Autophagy is important in cancer development, progression and response to therapy. It is widely thought that these activities ultimately rely on autophagy's well-known ability to modulate tumor cell death. Although we are already trying to target autophagy in >40 clinical trials and are inadvertently manipulating autophagy both positively and negatively in thousands of other trials and with standard cancer therapy, a central knowledge gap hampers our efforts to maximally benefit from these efforts. This knowledge gap is that we still have very little mechanistic understanding of how autophagy controls tumor cell apoptosis. This grant is a renewal of a project focused on the core question- how does autophagy regulate tumor cell apoptosis and what does this mean for tumor treatment? The grant builds on three novel discoveries that were made in the previous funding period. First, we found that autophagy variation in a cell population determines which tumor cells live or die in response to a future apoptotic stimulus. Second, we uncovered a specific mechanism by which autophagy allows tumor cells to recover from and avoid apoptosis and explains how autophagy inhibition potentiates canonical apoptosis. Third, we discovered that autophagy inhibition in dying tumor cells promotes growth of therapy-resistant sub-clones in the population. This work led to our central hypothesis: autophagy variation within a tumor cell population controls cell fat in a tumor cell autonomous manner by regulating the efficiency of apoptosis. This mechanism also controls non-cell autonomous signals from dying cells that regulate growth of therapy-resistant tumor subclones. This hypothesis will be tested with the following aims.
Specific Aim 1. Determine how autophagy variation in a population of tumor cells controls tumor cell fate to govern response to anti-cancer treatments.
Specific Aim 2. Determine how autophagy regulates PUMA to control tumor cell fate after mitochondrial apoptosis.
Specific aim 3. Determine role of autophagy's influence on non-cell autonomous signaling in the response of therapy resistant tumor cells in the tumor population.
Each aim builds on extensive preliminary data (some not yet published) and proposes complementary approaches that are intended to uncover the central mechanisms that control how autophagy regulates tumor cell fate. We believe these studies will provide new insights into tumor cell life/death decisions and help create a framework for applying these ideas to improve cancer treatment. Importantly, and, we believe, increasing potential overall impact, although this work focuses on what these mechanisms mean for cancer and its treatment, the mechanisms we are studying have important implications for cell fate decisions in other diseases and during normal physiological processes where the interplay between autophagy and apoptosis is also critical.
Autophagy is a normal process carried out in all cells that is thought to go awry in cancer. Autophagy is known to control whether or not tumor cell die, particularly after treatment with anti-cancer drugs. However, we have very little understanding of the mechanisms by which this happens. Without knowing these mechanisms, it will be impossible to effectively manipulate these processes in order to improve cancer treatment. This application is a renewal of a grant that has started to uncover these mechanisms. In the current project we intend to perform new experiments that will determine: 1. How autophagy varies in populations of tumor cells and what this means for determining whether or not tumor cells can be killed when we treat them. 2. How autophagy controls the most important step in determining whether or not a tumor cell dies. 3. How autophagy regulates the growth of tumor cells in a population that are resistant to treatment to affect the likelihood of tumor recurrence after treatment. Together these aims get to the central question of how autophagy controls tumor cell life and death and provide a framework to move forward to take advantage of this knowledge to improve cancer treatment.
| Fitzwalter, Brent E; Towers, Christina G; Sullivan, Kelly D et al. (2018) Autophagy Inhibition Mediates Apoptosis Sensitization in Cancer Therapy by Relieving FOXO3a Turnover. Dev Cell 44:555-565.e3 |
| Thorburn, Andrew (2018) Autophagy and disease. J Biol Chem 293:5425-5430 |
| Zhang, Yi; Mun, Su Ran; Linares, Juan F et al. (2018) ZZ-dependent regulation of p62/SQSTM1 in autophagy. Nat Commun 9:4373 |
| Thorburn, Jacqueline; Staskiewicz, Leah; Goodall, Megan L et al. (2017) Non-cell-autonomous Effects of Autophagy Inhibition in Tumor Cells Promote Growth of Drug-resistant Cells. Mol Pharmacol 91:58-64 |
| Levy, Jean M Mulcahy; Towers, Christina G; Thorburn, Andrew (2017) Targeting autophagy in cancer. Nat Rev Cancer 17:528-542 |
| Towers, Christina G; Thorburn, Andrew (2017) Targeting the Lysosome for Cancer Therapy. Cancer Discov 7:1218-1220 |
| Mulcahy Levy, Jean M; Zahedi, Shadi; Griesinger, Andrea M et al. (2017) Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors. Elife 6: |
| Towers, Christina G; Thorburn, Andrew (2016) Therapeutic Targeting of Autophagy. EBioMedicine 14:15-23 |
| Morgan, Michael J; Thorburn, Andrew (2016) Measuring Autophagy in the Context of Cancer. Adv Exp Med Biol 899:121-43 |
| 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 |
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