Identification of a Novel TGFβ/PKA Signaling Transduceome in Mediating Control of Cell Survival and Metastasis in Colon Cancer

Background: Understanding drivers for metastasis in human cancer is important for potential development of therapies to treat metastases. The role of loss of TGF beta tumor suppressor activities in the metastatic process is essentially unknown. Methodology/Principal Findings: Utilizing in vitro and in vivo techniques, we have shown that loss of TGF beta tumor suppressor signaling is necessary to allow the last step of the metastatic process - colonization of the metastatic site. This work demonstrates for the first time that TGF beta receptor reconstitution leads to decreased metastatic colonization. Moreover, we have identified a novel TGF beta/PKA tumor suppressor pathway that acts directly on a known cell survival mechanism that responds to stress with the survivin/XIAP dependent inhibition of caspases that effect apoptosis. The linkage between the TGF beta/PKA transduceome signaling and control of metastasis through induction of cell death was shown by TGF beta receptor restoration with reactivation of the TGF beta/PKA pathway in receptor deficient metastatic colon cancer cells leading to control of aberrant cell survival. Conclusion/Significance:This work impacts our understanding of the possible mechanisms that are critical to the growth and maintenance of metastases as well as understanding of a novel TGF beta function as a metastatic suppressor. These results raise the possibility that regeneration of attenuated TGF beta signaling would be an effective target in the treatment of metastasis. Our work indicates the clinical potential for developing anti-metastasis therapy based on inhibition of this very important aberrant cell survival mechanism by the multifaceted TGF beta/PKA transduceome induced pathway. Development of effective treatments for metastatic disease is a pressing need since metastases are the major cause of death in solid tumors.