Tumor-Infiltrating Nociceptor Neurons in Ovarian Cancer Treatment Resistance

Abstract

Patients with densely innervated tumors suffer with poor outcomes, thus identifying them could define a cohort that could benefit from aggressive treatments. Most cases and deaths from ovarian cancer are associated with high-grade serous ovarian carcinoma (HGSOC). We immunohistochemically analyzed the histological subtypes of ovarian cancer (high-grade serous, low-grade serous, clear cell, mucinous, and endometrioid) for nerves; only HGSOCs were densely innervated. We previously defined that tumor-released small extracellular vesicles (sEVs) recruit nerves to the tumor bed and thus tested whether the difference in nerve infiltration amongst ovarian cancers was associated with sEVs. Using an in vitro neurite outgrowth assay, we found that HGSOC sEVs harbored robust neurite outgrowth activity. Importantly, sEVs from fallopian tube cell lines (the primary cell of origin of HGSOC) predominantly lacked this activity. Implantation of a syngeneic mouse model of HGSOC into transgenic mice lacking tumor-infiltrating nerves slowed tumor growth, sensitized disease to carboplatin, and improved survival. Consistent with this, we show that recurrent, treatment-resistant disease in patients is significantly more innervated than its matched naïve (untreated) malignancy. Taken together, these data identify dense nerve infiltration of HGSOCs and show that innervation contributes to treatment resistance.