Autophagy is a conserved cell survival pathway that is crucial to proper cell function, yet it is implicated in many diseases including cancer initiation, progression, and response to therapy when altered. Gathering evidence shows that there are certain tumor types characterized by tumor suppressor loss that are highly dependent on autophagy for survival during stress and starvation. The Cramer lab validated MAP3K7/Tak1 as a tumor suppressor gene which is found to be deleted in 30-40% of prostate tumors and is associated with poor disease-free survival. Prostate cancer is the most commonly diagnosed cancer in the United States in men, and the second leading cause of cancer related deaths. Further, the Cramer lab also identified a particularly aggressive subtype of prostate cancer that is characterized by loss of both Tak1 and CHD1. Tak1 has also been shown to activate autophagy, but no direct link between CHD1 and autophagy has been determined. Interestingly, Tak1 loss has been shown to cause a robust cell death response to treatment with TNF-related apoptosis inducing ligand (TRAIL) that is shown in my preliminary data as through necroptosis and NOT canonical apoptosis. Further, my data show that autophagy plays a role in modulating this cell death. It is not fully understood how the loss of Tak1 causes such pronounced cell death when stimulated with TRAIL, and further research into its connection with autophagy is needed. There currently is a small number of genetically targetable mutations in prostate cancer, with little understanding of how common mutations cooperate in the progression of the disease or therapy outcome. Identification and understanding of targetable signaling pathways that are needed for survival, such as Tak1 with autophagy, will allow for more appropriate and direct therapies. Furthermore, identifying the role of coordinate loss of Tak1 and CHD1 in regard to aggressive prostate cancer will allow us to elucidate their role in altering autophagic flux and enable tailored treatments. The mechanism of how autophagy regulates cell death through necroptosis with loss of Tak1 and how Tak1 cells are sensitized to TRAIL will be evaluated in this proposal and could explain a previously unknown connection between pathways leading to targetable therapeutics. In this research proposal, I intend to examine the role of Tak1 loss on autophagy and how it relates to TRAIL sensitivity. I will use tissue recombination to determine how altered autophagy in Tak1 cells, in the context of CHD1 loss, modifies prostate cancer development, progression, and treatment response. Using shRNA, sgRNA, and chemical modifiers of autophagy, I will sensitize Tak1 null mouse prostate cells to anti- cancer therapies, specifically TRAIL. If sensitization of Tak1 null cells to TRAIL is achieved in vivo with autophagy inhibitors, it will demonstrate Tak1 as a selectable marker in prostate cancer. Thus, if successful, patients with the subtype of prostate cancers containing Tak1 and CHD1 loss would have targeted treatment options, TRAIL and autophagy inhibitors, increasing results in those who would benefit and avoiding unnecessary and potentially harmful treatments for those who would not.
Investigating the role of autophagy in Tak1 null prostate cancer and TRAIL sensitivity Autophagy is a conserved cell survival pathway that is crucial in cell function, implicating it in many diseases including cancer initiation, progression, and response to therapy when altered. A known effector of autophagy is the tumor suppressor MAP3K7/Tak1 and its loss has recently been shown to cause a robust cell death response to TRAIL. Tak1 loss is further associated with a particularly aggressive subtype of prostate cancer, ETS-/MAP3K7deleted/CHD1deleted which is found to be deleted in about 20% of prostate tumors and correlates with poor disease-free survival. Currently, prostate cancer is the most commonly diagnosed cancer in the United States in men and the second leading cause of cancer related deaths. There are currently very few genetically targetable mutations in prostate cancer, and with little understanding as to how common mutations cooperate in the progression of disease or therapies. Identification and understanding of targetable signaling pathways that are needed for survival or for cell death, such as Tak1 and CHD1 loss with autophagy, will allow for more appropriate and targeted therapies.
| Goodall, Megan L; Fitzwalter, Brent E; Zahedi, Shadi et al. (2016) The Autophagy Machinery Controls Cell Death Switching between Apoptosis and Necroptosis. Dev Cell 37:337-349 |
| Goodall, Megan L; Cramer, Scott D; Thorburn, Andrew (2016) Autophagy complexes cell death by necroptosis. Oncotarget 7:50818-50819 |
| Goodall, Megan L; Cramer, Scott D; Thorburn, Andrew (2016) Autophagy RIPs into cell death. Cell Cycle 15:3014-3015 |
