ABOVE: Ovarian cancer is the second most frequent gynecologic cancer in the United States, and it kills more women than any other cancer of the female reproductive system. ©ISTOCK, Dusan Stankovic
As an undergraduate student at Clemson University, Sharon Stack became fascinated with the study of the chemical processes and molecular interactions that take place inside living cells. While Stack’s early biochemistry studies were not in the cancer field, losing a family member to the disease refocused her research interest and motivated her to dive into the world of oncology.
Now, as a biochemist at the University of Notre Dame, Stack and her team collaborate with other scientists to investigate the processes and factors that contribute to ovarian cancer metastasis in the hope that their research might help fight this disease.
Stack was nominated for this interview through The Scientist’s Peer Profile Program submissions.
What motivated you to research ovarian cancer?
When I started studying ovarian cancer as a postdoctoral researcher in the early 1990s, it was an understudied disease. One in 87 women develops ovarian cancer during her lifetime, and the survival rate of those who have ovarian cancer with metastatic disease has not increased much over the past 30 to 40 years.1 The fact that ovarian cancer is such a pressing clinical problem motivates us to study it. As I learned more about it, I realized that ovarian cancer has a unique and interesting mechanism of metastasis, which stimulated me to keep investigating it.
What did you focus on when you first started studying ovarian cancer?
In the early days of my lab, we looked at ovarian cancer from a cell perspective. Tumors that shed from the ovary do not metastasize through the bloodstream like other cancer cells do. Instead, they adhere to tissues in the peritoneal cavity and seed multiple metastatic sites. To anchor themselves in these different tissues, the cells release proteases to degrade the extracellular matrix. Understanding the process of extracellular matrix proteolysis was one of our early goals, and we found that ovarian cancer cells produce potent matrix-degrading proteases.2
We were also interested in exploring the process by which tumor cells adhere to peritoneal tissues. We decided to look at cell-cell and cell-matrix adhesion molecules and how they interact in the context of ovarian cancer metastasis.3,4
How do aging and obesity influence ovarian cancer metastasis?
To investigate the interplay between aging, obesity, and tumor cells, we use mouse models. On the aging side, we found that older mice have a higher tumor burden as well as changes in peritoneal immunity compared to younger animals.5 Since the peritoneal cavity is rich in collagen, we reasoned that the increased tumor burden could be due to a collagen that is more susceptible to degradation by cancer cells. We found that tumor cells do not degrade more collagen in older mice. Instead, aged collagen has more fenestrations, which might provide enough space for tumor cells to proliferate and spread.6
To study the effects of obesity on ovarian cancer metastasis, we looked at tumor burden in mice that were fed a high-fat diet versus those on a standard diet. We found that animals fed the high-fat diet had more tumors in peritoneal organs and adipose tissue, showed changes in the proportion of some immune cells, and responded poorly to standard of care chemotherapy for ovarian cancer compared to mice on a standard diet.7,8
What questions would you like to see cancer researchers address in the coming years?
Our studies on aging and obesity showed that these factors alter the peritoneal immune landscape in mouse models of ovarian cancer. Since immunotherapy is a huge area in the cancer field, it would be interesting to figure out how to target this abnormal immunity to potentially improve the survival of ovarian cancer patients.
Another important area would be to understand cancer mutational processes in more diverse populations since most of what researchers know about cancer comes from data collected in people of European ancestry. Diversifying the population from which researchers obtain data and samples would allow them to explore the similarities and differences in tumor mutational pathways among these individuals, potentially revealing therapeutic targets that are appropriate for some patients and not others.
This interview has been edited for length and clarity.
- American Cancer Society. Ovarian cancer statistics: How common is ovarian cancer. American Cancer Society. 2024.
- Fishman DA, et al. Production of extracellular matrix-degrading proteinases by primary cultures of human epithelial ovarian carcinoma cells. Cancer. 1997;80(8):1457-1463.
- Fishman DA, et al. Biochemical characterization of primary peritoneal carcinoma cell adhesion, migration, and proteinase activity. Gynecol Oncol. 1997;67(2):193-199.
- Klymenko Y, et al. Cadherin composition and multicellular aggregate invasion in organotypic models of epithelial ovarian cancer intraperitoneal metastasis. Oncogene. 2017;36(42):5840-5851.
- Loughran EA, et al. Aging increases susceptibility to ovarian cancer metastasis in murine allograft models and alters immune composition of peritoneal adipose tissue. Neoplasia. 2018;20(6):621-631.
- Harper EI, et al. Another wrinkle with age: aged collagen and intra-peritoneal metastasis of ovarian cancer. Aging Cancer. 2022;3(2):116-129.
- Liu Y, et al. Obesity contributes to ovarian cancer metastatic success through increased lipogenesis, enhanced vascularity, and decreased infiltration of M1 macrophages. Cancer Res. 2015;75(23):5046-5057.
- Liu Y, et al. Host obesity alters the ovarian tumor immune microenvironment and impacts response to standard of care chemotherapy. J Exp Clin Cancer Res. 2023;42(1):165.