Approximately 90% of cancer deaths are due to metastatic disease, the spread of cancer cells from the primary tumor site to other tissues. Once established, the proliferation of cancer cells at metastatic sites alters a patient’s course of disease from one in which the impact is restricted primarily to areas surrounding the original tumor to a systemic disease with a deteriorating prognosis. Research into how cancer cells break free from the primary tumor and establish sites of metastatic growth has, until now, been limited by the inability to identify and track disseminated cancer cells (DCCs). Julio Aguirre-Ghiso and his research group at the Icahn School of Medicine at Mount Sinai are applying a novel barcode-tracking technology in combination with high resolution microscopy that enables researchers to tag and track DCCs for the purpose of studying DCC interactions with each other and the complex immune niche resident at sites of metastatic spread. Preliminary data from the team indicates early (eDCCs) and late (L-DCCs) cooperate to form metastases. In this project, Aguirre-Ghiso and his team will investigate the complex biology of DCC dissemination, dormancy, and reactivation by employing their tag and track technology to follow eDCC and L-DCC populations over time as they spread.
Aguirre-Ghiso and his team have discovered that cancer cells can disseminate in the very early stages of primary disease even before a detectable tumor mass has formed. Yet most mouse models of metastasis use tumors derived from large, advanced tumors, making it difficult to study the biology of early spread. Employing mouse models of early-stage lung cancer, the team will leverage the lab’s novel barcoding tool to study the dynamics of DCC interactions. Research will focus on discerning how eDCCs shape the immune microenvironment of a metastatic niche allowing for initial cancer cell dormancy as well as how eDCC proliferative capacity is reactivated later, possibly in response to seeding of the niche by L-DCCs. Unraveling the molecular and cellular mechanisms of DCC seeding and reactivation could provide information to facilitate development of metastasis-specific therapies targeting DCCs during both dormancy and reactivation that are distinct from therapies focused on control of primary tumor growth.
Rodriguez-Tirado C, Kale N, Carlini MJ, Shrivastava N, Rodrigues AA, Khalil B, Bravo-Cordero JJ, Alexander M, Ji J, Hong Y, Behbod F, Sosa MS. NR2F1 is a barrier to dissemination of early stage breast cancer cells. Cancer Res. 2022.