INVESTIGATING THE RELATIONSHIP BETWEEN THE NERVOUS SYSTEM AND HIGH-GRADE SEROUS OVARIAN CANCER

High-grade serous ovarian cancer (HGSC) is the most lethal gynecological malignancy in the developed world. This is primarily attributable to a lack of early detection and chemoresistance in advanced disease. With this in mind, ongoing efforts in the HGSC field aim to identify components of the tumor microenvironment (TME) that can be leveraged for novel diagnostic and therapeutic approaches. While numerous studies are investigating endothelial, stromal, and immune cells in the TME, HGSC patients have minimal or no durable response to treatment regimens such as immune checkpoint blockade and anti-angiogenics. Therefore, there is a critical need to identify novel TME interactions in HGSC that can be therapeutically exploited. One aspect of the TME that has recently gained attention is tumor innervation. In functional gastric, colon and prostate cancer studies, ablation of intratumoral nerves has been shown to decrease tumor burden. We have since focused on understanding how neural signaling may impact HGSC development. Preliminary data from our lab revealed that the loss of histone H2B monoubiquitination (H2Bub1) activates axon guidance pathways in HGSC precursor cells. Further, in vitro knockdown of H2Bub1 led to increased expression of the neural adhesion molecule L1CAM that confers HGSC precursor cells with protumorigenic capabilities. In addition to cancer-cell intrinsic changes in neural signaling, we also utilized primary dorsal root ganglia cultures to elucidate mechanisms by which HGSC cells can recruit sensory nerves directly to the tumor bed. Finally, we evaluated the contribution of local sympathetic nerves to the transformation of HGSC precursor cells in 2D and 3D, to find that norepinephrine may drive early disease events. Altogether, these findings provide novel therapeutic targets and mechanistic insight into the cancer cell-intrinsic and extrinsic causes and effects of neural signaling in HGSC.