Most lung-cancer-related deaths results from metastasis, which often grow in the liver, bone, and brain. Brain metastasis (BM) holds special importance in lung cancer for the following reasons: (i) over 50% of lung cancer patients develop BM; (ii) the brain serves as a protective microenvironment where cancer cells escape and serve as future seeds of relapse; (iii) the brain is often the site of recurrence following targeted therapy; and (iv) BM disrupts the normal physiology and cognitive functions of the host, and is ultimately fatal. Our knowledge of BM is still rudimentary, thus creating a major treatment challenge for lung cancer patients with BM. In this application, we will explore the pro-metastatic mechanisms of synucleins in BM.

Synucleins are primarily studied in the context of neurodegenerative diseases. Alpha-, beta-, and gamma-synuclein (abbreviated here as SNCA, SNCB and SNCG) comprise a family of small presynaptic proteins that normally function in vesicle trafficking and synaptic plasticity in the brain. However, abnormal accumulation of synuclein proteins in neuronal cells disrupts dopamine neurotransmission and causes neurotoxicity, giving rise to neurodegenerative diseases such as Parkinson’s disease (PD). Our preliminary studies show that synucleins might be mediating brain metastasis because suppression of these genes reduces brain metastasis in our lung cancer models.

Our study is novel and implicate that: (i) neurodegeneration-related synuclein proteins, which have not been previously studied in BM, could be important for BM development; (ii) drugs targeting synucleins that are currently being tested against neurodegenerative diseases could be repurposed to treat BM in lung cancers; and (iii) the expression of SNCA/SNCG genes in the BM cells from lung cancer patients at diagnosis could stratify lung cancer patients who might benefit from treatment with synuclein inhibitors.