Osteosarcoma (OS) is the most common primary malignancy of bone, occurring predominantly in adolescents. Studies of familial cancer syndromes and sporadic cases have strongly implicated both p53 and pRb in OS tumorigenesis. Thus, our lab created a fully penetrant mouse model of OS (mOS) based on the osteoblast-specific deletion of p53 and pRb. This model faithfully recapitulates the defining features of human OS, including pathology, metastatic behavior, and cytogenetic complexity and shares a transcriptional profile with the human disease. In order to probe the molecular genetics of OS, we screened short hairpin RNA (shRNA) libraries for stable loss-of-function phenotypes in cell lines derived from primary mouse osteosarcoma tumors that lack functional p53 and pRb. Utilizing a large-scale-arrayed, sequence-verified library comprising more than 67,676 shRNA expression plasmids targeting 28,801 mouse genes, we identified genes that are required for proliferation and survival of osteosarcoma cell lines in an unbiased fashion. Lethal shRNAs identified osteosarcoma-specific genes and pathways that may represent novel therapeutic targets for the treatment of OS.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2584.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO