In localized
tumors, basement membrane (BM) prevents invasive outgrowth of
tumor cells into surrounding tissues. When
carcinomas become invasive,
cancer cells either degrade BM or reprogram stromal fibroblasts to breach BM barrier and lead invasion of
cancer cells into surrounding tissues in a process called fibroblast-led invasion. However,
tumor-derived factors orchestrating fibroblast-led invasion remain poorly understood. Here it is shown that although early-stage primary colorectal
adenocarcinoma (SW480) cells are themselves unable to invade
Matrigel matrix, they secrete exosomes that reprogram normal fibroblasts to acquire de novo capacity to invade matrix and lead invasion of SW480 cells. Strikingly,
cancer cells follow leading fibroblasts as collective epithelial-clusters, thereby circumventing need for epithelial to mesenchymal transition, a key event associated with invasion. Moreover, acquisition of pro-invasive phenotype by fibroblasts treated with SW480-derived exosomes relied on exosome-mediated MAPK pathway activation. Mass spectrometry-based
protein profiling reveals that
cancer exosomes upregulate fibroblasts
proteins implicated in focal adhesion (ITGA2/A6/AV, ITGB1/B4/B5, EGFR, CRK), regulators of actin cytoskeleton (RAC1, ARF1, ARPC3, CYFIP1, NCKAP1, ICAM1, ERM complex), and signalling pathways (MAPK, Rap1, RAC1, Ras) important in pro-invasive remodeling of extracellular matrix. Blocking
tumor exosome-mediated signaling to fibroblasts therefore represents an attractive therapeutic strategy in restraining
tumors by perturbing stroma-driven invasive outgrowth.