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

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.

SUBMITTER: Kang M

PROVIDER: S-EPMC7260207 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Kang Min M Chong Kay Yi KY Hartwich Tobias M P TMP Bi Fangfang F Witham Allyson K AK Patrick David D Morrisson Madeline J MJ Cady Sarah L SL Cerchia Alexandra P AP Kelk Dawn D Liu Yifei Y Nucci Jonah J Madarikan Oluwagbemisola O Ueno Daiki D Shuch Brian M BM Yang-Hartwich Yang Y

Oncogenesis 20200529 5

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 t ...[more]

PMID: 32471985

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Project description:Ovarian cancer is the fifth leading cause of cancer death among US women. Evidence supports the hypothesis that high-grade serous ovarian cancers (HGSC) may originate in the distal end of the fallopian tube. Although a heterogeneous disease, 96% of HGSC contain mutations in p53. In addition, the “p53 signature”, or overexpression of p53 protein (usually associated with mutation), is a potential precursor lesion of fallopian tube derived HGSC suggesting an essential role for p53 mutation in early serous tumorigenesis. To further clarify p53-mutation dependent effects on cells, murine oviductal epithelial cells (MOE) were stably transfected with a construct encoding for the R273H DNA binding domain mutation in p53, the most common mutation in HGSC. Mutation in p53 was not sufficient to transform MOE cells, but did significantly increase cell migration. A similar p53 mutation in murine ovarian surface epithelium (MOSE), another potential progenitor cell for serous cancer, was not sufficient to transform the cells nor change migration suggesting tissue specific effects of p53 mutation. Microarray data confirmed expression changes in pro-migratory genes in p53R273H MOE compared to parental cells, which could be reversed by suppressing Slug expression. Combining p53R273H with KRASG12V activation caused transformation of MOE into high-grade sarcomatoid carcinoma when xenografted into nude mice. Elucidating the specific role of p53R273H in the fallopian tube will improve understanding of changes at the earliest stage of transformation and could help develop chemopreventative strategies to prevent the accumulation of additional mutations and reverse progression of the “p53 signature” thereby, improving survival rates. We used a microarray to determine global changes in gene expression as a result of the p53 mutation specifically in mouse oviductal epithelium. Murine oviductal cells (MOE) were obtained from Dr. Barbara Vanderhyden at the University of Ottawa. Stable cell lines were generated using antibiotic resistant plasmids containing p53 R273H (Addgene, plasmid: 16439, donated by Dr. Vogelstein, Johns Hopkins University school of Medicine, Baltimore, MD) or pCMV-Neo (Origene PCMV6XL4, Rockville, MD). Total RNA was extracted from cell pellets collected from consecutive passages.

Dataset Information

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

Publications

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

Similar Datasets

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