Data from: Ovarian BDNF promotes survival, migration, and attachment of tumor precursors originated from p53 mutant fallopian tube epithelial cells

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 comparing 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 gain-of-function 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（High-grade serous ovarian carcinoma, HGSOC）是致死性最高的妇科恶性肿瘤。多项新证据支持一项假说：高级别浆液性卵巢癌可起源于输卵管上皮（fallopian tube epithelium, FTE）。目前学界尚未明确，遗传改变与病理生理过程如何驱动输卵管上皮肿瘤前体进展为广泛播散的高级别浆液性卵巢癌。本研究揭示，卵泡液中的脑源性神经营养因子（brain-derived neurotrophic factor, BDNF）可刺激表达原肌球蛋白受体激酶B（tropomyosin receptor kinase B, TrkB）的输卵管上皮细胞，促进其存活、迁移与黏附。通过体外（in vitro）与体内（in vivo）模型，我们进一步证实：在输卵管上皮细胞中，常见TP53功能获得性（gain-of-function, GOF）突变的出现，相较于携带TP53功能丧失性（loss-of-function, LOF）突变的输卵管上皮细胞，可显著增强BDNF/TrkB信号通路活性。不同的突变型p53蛋白可分别通过上调TrkB的转录水平，或增强TrkB的内吞循环过程来调控该通路。本研究结果揭示了输卵管上皮肿瘤前体的遗传改变（即p53功能获得性突变）与病理生理过程（即排卵时卵泡液的释放）在输卵管起源的高级别浆液性卵巢癌起始阶段的潜在相互作用。本研究数据阐明了高级别浆液性卵巢癌发生与排卵之间关联的分子机制，而排卵这一生理过程已被证实与高级别浆液性卵巢癌的危险因素相关。