Ovarian cancer (OvCa) is the most lethal cancer of the female reproductive system due to the fact that it is most often diagnosed after it has already metastasized throughout the abdomen. During OvCa metastasis, cancer cells interact with adipocytes present in the omentum and other locations throughout the abdominal cavity. Adipocytes provide cancer cells with lipids that they use to fuel proliferation, invasion, and metastasis. Ultimately, the adipocytes in the microenvironment are replaced by cancer-associated fibroblasts (CAFs), specialized stromal cells that promote pro-tumorigenic behavior. The ultimate fate of adipocytes and the origins of CAFs in metastatic sites remains poorly understood.
By using mice in which mature adipocytes can be permanently fluorescently labeled to trace them over time, I have found that during metastasis OvCa cells cause adipocytes to differentiate into CAFs. I propose to perform experiments to understand the role of these adipocyte-derived CAFs (Ad-CAFs) in the metastatic microenvironment and identify proteins that are important for their functions and interactions with cancer cells. This will include 1) sequencing thousands of single cells from the mouse model and patient samples to identify genes that are important for Ad-CAF differentiation, 2) disrupting genes important for the transition of adipocytes to CAFs to test their roles in OvCa progression, and 3) identifying genes regulated in cancer cells by their interactions with Ad-CAFs. An important aspect of this project is the use of single-cell RNA-sequencing (scRNA-seq). This technique allows gene expression to be measured in thousands of cells in a high-throughput manner. Analysis of metastatic OvCa with scRNA-seq will not only facilitate the identification of Ad-CAF gene expression signatures, but also identify other subpopulations of stromal cells that may play important roles in metastasis. Functional experiments will focus on identifying gene expression changes in both Ad-CAFs and OvCa that promote metastasis and progression. This project will both provide a better understanding of the role of adipocytes in OvCa metastasis and better characterize the heterogeneity of the microenvironment. If successful, this approach may identify new pathways in adipocytes and cancer cells that may be targeted for the treatment of metastatic OvCa.
This research has been generously supported by Newk’s Cares, and Ovarian Cycle, Jackson, MS.
Dr. Mark Eckert is a research assistant professor in the Section of Gynecologic Oncology, Department of Obstetrics and Gynecology at the University of Chicago. He studied chemistry and biochemistry as an undergraduate at North Carolina State University before beginning his graduate work in Molecular Pathology in the laboratory of Dr. Jing Yang at the University of California, San Diego. There his research focused on the transcriptional regulation of breast cancer metastasis. After obtaining his Ph.D., he focused on understanding the genomics and proteomics of ovarian cancer metastasis in the laboratory of Dr. Ernst Lengyel at the University of Chicago. This has included a study that elucidated the genomics of ovarian cancer initiation and metastasis and the proteomic identification of the methyltransferase nicotinamide N-methyltransferase (NNMT) as a metabolic regulator of stromal epigenetics. With the support of the Ovarian Cancer Research Alliance, his work will focus on understanding the fate of adipocytes in the tumor microenvironment using a combination of lineage tracing mouse models and single-cell transcriptomics. Dr. Eckert has published his work in Nature, Cancer Cell, Nature Cell Biology, and Cancer Discovery, among others. He was a recipient of a Marsha Rivkin Foundation for Ovarian Cancer Research Scientific Scholar Award, a Department of Defense Breast Cancer Research Program Graduate Research Fellowship, and was a Howard Hughes Med-into-Grad Initiative Fellow. Dr. Eckert is currently co-PI of a Chan Zuckerberg Human Cell Atlas Seed Network to map the cells present in the normal female reproductive tract with Drs. Ernst Lengyel, Anindita Basu, and Mengjie Chen at the University of Chicago.