Tumorigenic Influence of Estrogen and Androgen on Fallopian Precursor Lesions in the Development of HGSOC

High grade serous ovarian cancer (HSGOC) is the fifth leading cause of cancer deaths among women. It is now known HGSOC tends to come from the fallopian tube, a physiologically dynamic reproductive organ that works in concert with the ovary to maintain fertility. Over the last few decades researchers and clinicians have identified epithelial lesions in the fimbriated end of the fallopian tube as putative precursors to HGSOC. Herein, we genetically engineered a cellular model for the earliest known lesion, a secretory cell outgrowth, and discovered a role for hormonal potentiation in the progression of these precursors. In light of this, we began to give close scrutiny to the impact of hormones on precursor lesions. Under normal physiological conditions, the fallopian tube and the ovary coordinate via bidirectional endocrine cross talk; however, abetter understanding of how this hormonal crosstalk may support fallopian tumorigenesis has been marred by the reliance on traditional in vitroand in vivomodel systems of the reproductive tract. To address this, we previously developed a microfluidic device that can support ex vivoorgan culture for extended periods of time. We deployed that device and demonstrated that the ability of the fallopian tube to support fertility via cilia beating is negatively impacted by exposure to a hyperandrogenic microenvironment. We then conducted a separatestudy wherein imaging mass spectrometry showed, for the first time, that tumor cellsoffallopian tube origin can themselves induce androgenismsecretionfrom the ovary. We found that the androgen, R1881, can induce tumorigenic phenotypes, such as proliferation and migration,in precursor lesions and surrounding fallopian tube epithelium. Lastly, we showed that this pro-tumorigenic induction wasconserved when patient-derived ex vivomodels, and 3D cellular models werecultured on a microfluidic device. Through this work, we have widened the field’s understanding of the role fallopian precursor lesions and hormones in the development of high grade serous ovarian cancer,and we contributed to the development of the next generation of multi-organ microfluidic devices.