Investigating the role of PKC-β in tumour activated stromal cells
Novel targeted therapies have substantially improved the prognosis of chronic lymphocytic leukaemia (CLL) and other B-cell malignancies. However, a significant fraction of patients will relapse despite initial deep remissions. Studies have highlighted that the tumour microenvironment provides protective niches in which tumour cells receive survival signals promoting drug resistance. The Ringshausen lab have previously shown PKC-β to be a bone marrow stroma cell (BMSC) - autonomous signalling pathway critical for survival of malignant B-cells. PKC-β dependent cell contact factors have been shown to regulate drug resistance, but the role of soluble-factors for this protection remains unknown. Moreover, the role of PKC-β in stromal cells of other cancers remains largely uncharacterised. Here I demonstrate novel mechanistic insights into BMSC- mediated drug resistance in CLL. Stromal PKC-β activation regulates levels of active transforming growth factor beta 1 (TGF-β1) and gene expression of distinct fibroblast growth factor (FGF) ligands. Interference with signalling pathways engaged by these factors overcomes drug resistance to both targeted and nontargeted therapies in B-cell malignancies. PKC-β remodels BMSC through potentiating intrinsic and extrinsic TGF-β signalling, and ECM regulation mediated in part by connective tissue growth factor (CTGF). BMSC- derived CTGF promotes CLL survival and drug resistance. My data show that PKC-β inhibitors antagonise activation of BMSCs to a cancer associated fibroblast (CAF)-like phenotype. In-vivo expression of PKC-β was confirmed in fibroblasts of both human and murine cancers. Translationally, microenvironmental PKC-β enhanced tumourigenesis in a murine lung cancer model that could be targeted by a small molecule inhibitor. Overall, I demonstrate PKC-β to be a novel regulator of the BMSC secretome and that targeting these signalling cascades with small molecule inhibitors offers a novel therapeutic option to overcome multi-drug resistance in CLL. I identify novel functions of PKC-β in regulating TGF-β and ECM pathways of BMSCs promoting a CAF-like phenotype. Moreover, PKC-β was activated in CAFs of solid malignancies, accelerating tumourigenesis in a murine lung cancer model representing a promising candidate microenvironmental-target.
Stroma, Lymphoma, PKC-β, CLL, microenvironment, drug resistance, Cancer associated fibroblast
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