Oral Presentation Australasian Extracellular Vesicles Conference 2018

Exosomes derived from human primary and metastatic colorectal cancer cells contribute to functional heterogeneity of activated fibroblasts by reprogramming their proteome (#17)

Alin Rai 1 , David Greening 1 , Maoshan Chen 1 , Rong Xu 1 , Hong Ji Richard 1 , Richard J Simposon 1
  1. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Melbourne, VIC, Australia

Cancer-associated fibroblasts (CAFs) are a heterogeneous population of activated fibroblasts that constitute a dominant cellular component of the tumour microenvironment (TME) performing distinct functions. Here, we investigated the role of tumour-derived exosomes in activating quiescent fibroblasts into distinct functional subtypes. Proteomic profiling and functional dissection revealed that early (SW480) and late-stage (SW620) colorectal cancer (CRC) cell-derived exosomes both activated normal quiescent fibroblasts (α-SMA-, CAV+, FAP+, VIM+) into CAF-like fibroblasts (α-SMA+, CAV- FAP+, VIM+). Fibroblasts activated by early stage cancer-exosomes (SW480-Exos) were highly pro-proliferative and pro-angiogenic and displayed elevated expression of pro-angiogenic (IL8, RAB10, NDRG1) and pro-proliferative (SA1008, FFPS) proteins. In contrast, fibroblasts activated by late stage cancer-exosomes (SW620-Exos) displayed a striking ability to invade through extracellular matrix through upregulation of pro-invasive regulators of membrane protrusion (PDLIM1, MYO1B) and elevated secretion of matrix-remodelling proteins (MMP11, EMMPRIN, ADAM10). Conserved features of exosome-mediated fibroblast reprogramming include enhanced ECM secretion (type I collagen, Tenascin C/X), oncogenic transformation and metabolic reprogramming (e.g., downregulation of metabolic switch CAV-1, upregulation of glycogen metabolism (GAA), amino acid biosynthesis (SHMT2, IDH2) and membrane transporters of glucose (GLUT-1), lactate (MCT4) and amino acids (SLC1A5/3A5)). This study highlights the role of primary and metastatic CRC tumour-derived exosomes in generating phenotypically and functionally distinct subsets of CAFs that may facilitate tumour progression.