Talk abstracts

Talk on Wednesday 10:20-10:40am submitted by Ryan Roberts

Everybody talks: exploiting tumor-tumor and tumor-host interactions that drive osteosarcoma progression

Ryan D. Roberts (Center for Childhood Cancer, Nationwide Childrens Hospital)

Abstract:
Tumors develop, progress, and metastasize surrounded by and intertwined with highly varied host tissues and cells. Longstanding clinical evidence suggests strong preferences of tumor cells for growth in specific tissue niches. Emerging research has begun to identify intercellular signaling pathways used by tumor cells to survive and proliferate within these metastatic niches. Our work has focused on osteosarcoma, a highly aggressive tumor of adolescents and young adults that kills patients primarily through relentless spread to the lungs. We hypothesized that by identifying the tumor-host signals that permit growth within lung tissue, we could therapeutically eliminate important signals to prevent and treat metastatic disease. Our work has identified a system where changes within certain osteosarcoma cells trigger aberrant expression of an alternatively-transcribed isoform of p63, ΔNp63. This ΔN isoform exhibits several gain-of-function activities, one of which directly promotes expression of two cell-cell signaling molecules, IL6 and CXCL8. Interactions between osteosarcoma cells and specific types of normal lung cells amplify these signals in a feed-forward fashion. Increased IL6 and CXCL8 expression then drives responses from the same host lung cells that facilitate both survival and proliferation of tumor cells within the metastatic niche and recruitment of additional tumor cells to that niche. Interestingly, these same signals mediate both tumor-host interactions and tumor-tumor interactions. This simple epigenetic change (ΔNp63 expression) endows otherwise non-metastatic osteosarcoma cells with the capacity to colonize murine lungs; blocking these pathways prevents metastasis with marked efficacy. This work demonstrates a proof of principle that detailed examination of tumor-host interactions can identify novel tumor susceptibilities, suggesting new ways of targeting otherwise untreatable tumors.

Keywords: tumor-host interactions, osteosarcoma, metastasis