Abstract 4592: CD44v6 promotes aggressive phenotypes mediated through activating EGFR pathway via COL11A1/PTPRG axis

Cell surface receptor CD44, an important player in stem cells and cancer biology, is expressed in multiple isoforms via alternative splicing. CD44 isoforms containing variant exon 6 (CD44v6)-encoded sequences are frequently overexpressed in human tumors. In many cancers, CD44v6 serves as a marker of cancer stem cells and accounts for the metastatic susceptibility of the tumors. CD44v6 predicts for poor prognosis in several cancers. However, the actions and underlying mechanisms related to CD44v6-mediated malignant phenotypes remain to be established. In this study, we performed cDNA microarray and Gene Set Enrichment Analysis (GSEA) of the genome-wide expression profiles in cells ectopically expressing the standard form CD44 (CD44s) or CD44v6, and showed that pathways related to cell migration, invasion and metastasis are enriched in CD44v6-expressing cells which are in contrast to cell growth regulatory pathways identified in CD44s cells. In support, overexpression of CD44v6 promoted cell migration and invasion. In silico analyses of genes preferentially regulated in CD44v6-expressing cells against a multi-cancer metastasis-associated gene expression signature dataset and the gene set indicative of embryonic stem cell identity, Collagen XIA1 (COL11A1) was identified as the top candidate in CD44v6-upregulated genes. COL11A1, encoding the α1 chain of the minor fibrillar collagen XI, has been found to be highly expressed in a variety of cancers, and is implicated in the processes of metastasis, angiogenesis, and drug resistance. COL11A1 expression is correlated with cancer aggressiveness and progression, and lymph node metastasis. Using gain- and loss-of-function approaches, we further demonstrated that CD44v6 drives tumor cell invasion in part mediated through the induction of metastasis-related gene COL11A1. Upon examining the involvement of receptor tyrosine kinase pathways, we showed that EGFR is constitutively activated in CD44v6-expressing cells, and that COL11A1 supports CD44v6-mediated EGFR activation via suppressing the expression of PTPRG, an EGFR negative regulator. Our data thus suggest that CD44v6 promotes aggressive phenotypes mediated through activating EGFR pathway via COL11A1/PTPRG axis. Citation Format: Joanne Jeou-Yuan Chen, Jing-You Guo. CD44v6 promotes aggressive phenotypes mediated through activating EGFR pathway via COL11A1/PTPRG axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4592.