An important unsolved question in cell death is to understand why different cells within a population vary in their responses. Which cells will live or die and what determines exactly how they die after exposure to a death stimulus? These questions underlie fundamental cell fate decisions and also have important practical ramifications, for example, during cancer therapy when non-heritable, heterogeneous responses to anti-cancer drugs underlie the eventual acquisition of resistance to therapy. Heterogeneity in cell responses can be driven by stable genetic differences between cells, which are easy to understand. However, such differences also occur even in genetically homogeneous cell populations. What underlies these differences? More important, can we manipulate these effects? Previous work supported by this grant discovered that even in a homogeneous population of cells under unstressed conditions, there is extensive variation in the amount of autophagic flux, which in turn predicts the outcome to future treatment with a death stimulus. And, in the last funding period, we discovered a specific mechanism by which autophagy controls the apoptosis threshold and a quite different mechanism by which the autophagy machinery can control necroptosis. Building on these previous studies, we hypothesize: autophagy controls apoptotic and necroptotic thresholds by regulating Mitochondrial Outer Membrane Permeabilization (MOMP). And, this explains cell death variation between cells in a population. We will test this hypothesis by completing the following aims using a variety of new approaches including the first method that allows optogenetic regulation of autophagy.
Specific Aim 1. Test if autophagy variation before and after a death stimulus controls heterogeneity in apoptosis responses in a cell population.
Specific Aim 2. Determine how autophagy regulates necroptosis. By completing these aims, we will gain new insights into the interplay between two major forms of programmed cell death (apoptosis and necroptosis) and uncover how autophagy regulates these processes.
It is unknown why some cancer cells within a given tumor cell population die while others do not when the whole population is exposed to a death stimulus like an anti-cancer drug. In this project, we test the hypothesis that these differences are due to cell-to-cell variation in the cellular recycling process, autophagy. Understanding these mechanisms may allow new approaches to control how we kill cancer cells and to reduce heterogeneity in tumor cells responses to therapy and thus provide a new way 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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