Neural Mechanisms Driving Comorbid Parkinson's and Melanoma

项目总结/文摘

Project Summary/Abstract A series of epidemiological studies have shown that people with Parkinson’s disease (PD) have a significantly higher risk of developing melanoma and vice-versa. However, research on this comorbidity is sparse. One possible point of convergence lies in the sympathetic nervous system (SNS). Studies have shown that activating sympathetic axons residing in breast adenocarcinomas increases cancer growth and metastasis. Extending this, our preliminary data suggest that mice implanted with melanoma allografts and carrying a knock-in form of the LRRK2-G2019S mutation, the most common genetic contributor to PD, have enriched populations of sympathetic axons in their tumor microenvironment. Therefore, I hypothesize that a PD environment produces an altered melanoma response by regulating the activity and innervation of sympathetic axons in the tumor microenvironment. To investigate this, I am first characterizing melanoma progression and its neural microenvironment in WT and LRRK2-G2019S-knock in (GSKI) mice. The data show that the extent and pattern of melanoma growth is altered significantly in GSKI mice and that immunolabeled tumors show altered patterns of innervation, macrophage infiltration and angiogenesis. These and additional data will be used to establish the conditions and timing for testing whether LRRK2-G2019S-mediated alterations in melanoma growth lie downstream of local sympathetic axonal activity and to ascertain whether positive results can be reversed by inhibition of LRRK2 kinase activity, which is significantly elevated with the G2019S mutation. Studying the downstream effects of sympathetic axonal activity and innervation in a tumor microenvironment will create a fuller understanding of the neural mechanisms connecting PD and melanoma.