CD44v6-competent tumor exosomes promote motility, invasion and cancer-initiating cell marker expression in pancreatic and colorectal cancer cells

Abstract

Cancer-initiating cells (CIC) account for metastatic spread, which may rely mostly on CIC exosomes (TEX) that affect host cells and can transfer CIC features into Non-CIC. The CIC marker CD44 variant isoform v6 (CD44v6) being known for metastasis-promotion, we elaborated in cells its contribution to migration and invasion and in TEX the tranfer of migratory and invasive capacity to Non-CIC, using a CD44v6 knockdown (CD44v6^kd) as Non-CIC model.

A CD44v6^kd in human pancreatic and colorectal cancer (PaCa, CoCa) lines led to loss of CIC characteristics including downregulation of additional CIC markers, particularly Tspan8. This aggravated the loss of CD44v6-promoted motility and invasion. Loss of motility relies on the distorted cooperation of CD44v6 and Tspan8 with associated integrins and loss of invasiveness on reduced protease expression. These deficits, transferred into TEX, severely altered the CD44v6^kd-TEX composition. As a consequence, unlike the CIC-TEX, CD44v6^kd TEX were not taken up by CD44v6^kd cells and CIC. The uptake of CIC-TEX was accompanied by partial correction of CIC marker and protease expression in CD44v6^kd cells, which regained migratory, invasive and metastatic competence. CIC-TEX also fostered angiogenesis and expansion of myeloid cells, likely due to a direct impact of CIC-TEX on the host, which could be supported by reprogrammed CD44v6^kd cells.

Taken together, the striking loss of tumor progression by a CD44v6^kd relies on the capacity of CD44v6 to cooperate with associating integrins and proteases and its promotion of additional CIC marker expression. The defects by a CD44v6^kd are efficiently corrected upon CIC-TEX uptake.