The role of LRRK2 in lung adenocarcinoma

Lung cancer is the leading cause of cancer-related deaths worldwide and the most commonlung cancer subtype is lung adenocarcinoma (LUAD). Frequently mutated genes involveactivating mutations in KRAS and loss of function mutations in TP53. LUADs primarily arisefrom alveolar type II cells (ATII), a very specialized lung epithelial cell type that is characterizedby the expression of surfactant protein C (SPC). During tumor progression, cancer cellsundergo de-differentiation to adapt and survive in the continuously changing tumorenvironment. 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 theLeucin-rich repeat kinase 2 (Lrrk2). Lrrk2 is a multidomain protein that has both a kinase anda 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 affectspositively the kinase activity of the enzyme.In our study, we focused on the role of Lrrk2 in lung adenocarcinoma. For that, we used thetransgenic mouse model Kras LSL-G12D/WT; Tp53 fl/fl (KP), in which we intratracheally instilledAd5.SPC-Cre viral vectors to specifically target ATII cells (SPC+) and initiate tumors. In atranscriptomic analysis of magnetically sorted CD45 negative KP and Kras LSL-G12D/WT; Tp53fl/fl; Glut1 fl/fl (KPG1) tumors cells, we found that Lrrk2 together with some other genes that areimportant for the lamellar bodies were downregulated in KP cells. Lamellar bodies (LBs) arelysosome-related organelles that are produced and stored by ATII cells. In normal lungs, theystore surfactant that they release in the alveolar space to reduce the tension in the air-liquidinterface. Bioinformatic analysis of LUAD patient data from the cancer genome atlas (TCGA)database, revealed that the high LRRK2 expression correlates with better patient survival andthat this LRRK2-high group, maintained genes that are enriched in normal ATII cells, likesurfactant protein C (STFPC) and ATP-cassette transporter A3 (ABCA3). Overexpression ofLRRK2 in human lung cancer cell lines induced their apoptotic cell death in vitro. Thus, thepositive correlation of the LRRK2-high group with a better patient outcome and the cell deathinduction upon LRRK2 overexpression, made us hypothesize that LRRK2 acts as a tumorsuppressor 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 andultrastructural changes in the ATII cells and their LBs respectively. Localization of Lrrk2 in thepro-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, andquantification of the Lrrk2 protein levels by immunofluorescence revealed that KPL cellsmaintain more Lrrk2 protein levels than KPs. Finally, considering together RNA-sequencing,in vitro, and in vivo results, we think that both the wild-type and R1441C Lrrk2 can inhibitautophagy, with this effect being exacerbated in mutant cells. We suggest that Lrrk2 regulatesautophagy via inhibition of the PI3K-II/Beclin-1 pathway, which in turn can regulate tumorgrowth.