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theses

ETD doctoral

Macroautophagy (autophagy hereafter) is a protective process that recycles cellular components to maintain homeostasis and survival. By removing damaged protein and organelles, autophagy ensures protein and organelle quality control. In cancer, the role of autophagy is context dependent. Autophagy is an essential survival mechanism during starvation that promotes tumor progression, but there are also cases where autophagy can suppress tumorigenesis in mouse models. Thus, understanding the role of autophagy modulation in cancer is critical for cancer therapy. Tumors with RAS mutations require autophagy to tolerate metabolic stress, suggesting that autophagy inhibition may be a potential approach in cancer therapy. However, how systemic autophagy inactivation differentially affects normal and tumor tissues is unknown. To assess the functional significance of autophagy, we conditionally deleted the essential autophagy gene, Atg7, throughout adult mice. In that way, we could model the consequences of autophagy inactivation simultaneously to both normal and tumor tissue to simulate autophagy inhibition in cancer therapy. First, we wanted to identify what happens to an adult mouse when autophagy is turned off. We generated a mouse model to delete Atg7, throughout the entire mouse to determine the role of autophagy in adult mammal. Systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2-3 months. Moreover, autophagy was required to maintain fat stores and to mobilize free fatty acids specifically in response to fasting. Also, upon fasting, autophagy-deficient mice suffered muscle wasting and fatal hypoglycemia that is mediated by p53. Not only limited to the starvation stress response, inhibiting autophagy also increased sensitivity to γ-irradiation-induced death. Second, knowing that there is a window of time that adult mice can survive without autophagy, we examined if autophagy ablation is selectively toxic to tumors while sparing normal tissues. For this purpose, we generated another mouse model to induce non-small-cell lung cancer (NSCLC) and then prior to or once tumors were established, we acutely ablated autophagy. Prior autophagy ablation did not alter the efficiency of NSCLC initiation by activation of oncogenic KrasG12D and deletion of the Trp53 tumor suppressor. Acute autophagy ablation in mice with pre-existing NSCLC, however, blocked tumor growth, promoted tumor cell death, and generated more benign cancer with oncocytic changes. Moreover, host autophagy contributed to tumor growth. This anti-tumor activity occurred prior to destruction of normal tissues, suggesting that, acute autophagy inhibition may be therapeutically beneficial in cancer.

ETD_6051

doi:10.7282/T31J9CHM

Ph.D.

Includes bibliographical references

by Gizem Karsli Uzunbas

The author owns the copyright to this work.