The Hawkins Lab

Hawkins

The Hawkins laboratory focuses on studying benign and malignant diseases in the female reproductive tract. Researchers in this lab study ovarian cancer from the perspective of the endometriotic tumor microenvironment. They also create models that recapitulate human disease. In addition, the lab is active in training gynecologists, emergency medicine physicians and medical, graduate, undergraduate and high school students.

Endometriosis

Endometriosis is a common disease where endometrial tissue grows outside the uterine cavity, leading to painful periods, chronic pelvic pain and difficulty becoming pregnant. An estimated 5 million women in the United States suffer from endometriosis. Endometriosis leads to poor quality of life in addition to significant economic impact.

Unfortunately, there is no cure for endometriosis. Both medical and surgical management have high recurrence rates. The Hawkins lab uses well-characterized endometriosis tissues and next generation sequencing as an unbiased approach to determining new pathways that can be targeted for therapy. Importantly, this unbiased approach uses multiple next generation sequencing platforms (miRNAs and mRNAs) combined with bioinformatical analyses. Originally, the lab studied miR-29c, which was significantly overexpressed in endometriomas, playing a role in uterine dysfunction, possibly contributing to infertility.

Future studies in this area involve studying additional miRNA molecules, their regulatory mechanisms, and the downstream impactful gene targets of these miRNA molecules. The Hawkins lab uses a combination of unique cell lines in traditional monolayer, spheroid and 3D bioprinted models to test novel pharmacologic means to regulate these impactful miRNA-mediated pathways. Additionally, the lab has developed the first genetically-engineered mouse model that spontaneously develops ovarian endometriosis. The Hawkins lab received funds from the American Association of Obstetricians and Gynecologists Foundation (AAOGF) to support further study of this mouse model and refinement of a 3D bioprinted model of endometriosis.

Endometriosis-associated Ovarian Cancer

Women with endometriosis are at a two-fold increased risk of developing ovarian endometrioid adenocarcinoma and a three-fold increased risk of developing ovarian clear cell adenocarcinoma. Because of this, ovarian endometrioid and clear cell adenocarcinomas are considered endometriosis-associated ovarian cancers. Clinically important, women with endometriosis at the time of ovarian cancer staging have improved prognosis.

Multiple studies have shown that these endometriosis-associated ovarian cancers have frequent loss of function mutations in ARID1A, a putative tumor suppressor gene involved in chromatin remodeling. Using genetically-engineered mouse models, the Hawkins lab showed that conditional deletion of Arid1a in the female reproductive tract (i.e., Pgr-Cre and Amhr2-Cre) was not sufficient to initiate cancer. To determine additional molecular factors important in these cancers, the Hawkins lab procured specimens of ovarian endometrioid adenocarcinoma from women with and without endometriosis. Using an unbiased approach, the Hawkins lab showed that ovarian endometrioid adenocarcinomas from women with concurrent endometriosis had a distinct molecular profile compared to ovarian endometrioid adenocarcinomas from women without concurrent endometriosis. Ovarian tumors with endometriosis showed enrichment of oncogenic KRAS signaling.

The Hawkins lab received an R03 from the National Cancer Institute to study the reproductive contributions of ARID1A and KRAS in ovarian cancer using genetically-engineered mouse models and genetically-modified in vitro systems. Recently, the Hawkins lab received pilot funds from the Rivkin Center for Ovarian Cancer to develop a novel 3D bioprinted model of ovarian cancer within the endometriotic tumor microenvironment. This 3D bioprinted model uses innovative Kenzan technology available at Indiana University School of Medicine. This model will be used as a tool for target discovery and therapeutic testing. Future studies will focus on similar studies in ovarian clear cell adenocarcinomas including use of bioinformatical approaches to determine novel pharmacology therapies based on unique molecular signatures.

Endometrial Cancer

Endometrial cancer is the most common gynecologic cancer in the United States. Multiple studies suggest that dysregulated miRNA molecules play a role in endometrial cancer. To study this, the Hawkins lab used conditional genetically-engineered mouse models to delete DICER, a key enzyme in miRNA biogenesis, (PgrCre; Dicerf/f). These mice had significantly dysregulated miRNA expression and infertility but did not develop endometrial cancer. The most common gene defect in endometrial cancer is functional loss of the tumor suppressor, PTEN.

Conditional deletion of Pten in the mouse uterus (PgrCre; Ptenf/f) leads to low-grade endometrioid adenocarcinoma of the uterus. Women with low-grade endometrioid tumors do well clinically. However, women with high-grade tumors have poor five-year survival. Additionally, therapies that are effective against these aggressive tumors are unknown. Combination of loss of Dicer and loss of Pten leads to aggressive high-grade clear cell endometrial cancers in the mice. Future studies will focus on steroid hormone effects, the role of specific miRNA molecules in aggressive tumors and the role of uterine stem cells. Additional studies developing genetically similar in vitro models using CRISPR/Cas9 will be used.

Active Research

Creation and Validation of Novel Mouse and In Vitro Models of Endometriosis

3D Bio-Assembled Model of Endometriosis-Associated Ovarian Cancer Using the Kenzan Method

Dissecting the Role of ARID1A in Ovarian Cancer Using a 3D Bio-Assembled Model of the Endometriotic Tumor Microenvironment

Novel Integration of miRNA for Discovery of Unique Molecular Networks in Endometrioid Ovarian Cancer with Concurrent Endometriosis

Biologic and Molecular Impact of Dicer Haploin Sufficiency on miRNA Processing, Tumor Transcriptome and RNA Binding Proteins in the Pathogenesis of Endometrial Cancer

Research Faculty

Shannon M. Hawkins, PhD,  MD

Shannon M. Hawkins, PhD, MD

Associate Professor of Obstetrics & Gynecology

Research Team

Research team members in the Hawkins lab include Xiyin Wang, MS, Research Associate; Jillian Hufgard Wendel, PhD, Postdoctoral Fellow; and Kaitlyn Collins, BS, Medical Science Training Program (MSTP) student.