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

Min Kang,Allyson K Witham,Kay Yi Chong,Madeline J Morrisson,Yang Yang-Hartwich,David Patrick,Tobias M P Hartwich,Alexandra P Cerchia,Daiki Ueno,Dawn Kelk,Brian M Shuch,Sarah L Cady,Yifei Liu,Jonah Nucci,Oluwagbemisola Madarikan,Fangfang Bi

doi:10.1038/s41389-020-0243-y

Abstract

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.

Highlights

High-grade serous ovarian carcinoma (HGSOC) is the most common histologic type of ovarian cancer
We have identified that fallopian tube epithelial cells (FTEs) express tropomyosin receptor kinase B (TrkB), which responds to the ovary-secreted brain-derived neurotrophic factor (BDNF) to promote their survival, migration, and adhesion
We demonstrated that KGN conditional medium (CM) promoted the migration of FT240 cells, which was inhibited by TrkB-shRNAs and ANA-12, a TrkB antagonist (Fig. 2c)

Summary

Results

P53 mutation and detachment from ECM induce TrkB expression in FTEs We identified that human and mouse normal FTEs expressed TrkB Mutant p53 significantly increased the FTE attachment to collagen I-coated beads and their BDNF-stimulated attachment (Fig. 3c) These data support the hypothesis that TP53 GOF mutations R175H, R248W, and R273H enhance the oncogenic function of BDNF/TrkB signaling in tumor precursors. Endosomes, Golgi Associated Gamma Adaptin Ear Containing ARF Binding Protein 3 (GGA3) promotes the switch towards receptor recycling and sustains the activation of downstream pathways[61,62], which may account for the increased levels of TrkB protein, leading to the prolonged activation of TrkB pathway as evidenced by the enhanced phosphorylation of TrkB, AKT, and ERK (Fig. 3f) In support of this hypothesis, GGA3 protein level was significantly higher in FTEs that overexpressed p53R248W or p53R273H compared to the control FTEs that overexpressed GFP (Fig. 4a, b). Our data suggested their roles as downstream genes of BDNF

Discussion

Findings

Materials and methods