Researchers at the University of Pittsburgh have identified a novel trigger of a deadly form of ovarian cancer. Discovery of a subset of high-risk progenitor cells that reside in fallopian tube supportive tissue, or stroma, could pave the way for better approaches to prevent and detect high-grade serous ovarian cancer (HGSOC), the most common form of ovarian cancer, which kills more than 12,000 women in the United States each year.
“Ovarian cancer is the leading cause of death from gynecologic cancer in the Western world, but we currently have no way to detect it early and no prevention strategies apart from surgical castration, which is only indicated in high-risk women,” said Lan Coffman, MD, PhD, associate professor of malignant hematology and medical oncology in the Pitt School of Medicine and member of Magee-Womens Research Institute and UPMC Hillman Cancer Center. “Understanding the underlying biology of how ovarian cancer forms is critical to improving outcomes for our patients.”
Coffman is co-senior author of the team’s published paper in Cancer Discovery (“Aged and BRCA mutated stromal cells drive epithelial cell transformation”), in which the researchers noted, “This work highlights the importance of the stromal microenvironment in HGSOC initiation and provides support to investigate similar stroma-mediated functions at other sites of oncogenesis.”
“High-grade serous ovarian carcinoma (HGSOC) is the most common ovarian cancer subtype, with more than 70% of patients presenting with metastatic disease at the time of diagnosis,” the authors wrote. “There is a critical need to identify and understand the mechanisms of HGSOC initiation, which can then be leveraged to derive effective prevention and early diagnosis approaches.”
Lan Coffman, M.D., Ph.D., associate professor of malignant hematology and medical oncology in the University of Pittsburgh School of Medicine and member of Magee-Womens Research Institute and UPMC Hillman Cancer Center
Lan Coffman, MD, PhD
HGSOC begins in the fallopian tubes when healthy epithelial cells transform into precursor lesions known as serous tubal intraepithelial carcinoma (STIC). “Convincing evidence has demonstrated that the majority of HGSOC tumors arise from the fallopian tube epithelium (FTE), …” the team further noted. Similar to how precancerous colon polyps can become colorectal cancer, STIC lesions often develop into HGSOC tumors. But why do healthy cells become STIC? To find out, Coffman and colleagues turned to the stroma, the non-cancerous connective tissue that helps cancer grow.
“Most researchers have been focused on the epithelial cells that turn into these STIC lesions and eventually into cancer,” said Coffman. “Until now, no one has really looked at the surrounding stromal microenvironment of these lesions.” In the stroma of ovarian cancer, a type of progenitor cell normally involved in the growth and repair of healthy tissue—mesenchymal stem cells (MSCs)—become reprogrammed by tumor cells to support cancer growth. “Our group previously demonstrated that mesenchymal stromal/stem cells (MSCs), a multipotent stromal progenitor cell found in most adult tissues, can be reprogramed by cancer cells to form cancer-associated mesenchymal stem cells (CA-MSCs),” the team explained.
The researchers started by asking when these cancer-associated MSCs form and how early they play a role in cancer formation. They profiled MSCs in the fallopian tubes of patients who did not have cancer, and were surprised to find cells that looked like cancer-associated MSCs in these healthy women. “… using a cohort of primary patient samples, we identified a subset of fallopian tube-derived MSCs from women without cancer that phenocopy cancer-educated CA-MSCs,” the investigators further noted. These cells, which the researchers named high-risk MSCs (hrMSCs), were more common in women with higher risk of ovarian cancer—those of older age or with mutations in the BRCA gene—suggesting that they play a role in cancer initiation. The scientists further explained, “This subset of MSCs is enriched in women with BRCA1 or -2 mutations, increases with age, and is found within the stroma surrounding STIC lesions creating a stromal ‘field effect’ which extends well beyond the borders of the transformed epithelium.”
When the researchers introduced these high-risk MSCs into organoids, or mini-organs, derived from patient fallopian tube tissue, healthy epithelial cells transformed into cancerous cells. “High-risk MSCs promote DNA damage in epithelial cells and then help those mutated cells survive,” explained Coffman. “It’s the perfect storm for cancer initiation.”
High-risk MSCs (yellow) are more abundant in fallopian tubes from patients with STIC lesions (bottom) compared to those without these lesions (top). [Garcia et al. 2025, Cancer Discovery]
High-risk MSCs (yellow) are more abundant in the fallopian tubes of patients with STIC lesions (bottom) compared to those without these lesions (top). [Garcia et al. 2025, Cancer Discovery]
High-risk MSCs also promoted tumor cell growth and increased resistance to a chemotherapy drug. In search of a mechanism for why high-risk MSCs drive ovarian cancer, the researchers found that these cells have a loss of an antioxidant called AMP kinase. Lower levels of AMP kinase led to higher levels of a protein called WT1, which in turn drove the formation of compounds that cause DNA damage. “We also demonstrate that hrMSCs lose expression of AMPKα1, likely through epigenetic silencing. AMPK loss results in increased JNK/c-JUN signaling which transcriptionally upregulates WT1 thus driving the hrMSC phenotype,” they stated.
The authors concluded that their work demonstrates a critical role of fallopian tube stromal cells in HCSOC initiation, “… with implications for the pathophysiology of HGSOC formation and the development of prevention and early detection strategies critically needed in this disease.”
Coffman concluded, “This is the first report that stromal changes in the fallopian tube actually have a causative role in ovarian cancer initiation. It also points to a path where we might be able to intervene.” For example, already existing drugs that upregulate AMP kinase could potentially prevent or reverse early changes in the stroma that lead to ovarian cancer. The findings could also inform approaches for early detection, which are sorely lacking for ovarian cancer. According to Coffman, compounds secreted by high-risk MSCs that are detectable in the bloodstream could act as biomarkers for early-stage ovarian cancer.
“To date, biomarkers associated with HGSOC have not reached the necessary sensitivity and specificity to be useful for early detection of ovarian cancer,” the authors pointed out. “Understanding the role of the fallopian tube stroma in HGSOC initiation may enable the discovery of stroma-based biomarkers to improve the development of methods for early detection.” Identification of stromal-mediated epithelial transformation in addition has “… broad implications for understanding pan-cancer initiation.”