Details

Autor(en) / Beteiligte

• Gagliano, Teresa
• Shah, Kalpit
• Gargani, Sofia
• Lao, Liyan
• Alsaleem, Mansour
• Chen, Jianing
• Ntafis, Vasileios
• Huang, Penghan
• Ditsiou, Angeliki
• Vella, Viviana
• Yadav, Kritika
• Bienkowska, Kamila
• Bresciani, Giulia
• Kang, Kai
• Li, Leping
• Carter, Philip
• Benstead-Hume, Graeme
• OHanlon, 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

Titel

PIK3C[delta] expression by fibroblasts promotes triple-negative breast cancer progression

Ist Teil von

• The Journal of clinical investigation, 2020-06, Vol.130 (6), p.3188

Ort / Verlag

American Society for Clinical Investigation

Erscheinungsjahr

2020

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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 PIK3C[delta] (f- PIK3C[delta]) as a key regulator of cancer progression. Although PIK3C[delta] 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-PIK3C[delta] in TNBC cell invasion. Integrated secretomics and transcriptomics analyses revealed a paracrine mechanism via which f-PIK3C[delta] confers its protumorigenic effects. Inhibition of f-PIK3C[delta] 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 PIK3C[delta] in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3C[delta] 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 PIK3C[delta] inhibition. Finally, analysis of BC patient cohorts and TCGA data sets identified f-PIK3C[delta] (protein and mRNA levels) as an independent prognostic factor for overall and disease-free survival, highlighting it as a therapeutic target for TNBC.