Fallopian Tube-Derived High-Grade Serous Cancers Influence Ovarian Production of Norepinephrine and Generate Specific Metabolomic Signatures

High-grade serous ovarian cancer is the most common and
lethal
gynecologic malignancy, which is often attributed to the lack of available
screenings, allowing the disease to progress unnoticed until it is
diagnosed at more aggressive stages. As such, identifying signals
in the tumor microenvironment involved in the primary metastasis of
tumorigenic fallopian tube epithelial (FTE) cells to the ovary could
provide new avenues for prevention, diagnostics, or therapeutic intervention.
Since our previous work identified that the interaction of tumorigenic
FTE and the ovary causes the release of norepinephrine (NE) from the
ovary, we intended to determine the effects of ovarian NE on signaling
and invasion of tumorigenic FTE models and high-grade serous ovarian
cancer cell lines. We demonstrate that NE does not universally enhance
migration, invasion, or adhesion by using multiple cell types but
does alter specific oncogenic protein expression in certain models. In vivo, we found that blocking NE signaling via slow-release
propranolol pellets significantly increased survival time in mice
injected intraperitoneally with murine FTE cells engineered to stably
express shRNA for PTEN and an activated KRAS expression construct.
Finally, we identified that the metabolome released from the ovary
is variable depending upon which cell type it is cocultured with,
suggesting that distinct driver mutations in fallopian tube epithelial
tumor models and early lesions can alter specific metabolomes within
the surrounding ovarian microenvironment. These metabolomes provide
the next frontier for evaluating local signals of the tumor microenvironment
that facilitate ovarian spread of FTE lesions.