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PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression.
The Journal of Clinical Investigation ( IF 12.282 ) Pub Date : 2020-05-11 , DOI: 10.1172/jci128313
Teresa Gagliano,Kalpit Shah,Sofia Gargani,Liyan Lao,Mansour Alsaleem,Jianing Chen,Vasileios Ntafis,Penghan Huang,Angeliki Ditsiou,Viviana Vella,Kritika Yadav,Kamila Bienkowska,Giulia Bresciani,Kai Kang,Leping Li,Philip Carter,Graeme Benstead-Hume,Timothy O'Hanlon,Michael Dean,Frances Mg Pearl,Soo-Chin Lee,Emad A Rakha,Andrew R Green,Dimitris L Kontoyiannis,Erwei Song,Justin Stebbing,Georgios Giamas

As there is growing evidence for the tumor microenvironment's 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 cancer progression. Although PIK3Cδ was expressed in primary fibroblasts derived from TNBC patients, it was barely detectable in breast cancer (BC) cell lines. Genetic and pharmacological gain- and loss-of-function 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 protumorigenic effects. Inhibition of f-PIK3Cδ promoted the secretion of factors, including PLGF and BDNF, that 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 in tumor metastasis, emphasizing the potential immune-independent effects of PIK3Cδ inhibition. Finally, analysis of BC patient cohorts and TCGA data sets 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.
更新日期:2020-03-10

 

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