Mucinous adenocarcinoma (MAC) is therapeutically resistant and highly metastatic, with poor patient outcomes. However, the molecular basis of MAC remains elusive. Moreover, neither mouse models or biomarkers for premalignant MAC are present, and therapeutic options are limited. Thus, it is imperative to understand the pathobiology of MAC and to develop therapeutic applications for treatment and prevention of MAC. The proposed study will dissect the cellular and molecular mechanisms of mucinous tumorigenesis and use that knowledge to develop therapeutic and preventive approaches for MAC. Recently, the principal investigator (PI) identified a new tumor suppressor, called CRAD (Cancer-related R...

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Mucinous adenocarcinoma (MAC) is therapeutically resistant and highly metastatic, with poor patient outcomes. However, the molecular basis of MAC remains elusive. Moreover, neither mouse models or biomarkers for premalignant MAC are present, and therapeutic options are limited. Thus, it is imperative to understand the pathobiology of MAC and to develop therapeutic applications for treatment and prevention of MAC. The proposed study will dissect the cellular and molecular mechanisms of mucinous tumorigenesis and use that knowledge to develop therapeutic and preventive approaches for MAC. Recently, the principal investigator (PI) identified a new tumor suppressor, called CRAD (Cancer-related Regulator of Actin Dynamics). While CRAD is ubiquitously expressed in the normal epithelial cells, its expression is lost in MAC. CRAD protein controls the cellular skeleton composed of actin protein, whereas the loss of CRAD initiates MAC development in mouse models. Based on the preliminary results, the PI hypothesizes that the loss of CRAD impairs DNA repair, which results in the genomic instability for MAC development. Additionally, employing genetically engineered mouse models, the PI’s team will unveil the cells-of-origin of MAC, which will lead to developing new regimens and biomarkers for MAC. Together, the completion of the proposed study will (1) establish the new paradigm regarding the essential roles of actin dynamics in the maintenance of genomic integrity; (2) develop therapeutic and preventive applications for MAC; (3) generate preclinical mouse models of MAC and DNA repair.

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