breakthrough board scholar

Understanding and Exploiting Organ-specific Mechanisms in Metastatic Pancreatic Cancer

Dr. Tsanov’s work is focused on Pancreatic Ductal Adenocarcinoma ((PDAC) and the deadly way that it commonly spreads to the liver and lungs. The metastatic tumors associated with PDAC have distinct molecular and clinical features, but far more study has been focused on the originating PDAC and much less is known about the resulting metastatic disease. As a result, these metastatic tumors are treated without regard to their differences and there is an urgent need to better understand the differences between liver and lung metastases so that we can better target them specifically. Dr. Tsanov recently discovered that a particular gene SMAD4, which is inactivated in roughly half of all PDAC cases and is linked to metastatic progression and poor outcomes, has a different effect on metastatic tumors depending on their location. The SMAD4 gene suppresses PDAC-related liver metastases but promotes PDAC-related lung metastases. Further, his preliminary data suggests that SMAD4’s function depends on two additional genes: KLF4 in the liver and RUNX1 in the lung.

Using his Young Investigator Award, Dr. Tsanov hopes to understand the interplay between SMAD4 and these two genes and map out how SMAD4 impacts local immune response in liver and lung metastases. He will use a new genetically engineered mouse model that allows him to both cause and reverse the inactivation of SMAD4 at different PDAC stages to figure out how KLF4- and RUNX1 work with SMAD4 to affect metastatic growth in the liver and lungs and to see if there is a way to manipulate this process to restore anti-tumor immunity. If successful, this study may not only provide new therapeutic targets for PDAC patients with metastatic disease but also reframe how oncologists consider metastatic site when they interpret and treat specific tumors. This metastasis-focused approach promises to uncover novel mechanism-based therapeutic targets and a new type of “organ-informed” therapy that is tailored to metastatic tumors.