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Discovery of a novel tumor suppressor from the autophagy regulatory network: LRRK2 in lung adenocarcinoma

Resource type
Thesis type
(Thesis) Ph.D.
Date created
2019-08-14
Authors/Contributors
Abstract
(Macro)autophagy captures, degrades and recycles cytoplasmic components and organelles, via fusion of double-membraned autophagosomes with lysosomes. Basal autophagy is homeostatic, while increased rates of autophagy are stress adaptive. Autophagy is a potent tumor cell survival mechanism during stress, while in pre-malignant cells, it can provide a barrier against transformation. Mechanisms of autophagic cytoprotection and tumor promotion are established in preclinical models; however, whether the autophagy pathway is a target for recurrent molecular alteration in patient tumors remains unknown. I present a survey of 211 human autophagy-associated genes for tumor-related alterations to DNA sequence and RNA expression levels and an examination of their association with patient survival outcomes, in multiple cancer types with publicly available sequence data from The Cancer Genome Atlas (TCGA) consortium. In general, the core autophagy machinery was not a target of recurrent mutation in patients; therefore, the pathway remains functional and exploitable for tumor cell survival. However, autophagy regulators were targets of recurrent mutation and dynamic expression ─ between specific patient groups, in select cancers. Hence, context-dependent autophagy regulation contributes to tumor heterogeneity in patients. I further established that knockout of LRRK2, a previously described autophagy modulator that appears transcriptionally repressed in TCGA lung adenocarcinoma (LUAD), increased tumor initiation in a murine model of carcinogen-driven lung cancer. LRRK2 is an overactive kinase in Parkinson’s disease (PD) and LRRK2 inhibition in primates produces immature lamellar bodies in a main LUAD cell-of-origin. Lamellar bodies are lysosome-related secretory organelles that exocytose pulmonary surfactant, a mixture of phospholipids and lipoproteins key to innate lung defence. In TCGA LUAD patients, reduced LRRK2 was associated with current smoking, worse overall survival, genomic instability and gene signatures of poor differentiation, reduced surfactant metabolism and immunosuppression. LRRK2 was recently identified as an alveolarization gene in mouse lung development. I identified shared transcriptional signals of increased proliferation concomitant with decreased surfactant metabolism, in LRRK2-low LUAD and postnatal alveolar septation in mice, suggesting aberrant activation of a cell-of-origin developmental program in these tumors. I conclude that LRRK2 has tumor suppressive properties in LUAD, warranting further consideration for LRRK2 inhibition strategies in PD.
Document
Identifier
etd20479
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Scholarly level
Supervisor or Senior Supervisor
Thesis advisor: Gorski, Sharon
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