Figure 6. A Model for Organ-Specific Hematogenous Colonization by PDA.

A. A missense mutation in p53, denoted by the yellow star, confers a gain of function that cooperates with TGFβ signaling to produce a prometastatic secretome. The mechanism by which this cooperation occurs may be due to altered epigenetic regulation of specific genes, altered protein-protein interactions of the mutant p53 protein, or secondary effects on gene expression, among other possibilities. B. Mutant p53 together with TGFβ signaling leads to a high level of cellular fitness of the pancreatic cancer cells (blue cells) within the primary tumor. The high cellular fitness coupled with protein expression of prometastastic mediators supports efficient colonization of the liver and lung by disseminated cancer cells. C. Attenuation of TGFβ signaling decreases the prometastatic effects of mutant p53 and lowers the overall fitness of cancer cells (yellow cells). Upon dissemination they are unable to maintain expression of the secretome resulting in vastly reduced metastatic efficiency to hematogenous organs, an altered pattern of hepatic colonization, and a prolonged latency to development of clinically evident metastatic disease in general.