title: 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 (CD44v6kd) as Non-CIC model.A CD44v6kd 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 CD44v6kd-TEX composition. As a consequence, unlike the CIC-TEX, CD44v6kd TEX were not taken up by CD44v6kd cells and CIC. The uptake of CIC-TEX was accompanied by partial correction of CIC marker and protease expression in CD44v6kd 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 CD44v6kd cells.Taken together, the striking loss of tumor progression by a CD44v6kd 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 CD44v6kd are efficiently corrected upon CIC-TEX uptake.
authors.affiliation: Tumor Cell Biology, University Hospital of Surgery, Heidelberg, Germany.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Tumor Cell Biology, University Hospital of Surgery, Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: von Au
authors.affiliation: Proteome Analysis Department, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Schnölzer
authors.affiliation: Section Pancreas Research, University Hospital of Surgery, Heidelberg, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Hackert
authors.affiliation: Tumor Cell Biology, University Hospital of Surgery, Heidelberg, Germany.
authors.forename: Margot
authors.initials: M
authors.lastname: Zöller
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000473:pathology*; D055354:Exosomes / Q000502:physiology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis / Q000502:physiology*; D051379:Mice; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000737:chemistry*; D010190:Pancreatic Neoplasms / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; C112697:CD44v6 antigen; D018960:Hyaluronan Receptors
keywords: CD44v6; adhesion molecules; cancer stem cells; exosomes; metastasis