High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological malignancy. New evidence supports a hypothesis that HGSOC can originate from fallopian tube epithelium (FTE). It is unclear how genetic alterations and pathophysiological processes drive the progression of FTE tumor precursors into widespread HGSOCs. In this study, we uncovered that brain-derived neurotrophic factor (BDNF) in the follicular fluid stimulates the tropomyosin receptor kinase B (TrkB)-expressing FTE cells to promote their survival, migration, and attachment. Using in vitro and in vivo models, we further identified that the acquisition of common TP53 gain-of-function (GOF) mutations in FTE cells led to enhanced BDNF/TrkB signaling compared to that of FTE cells with TP53 loss-of-function (LOF) mutations. Different mutant p53 proteins can either increase TrkB transcription or enhance TrkB endocytic recycling. Our findings have demonstrated possible interplays between genetic alterations in FTE tumor precursors (i.e., p53 GOF mutations) and pathophysiological processes (i.e., the release of follicular fluid upon ovulation) during the initiation of HGSOC from the fallopian tube. Our data revealed molecular events underlying the link between HGSOC tumorigenesis and ovulation, a physiological process that has been associated with risk factors of HGSOC.

高级别浆液性卵巢癌（HGSOC）是最致命的妇科恶性肿瘤。新证据支持 HGSOC 可以源自输卵管上皮 (FTE) 的假设。目前尚不清楚遗传改变和病理生理过程如何推动 FTE 肿瘤前体进展为广泛的 HGSOC。在这项研究中，我们发现卵泡液中的脑源性神经营养因子 (BDNF) 会刺激表达原肌球蛋白受体激酶 B (TrkB) 的 FTE 细胞，以促进它们的存活、迁移和附着。使用体外和体内模型，我们进一步确定，与具有TP53的 FTE 细胞相比，FTE 细胞中常见的 TP53 功能获得（GOF）突变导致 BDNF/TrkB 信号增强功能丧失（LOF）突变。不同的突变 p53 蛋白可以增加 TrkB 转录或增强 TrkB 内吞循环。我们的研究结果表明，在从输卵管开始 HGSOC 期间，FTE 肿瘤前体的遗传改变（即 p53 GOF 突变）与病理生理过程（即排卵时卵泡液的释放）之间可能存在相互作用。我们的数据揭示了 HGSOC 肿瘤发生和排卵之间联系的潜在分子事件，这是一种与 HGSOC 危险因素相关的生理过程。