Determinants of Metastatic Progression

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DESCRIPTION (provided by applicant): It remains poorly understood how and to what extent advanced cancer traits, such as invasion and metastasis, are determined by the initial differentiation status of the target cell population. The mouse prostate is a uniquely suitable model for such studies because of established anatomical location of stem cell and transit-amplifying cell compartments. Recently, we have established a new autochthonous mouse model of metastatic prostate cancer associated with deficiency for p53 and Rb pathways. In this model neoplasms exhibit features of both luminal and neuroendocrine differentiation and are marked with multiple signature gene expressions commonly found in human prostate carcinomas. Intriguingly, all malignant neoplasms arise only from the proximal region of prostatic ducts, the compartment highly enriched for prostatic stem/progenitor cells, and contain recurrent amplification of L-myc. Based on our preliminary observations, we hypothesize that synergistic effects of p53 and Rb alterations on prostate carcinogenesis are particularly effective in the context of the stem cell compartment and L-myc cooperates with p53/miR-34 pathway in up-regulation of Met, which represents an essential step towards selection of a subset of highly metastatic cells. To test this hypothesis we propose (1) To determine p53 and Rb roles in controlling predisposition to advanced cancer traits as a function of cellular differentiation state and (2) to determine role of L-myc in prostate carcinogenesis associated with p53 and Rb deficiency. PUBLIC HEALTH RELEVANCE: Metastatic progression is the main cause of death from cancer and better understanding of molecular mechanisms determining this process is of critical importance. Alterations in p53, Rb, Myc and Met pathways are associated with poor prognosis and elucidation of their involvement in stem cell transformation and its potential conjunction with metastatic phenotype may lead to development of new diagnostic, prognostic and therapeutic approaches.