PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression
| Autor: | Emad A. Rakha, Angeliki Ditsiou, Graeme Benstead-Hume, Michael Dean, Viviana Vella, Timothy O’Hanlon, Leping Li, Kritika Yadav, Erwei Song, Kamila Bienkowska, Andrew R. Green, Justin Stebbing, Philip Carter, Vasileios Ntafis, Dimitris L. Kontoyiannis, Jianing Chen, Kalpit Shah, Mansour Alsaleem, Frances M. G. Pearl, Sofia Gargani, Kai Kang, Teresa Gagliano, Soo-Chin Lee, Liyan Lao, Georgios Giamas, Giulia Bresciani, Penghan Huang |
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| Přispěvatelé: | Imperial College Healthcare NHS Trust- BRC Funding, National Institute for Health Research |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Class I Phosphatidylinositol 3-Kinases Immunology Mice Transgenic Triple Negative Breast Neoplasms Biology Signal transduction medicine.disease_cause Gene Expression Regulation Enzymologic Metastasis Mice 03 medical and health sciences 0302 clinical medicine Breast cancer Protein kinases medicine Animals Humans Neoplasm Invasiveness Kinome Neoplasm Metastasis Triple-negative breast cancer 11 Medical and Health Sciences Tumor microenvironment Cell Biology Oncology Cancer General Medicine Secretomics Fibroblasts medicine.disease R1 Neoplasm Proteins Gene Expression Regulation Neoplastic 030104 developmental biology 030220 oncology & carcinogenesis Cancer research Heterografts Female Carcinogenesis Neoplasm Transplantation Research Article |
| Zdroj: | J Clin Invest |
| ISSN: | 0021-9738 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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