored by Teresa Gagliano, Kalpit Shah, Sofia Gargani, Liyan Lao, Mansour Alsaleem, Jianing Chen, Vasileios Ntafis, Penghan Huang, Angeliki Ditsiou, Viviana VellaViviana Vella, Kritika Yadav, Kamila Bienkowska, Graeme Benstead-Hume, Frances PearlFrances Pearl, Georgios GiamasGeorgios Giamas, othersAs 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.
Funding
Deciphering the paracrine role of stromal cells in cancer development; G2467; ACTION AGAINST CANCER; 012018-02
History
Publication status
- Published
File Version
- Accepted version
Journal
Journal of Clinical InvestigationISSN
0021-9738Publisher
American Society for Clinical InvestigationExternal DOI
Issue
6Volume
130Page range
3188-3204Department affiliated with
- Biochemistry Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2020-03-17First Compliant Deposit (FCD) Date
2020-03-16Usage metrics
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