Abstract IA004: Fallopian tube cancer precursors sculpt the tumor microenvironment in novel ways
Authors: Knarr Matthew , Restaino Anthony C. , Barr Jeffrey , Reavis Hunter D. , Schwartz Lauren E. , Vermeer Paola T. , Drapkin Ronny I. 
Published: March 2024

High grade serous ovarian cancer (HGSOC) is currently one of the deadliest cancers diagnosed in women. The majority (&gt;70%) of HGSOC patients develop resistant disease after initial platinum/taxane therapy and recur within 5 years. Thus, there is a critical need to identify novel therapeutic strategies that can overcome HGSOC chemoresistance. In recent years, there has been an increased effort to understand the complex interactions between cancer cells and components of the surrounding tumor microenvironment that promote cancer progression. This has led to the development of new tumor microenvironment-targeted therapies (TMETs). A key unresolved problem in ovarian cancer treatment is that most HGSOC patients, including BRCA1/2 mutation carriers, have minimal or no durable response to current TMETs. A promising and novel TME interaction is the ability of cancer cells to recruit nerve fibers from the peripheral nervous system into the TME in a process termed tumor innervation. We recently reported that early loss of an epigenetic mark, called mono-ubiquitylation of histone H2B (H2Bub1), leads to an increase in migration, clonogenicity, and anchorage-independent growth in fallopian tube precursor lesions. RNA-Seq and ATAC-Seq revealed that, in addition to an increase in immune signaling and cell adhesion, loss of H2Bub1 leads to an increase in neural signaling and axonal guidance pathways. We show that HGSOC are innervated by TRPV1-positive sensory nerves. To identify the source of these nerve fibers, we used a syngeneic mouse model and performed axon tracing with fluorescent retrograde tracers to show that the fibers come from thoracic spinal dorsal root ganglia (DRG). We asked whether the nerve fibers in the tumor bed are active. Using multi-electrode arrays, we show that human HGSOCs harbor significantly higher electrical activity than benign disease or normal tissues. We also show that we can pharmacologically silence tumoral electrical activity. To determine the functional consequence of tumor innervation, we developed a syngeneic mouse model from C57Bl6 oviducts. Oviductal cells deleted for Trp53; Pten +/- Brca2 formed tumors in C57Bl6 female animals and were innervated by TRPV1 sensory nerves. Genetic ablations of TRPV1 fibers in recipient mice led to a profound reduction in tumor burden and an increase in survival compared to wildtype littermates. TRPV1 ablation also led to a decrease in electrical activity in the tumors that grew. Ongoing studies suggest that tumor innervation modulates the immune microenvironment in a pro-tumorigenic manner. Our findings identify a mechanism whereby intratumoral nerves promote cancer progression.

Citation Format: Matthew Knarr, Anthony C. Restaino, Jeffrey Barr, Hunter D. Reavis, Lauren E. Schwartz, Paola T. Vermeer, Ronny I. Drapkin. Fallopian tube cancer precursors sculpt the tumor microenvironment in novel ways [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA004.