CCBIO seminar: Cédric Zeltz
Importance of the tumor microenvironment in non-small cell lung cancer: Examples of stromal proteins as potential therapeutical targets
Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, ON, Canada
Non-small cell lung carcinoma (NSCLC) accounts for 85% of all lung cancers, the leading cause of cancer-related deaths worldwide. NSCLC cells exist within a complex microenvironment comprised of an extracellular matrix scaffold populated by stromal cells including carcinoma associated fibroblasts (CAFs), vascular endothelial cells, and immune cells. CAFs are well known to strongly influence tumor development, progression and metastasis. Their characteristics and prognostic role in NSCLC patients have been recognized.
Microarray gene-expression analysis of matched CAF and normal fibroblasts from resected NSCLC identified 46 differentially expressed genes; among them ITGA11 and COL11A1 were up-regulated in CAF:
Integrin α11 (ITGA11) promoted tumor growth and metastatic potential of NSCLC cells and was closely associated with collagen cross-linking and the organization and stiffness of fibrillar collagen matrices. Further analysis reveals LOXL1, a matrix cross-linking enzyme, being regulated through integrin α11. We demonstrated that overexpression of LOXL1 in NSCLC tumor stroma resulted in an increase of tumor growth and invasion, due to a change in the matrix reorganization.
Collagen XI (COL11A1) is a fibrillar collagen whose expression is correlated with integrin α11 expression. We showed that the presence of collagen XI in NSCLC stroma is a prognostic factor for recurrence in the UHN cohort of 165 NSCLC patients. Furthermore, collagen XI enhanced lung adenocarcinoma dissemination via integrin α2 and DDR1.
Finally, we characterized two subsets of CAFs from NSCLC patient tumors that were scored and classified based on desmoplasia, which is a prognostic factor in NSCLC. Our findings demonstrate that functional heterogeneity of desmoplastic CAF is a determinant factor of NSCLC aggressiveness; high desmoplastic CAFs represent a phenotypic subtype with a functional role for polysialyltransferase ST8SIA2 in promoting NSCLC invasion.
Chairperson: Donald Gullberg, CCBIO