Marusyk, Andriy and Polyak, Kornelia (2016) Spatial proximity to fibroblasts increases heterogeneity in breast tumors and impacts therapeutic sensitivity and clinical outcome. Cancer research, Epub a (Epub a). pp. 1-29. ISSN 1538-7445; 0008-5472

Abstract

ABSTRACT
Using a 3D culture model, we determined that contact with cancer-associated fibroblasts (CAFs)
significantly changes the therapeutic sensitivity, gene expression and metabolic profiles of breast
cancer cells, the majority of which is sub-type and cell line specific. Close proximity to CAFs in 3D,
but not in 2D cultures, conferred resistance to lapatinib, attributable to reduced accumulation of
lapatinib inside carcinoma cells and an elevated apoptotic threshold. Using synthetic lethality
approaches, we identified molecular pathways whose inhibition sensitizes HER2+ breast cancer cells
to lapatinib and found that sensitization per se failed to overcome the stromal protection. In contrast, targeting hyaluronic acid, a major component of the extracellular matrix produced by CAFs, completely overcame stromal protection by sensitizing fibroblasts to lapatinib. Consistently, in
xenograft models, hyaluronidase enhanced the anti-tumor effects of lapatinib. Our studies identify
molecular changes induced in cancer cells by interactions with CAFs and offer novel approaches for
overcoming microenvironmental protection by therapeutically targeting CAFs.

Item Type:	Article
Date Deposited:	12 Oct 2016 00:45
Last Modified:	12 Oct 2016 00:45
URI:	https://oak.novartis.com/id/eprint/29182