Loss of Parkinson’s susceptibility gene LRRK2 promotes carcinogen-induced lung tumorigenesis

Abstract

Pathological links between neurodegenerative disease and cancer are emerging. LRRK2 overactivity contributes to Parkinson’s disease, whereas our previous analyses of public cancer patient data revealed that decreased LRRK2 expression is associated with lung adenocarcinoma (LUAD). The clinical and functional relevance of LRRK2 repression in LUAD is unknown. Here, we investigated associations between LRRK2 expression and clinicopathological variables in LUAD patient data and asked whether LRRK2 knockout promotes murine lung tumorigenesis. In patients, reduced LRRK2 was significantly associated with ongoing smoking and worse survival, as well as signatures of less differentiated LUAD, altered surfactant metabolism and immunosuppression. We identified shared transcriptional signals between LRRK2-low LUAD and postnatal alveolarization in mice, suggesting aberrant activation of a developmental program of alveolar growth and differentiation in these tumors. In a carcinogen-induced murine lung cancer model, multiplex IHC confirmed that LRRK2 was expressed in alveolar type II (AT2) cells, a main LUAD cell-of-origin, while its loss perturbed AT2 cell morphology. LRRK2 knockout in this model significantly increased tumor initiation and size, demonstrating that loss of LRRK2, a key Parkinson’s gene, promotes lung tumorigenesis.

Parkinson’s disease and cancer: a systematic review and meta-analysis of over 17 million participants

“…89 However, a recent study demonstrated that loss of LRRK2 could promote lung cancer development, adding to the complexicity of LRRK2cancer link. 90 We found that only 14 of the included studies specifically identified idiopathic PD and excluded genetically determined PD. This limits our systematic review to distinguish genetic forms of PD from idiopathic PD and fully synthesise the potential genetic overlaps between PD and cancer.…”

The Genetics of Parkinson’s Disease and Implications for Clinical Practice

“…Moreover, LRRK2 kinase activity is enhanced in post-mortem brain tissue of people with idiopathic PD who lack LRRK2 variants [ 95 ]. Despite animal models suggesting off target effects of LRRK2 inhibition [ 96 , 97 ], the apparent benign presence of heterozygous loss of function LRRK2 variants in humans is reassuring that partial reduction in LRRK2 function is safe [ 98 , 99 ].…”

The development of inhibitors of leucine‐rich repeat kinase 2 (LRRK2) as a therapeutic strategy for Parkinson's disease: the current state of play

“…This group had previously reported lowered LRRK2 expression in lung adenocarcinoma (Lebovitz et al, 2015), but have since looked at the connection in greater detail. They report that lower levels of LRRK2 are associated with decreased patient survival, and that Lrrk2 KO mice are more prone to developing lung adenomas when exposed to urethane, a cigarette smoke carcinogen (Lebovitz et al, 2021). These results are concerning, but it is probably pertinent to observe that lower LRRK2 expression is most strongly correlated with lung cancer in patients who are smokers, and that there is currently little evidence to suggest decreased LRRK2 expression is sufficient to cause lung cancer (Lebovitz et al, 2021).…”

“…They report that lower levels of LRRK2 are associated with decreased patient survival, and that Lrrk2 KO mice are more prone to developing lung adenomas when exposed to urethane, a cigarette smoke carcinogen (Lebovitz et al, 2021). These results are concerning, but it is probably pertinent to observe that lower LRRK2 expression is most strongly correlated with lung cancer in patients who are smokers, and that there is currently little evidence to suggest decreased LRRK2 expression is sufficient to cause lung cancer (Lebovitz et al, 2021). Thus, LRRK2 inhibitors may not be suitable for current or recent smokers, but otherwise the risk of lung cancer appears small.…”