Role of ATAD2 in Prostate Cancer Progression and Metastasis

About This Grant

Prostate cancer remains the second-leading cause of cancer-related deaths in US men, mainly due to metastatic disease. Metastasis occurs most frequently in bones, thus entailing significant patient morbidity including pain, propensity to fractures and potential spinal cord compression. Moreover, the bone is a favored reservoir for undetectable disseminated tumor cells that maintain minimal residual disease and can thus critically define future patient outcomes. Despite this pressing clinical need, the mechanisms of progression to bone metastasis remain incompletely understood. Our overall goal is thus to understand the functional determinants of progression to lethal metastatic prostate cancer in order to develop more efficient therapies. Given that tumor progression and metastasis occur through multiple steps involving interactions with different benign cells and tissues, experimental models in which prostate cancer progression may be studied in a whole immunocompetent organism may help identify hitherto unappreciated mechanisms of progression. Our preliminary studies using novel mouse and human prostate cancer models show that ATAD2, an epigenetic and transcriptional regulator, is a critical mediator of metastasis (including bone) and of antitumoral immune responses. ATAD2 is progressively overexpressed during prostate cancer progression and may be an important therapeutic target because of its restricted expression in normal adult tissues as well as the presence of a potentially druggable and specific bromodomain. Furthermore, despite its widely reported association to worse survival in multiple cancer types, remarkably little is known about its functional role in metastasis. In this proposal we will determine the functional significance of ATAD2 expression for prostate cancer progression and metastasis. We will focus on its ability to modulate bone colonization and antitumoral immune responses, two critically relevant steps in the development of metastasis, and uncover the chromatin and transcriptional mechanisms through which it acts. Using state-of-the art syngeneic mouse models, ex-vivo epigenetic editing, human organoids and advanced tissue engineering technologies, our expert multidisciplinary team is uniquely poised to have a positive impact on our understanding of how tumor cells progress to lethal metastatic disease. Our studies will uncover novel mechanisms linking metastasis and immune escape, paving the way for future biomarker driven targeted therapies that may lead to durable and systemic therapeutic responses in currently incurable metastatic disease.