Autophagy is an evolutionarily conserved lysosomal degradation process crucial for adaptation to stress and for cellular homeostasis. To date, the rationale for targeting autophagy against cancer has been attributed to its cell-autonomous effects as a tumor cell survival pathway. In contrast, the role of autophagy in the development and function of the tumor microenvironment, a critical mediator of tumor initiation, progression and response to therapy, remains obscure. This project merges our expertise in autophagy and angiogenesis to define the functions of the autophagy pathway in the microenvironmental control of invasion and angiogenesis. We seek to answer two fundamental questions in the field. First, how does tumor cell autophagy generate a microenvironment conducive for survival and invasion? Second, is endothelial cell autophagy a prerequisite for the initiation of angiogenesis and during reneovascularization to escape therapeutic vascular growth restrictions imposed by anti-angiogenic therapy? Our preliminary studies implicate autophagy in the production of pro-migratory cytokines, thereby facilitating tumor cell invasion directly, or by activating monocytes via paracrine signaling cues. In addition, our pilot studies indicate that endothelial cell-targete autophagy deletion impairs neovascularization in vivo, thereby revealing a cell specific functional requirement for autophagy for angiogenesis. Based on these results, we will leverage powerful in vivo cancer models uniquely available in our laboratories to pursue two specific aims.
In Aim 1, we will define the role of tumor cell autophagy in promoting glioblastoma multiforme (GBM) invasion and resistance to anti-angiogenic therapy.
In Aim 2, we will determine the functions of endothelial cell autophagy during neovascularization and response to anti-angiogenic therapy. Overall, this proposal will define new interconnections between autophagy and the microenvironment that direct cancer cell invasion, angiogenesis and therapeutic resistance.
Despite immense interest in inhibiting autophagy, a tightly regulated lysosomal degradation process, to treat cancer, we have little appreciation for how these strategies will impact the tumor microenvironment, a critical mediator of cancer progression and response to therapy. This project will define the functions of the autophagy pathway in the microenvironmental control of invasion, angiogenesis, and therapeutic resistance. As a result, we will provide unique, timely insight into how to most effectively exploi autophagy to treat cancer patients.
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| Monkkonen, Teresa; Debnath, Jayanta (2018) Inflammatory signaling cascades and autophagy in cancer. Autophagy 14:190-198 |
| Ilkhanizadeh, Shirin; Sabelström, Hanna; Miroshnikova, Yekaterina A et al. (2018) Antisecretory Factor-Mediated Inhibition of Cell Volume Dynamics Produces Antitumor Activity in Glioblastoma. Mol Cancer Res 16:777-790 |
| Cadwell, Ken; Debnath, Jayanta (2018) Beyond self-eating: The control of nonautophagic functions and signaling pathways by autophagy-related proteins. J Cell Biol 217:813-822 |
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| Vlahakis, Ariadne; Debnath, Jayanta (2017) The Interconnections between Autophagy and Integrin-Mediated Cell Adhesion. J Mol Biol 429:515-530 |
| Liu, J; Debnath, J (2016) The Evolving, Multifaceted Roles of Autophagy in Cancer. Adv Cancer Res 130:1-53 |
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| Kenific, Candia M; Stehbens, Samantha J; Goldsmith, Juliet et al. (2016) NBR1 enables autophagy-dependent focal adhesion turnover. J Cell Biol 212:577-90 |
| Kenific, Candia M; Wittmann, Torsten; Debnath, Jayanta (2016) Autophagy in adhesion and migration. J Cell Sci 129:3685-3693 |
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