Angela Russo

Defining the Ovarian Cancer Precancerous Landscape through Modeling Fallopian Tube Epithelium Reprogramming Driven by Extracellular Vesicles

Abstract Serous tubal intraepithelial carcinomas (lesions) in the human fallopian tube epithelium (hFTE) are theorized to give rise to high-grade serous ovarian cancers. Small extracellular vesicles (sEV) are known to mediate key signaling in both normal and cancerous tissues, but few ex vivo systems exist for studying the impact of sEV on hFTE tissue. In this study, we present a microfluidic tissue culture platform with combined spatial transcriptomic and proteomic readouts that allows us to profile dual responses in tissue exposed to sEV “messages”—capturing both short-term transcriptomic shifts in the tissue and long-term changes in protein cargo of secreted EVs (the “reply”). Using spatial transcriptomics, we show that the short-term 1-day exposure to ovarian cancer–derived sEVs alters expression of 68 transcripts in secretory cells, the progenitor of high-grade serous ovarian cancer, notably upregulating immune-related mRNA, including CXCL family chemokines, VCAM1, and pro-inflammatory mediators (NFKB1, IL1B, and IFNA7/17). Additionally, we observed that the long-term 14-day exposure to sEVs alters the expression of seven transcripts and 25 EV cargo proteins of fallopian tube–derived EVs (“secondary release EVs”) following stimulus from cancer EVs. Together, tissue transcriptomics and tissue-derived EV proteomics indicate that ovarian cancer–derived sEVs rewire target cell signaling to modify the tubal immune landscape. This study provides insights into the early molecular changes associated with the pathogenesis of ovarian cancer in its tissue of origin, providing a platform to study EV–tissue interactions and identify how sEVs drive cell signaling reprogramming in hFTE. Significance: We model the fallopian tube preneoplastic landscape using a microfluidic platform to study EV-induced stress and show that cancer EVs promote immune signaling changes representing the earliest stages of ovarian cancer pathogenesis.

Identifying gaps in women’s preventive health services for women living with HIV in Vermont

Women living with HIV (WLHIV) in the United States experience higher rates of death from cervical and breast cancer and lower screening rates for both compared to women without HIV. These disparities highlight the need to better understand access to and uptake of women's preventive health services-particularly cervical cancer screening, breast cancer screening, and HPV vaccination. Most existing data on these services among WLHIV come from urban settings; therefore, the purpose of this study was to investigate factors affecting adherence to these preventive health measures among WLHIV in Vermont, a rural state with unique healthcare challenges. This cross-sectional study included a retrospective analysis of electronic medical record (EMR) data and a one-time quantitative survey. The EMR analysis assessed cervical Papanicolaou (Pap) smear, mammography, and human papillomavirus (HPV) vaccination rates among WLHIV and women without HIV enrolled in care at University of Vermont-affiliated sites from January 2017 to December 2020. The survey collected demographic information and details regarding care received from WLHIV. Among 98 WLHIV and 481 women without HIV, WLHIV were significantly less likely to receive appropriate Pap smears (56.1% vs. 74.2%, p < 0.001), mammographies (57.1% vs. 88.4%, p < 0.001), and at least one dose of the HPV vaccine (7.1% vs. 20.0%, p = 0.002). Survey data from 41 WLHIV revealed that being sexually active, heterosexual, in a relationship, premenopausal, and housing secure were associated with higher Pap smear adherence. These findings underscore the importance of addressing both individual and systemic factors to improve the provision and receipt of women's preventive health services WLHIV, especially in rural healthcare settings.