The role of LRRK2 in lung adenocarcinoma

Lung cancer is the leading cause of cancer-related deaths worldwide and the most common lung cancer subtype is lung adenocarcinoma (LUAD). Frequently mutated genes involve activating mutations in KRAS and loss of function mutations in TP53. LUADs primarily arise from alveolar type II cells (ATII), a very specialized lung epithelial cell type that is characterized by the expression of surfactant protein C (SPC). During tumor progression, cancer cells undergo de-differentiation to adapt and survive in the continuously changing tumor environment. Changes may include the upregulation of genes like the glucose transporter 1 (Glut1) which facilitates the uptake of glucose, and the downregulation of others, like the Leucin-rich repeat kinase 2 (Lrrk2). Lrrk2 is a multidomain protein that has both a kinase and a GTP catalytic activity and point mutations of it have been linked with Parkinson's disease (PD). R1441C Lrrk2 is one of the PD mutations that is found in the GTP domain and affects positively the kinase activity of the enzyme. In our study, we focused on the role of Lrrk2 in lung adenocarcinoma. For that, we used the transgenic mouse model Kras LSL-G12D/WT; Tp53 fl/fl (KP), in which we intratracheally instilled Ad5.SPC-Cre viral vectors to specifically target ATII cells (SPC+) and initiate tumors. In a transcriptomic analysis of magnetically sorted CD45 negative KP and Kras LSL-G12D/WT; Tp53 fl/fl; Glut1 fl/fl (KPG1) tumors cells, we found that Lrrk2 together with some other genes that are important for the lamellar bodies were downregulated in KP cells. Lamellar bodies (LBs) are lysosome-related organelles that are produced and stored by ATII cells. In normal lungs, they store surfactant that they release in the alveolar space to reduce the tension in the air-liquid interface. Bioinformatic analysis of LUAD patient data from the cancer genome atlas (TCGA) database, revealed that the high LRRK2 expression correlates with better patient survival and that this LRRK2-high group, maintained genes that are enriched in normal ATII cells, like surfactant protein C (STFPC) and ATP-cassette transporter A3 (ABCA3). Overexpression of LRRK2 in human lung cancer cell lines induced their apoptotic cell death in vitro. Thus, the positive correlation of the LRRK2-high group with a better patient outcome and the cell death induction upon LRRK2 overexpression, made us hypothesize that LRRK2 acts as a tumor suppressor for lung cancer cells. To elucidate that, we crossed KP with Lrrk2 R1441C/Wild-Type (L) mice to generate the Kras LSL-G12D/WT; Tp53 fl/fl; Lrrk2 R1441C/Wild-Type (KPL) mouse model. Firstly, analysis of healthy wild-type and R1441C Lrrk2 lungs revealed no morphological and ultrastructural changes in the ATII cells and their LBs respectively. Localization of Lrrk2 in the pro-SPC + regions in ATII cells implies a functional role of Lrrrk2 in the LBs. Furthermore, tumor-bearing KPL mice did not show a consistent reduction in their tumor growth rate, and q