Tumour microenvironment and cancer : Research : Giamas Lab : School of Life Sciences : University of Sussex

Despite mounting evidence for the role of the tumour microenvironment (TME) in affecting surrounding cells and its involvement in metastatic progression, little is known about how stromal cells can influence the behaviour of cancer epithelial cells and how they affect their response to target therapy. Under normal physiological conditions, the stroma serves as a barrier to epithelial cell transformation, while the interplay between epithelial cells and the microenvironment can maintain epithelial polarity and modulate growth inhibition.

PAPER: PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression (JCI, 2020)

In this work, 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 protumorigenic 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.