Dissecting the extrinsic regulators of cancer dormancy in the local and distant microenvironments

Abstract public domain (NIH RePORTER)

Metastatic cancers often manifest in the skeleton. The lesions arise from disseminated tumor cells (DTCs) that often persist in a dormant state for months to decades after initial primary tumor treatment. Despite our knowledge that DTCs give rise to incurable bone metastatic cancer, there remains gaps in our understanding as to the cellular changes within the local and distant microenvironments underpinning entry and reawakening from the dormancy program. Insight into those mechanisms could yield new therapeutic approaches that would prevent the metastatic relapse and ultimately death of numerous cancer patients each year. To address this, we have developed novel syngeneic mouse models of cancer dormancy and reawakening across multiple cancer types including breast, prostate, and pancreatic cancer. These syngeneic models allow the investigation of how dormant DTCs within the bone alters the microenvironment around to facilitate or prevent metastatic outbreak in the bone. Moreover, these models allow the investigation of systemic changes (macroenvironment) resulting from dormant DTCs inhabiting the bone marrow. This investigation is of critical importance for prostate and breast cancer patients among others, because cancer cells often metastasize to the bone microenvironment, while patients succumb due to one or multiple metastases such as liver or lung metastases. Taken together we aim to investigate how dormant DTCs alter the microenvironment to prevent or facilitate reawakening of DTCs within the local or distant microenvironments.

Public health relevance public domain (NIH RePORTER)

Metastasis remains to be the leading cause of cancer death worldwide across many cancer types, which poses poor prognosis for patients diagnosed with it. Understanding how metastatic tissue biological players contribute to dormancy and reawakening is paramount to improving treatment strategies to control metastasis and extend patients overall survival rates. This research proposal will identify extrinsic regulators of cancer dormancy to provide a better understanding of metastasis initiation.