Stem cell scientists at Cedars-Sinai Medical Center have revealed the origins of a common type of ovarian cancer by modeling fallopian tube tissues. Studies using the fallopian tube organoids allowed the researchers to characterize how BRCA1 mutations put women at high risk for high-grade serous cancer (HGSC). The tissue models could potentially help scientists predict which individuals will develop ovarian cancer years or even decades in advance, allowing for early detection and prevention strategies.

“We created these fallopian organoids using cells from women with BRCA1 mutations who had ovarian cancer,” explained Clive Svendsen, PhD, Svendsen, professor of Biomedical Sciences and Medicine, and executive director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute. “Our data supports recent research indicating that ovarian cancer in these patients actually begins with cancerous lesions in the fallopian tube linings. If we can detect these abnormalities at the outset, we may be able to short-circuit the ovarian cancer.”

Svendsen, together with co-corresponding author Beth Karlan, MD, now professor of Obstetrics and Gynecology in the David Geffen School of Medicine at UCLA and director of cancer population genetics at the UCLA Jonsson Comprehensive Cancer Center, and colleagues, reported on their findings in Cell Reports, in a paper titled, “Human iPSC-derived fallopian tube organoids with BRCA1 mutation recapitulate early-stage carcinogenesis.”

Ovarian cancer is the leading cause of gynecologic cancer deaths in the US, partly because symptoms are often subtle and most tumors elude detection until they are in advanced stages and have spread past the ovaries. While the lifetime risk of developing ovarian cancer is less than 2% for the general female population, the estimated risk for women who carry BRCA1 gene mutations jumps over 30-fold to 40%–59%, the researchers noted. High-grade serous cancer (HGSC) is the most common and lethal subtype of ovarian cancer, with approximately 70% of newly diagnosed ovarian cancer cases classified as HGSC.

The strongest genetic risk factor for developing HGSC is carrying a germline mutation in the BReast Cancer (BRCA1) gene (BRCA1mut). “HGSC is the most common form of epithelial ovarian cancer, with a 5-year survival rate of 90% if detected at stage I,” the authors further noted. “Unfortunately, no clinical biomarkers exist to reliably detect stage I/II HGSC, and there is a wide range of clinical presentation and behavior in BRCA1mut carriers and other high-risk populations.” And faced with steep odds, some women with BRCA1 mutations choose to have their breasts or ovaries and fallopian tubes surgically removed even though they may never develop cancers in these tissues.

Historically, ovarian cancer was believed to originate from the ovarian surface epithelium. “Yet, recent studies have indicated that fallopian tube epithelial (FTE) cells are a common cell of origin for HGSC particularly in germline BRCA1mut carriers,” the scientists noted. However, to date, “No human models capture the sequence of events for disease initiation and progression … To address these clinical challenges, it is essential to better understand and model key molecular events involved in BRCA1-related ovarian cancer initiation and progression to improve predictive outcomes and interventions.”

For their studies, the research team generated induced pluripotent stem cells (IPSCs) from healthy women, and from young ovarian cancer patients who had the BRCA1 mutations. The scientists then used the iPSCs to produce organoids modeling the lining of fallopian tubes and they compared the control organoids with organoids derived from the iPSCs from women with BRCA1-mutant ovarian cancer.

“We were surprised to find multiple cellular pathologies consistent with cancer development only in the organoids from the BRCA1 patients,” said Nur Yucer, PhD, project scientist in Svendsen’s lab and first author of the paper in Cell Reports. “Organoids derived from women with the most aggressive ovarian cancer displayed the most severe organoid pathology.”

As the scientists reported in their published paper, “Following differentiation into FTE organoids, the BRCA1mut lines were found to exhibit cellular abnormalities consistent with neoplastic transformation, when compared with controls,” the team noted. “BRCA1mut organoids show an increased production of cancer-specific proteins and survival following transplantation into mice. Organoids from women with the most aggressive ovarian cancer show the greatest pathology, indicating the potential value to predict clinical severity prior to disease onset.”

The organoid technology could have multiple applications, the team suggested. As well as showing how ovarian cancer is “seeded” in the fallopian tubes of women with mutated BRCA1, the platform could potentially be used to determine if a drug might work against the disease in an individual, Svendsen said. Each organoid carries the genes of the person who provided the blood sample, making it a twin of that person’s own fallopian tube linings. Multiple drugs could then be tested on the organoids without exposing the patient to them.

“This model offers a promising, biologically relevant platform to validate new drugs and targets for a cancer that is not well understood,” the team concluded. “By generation of 3D organoid models from various BRCA1mut patients, BRCA1mut-dependent responses to treatment can be elucidated and the information can help predict the drug sensitivity of individual patients based on their unique genetics … This iPSC-based BRCA model can provide a basis for personalized early detection and preventative strategies for women carrying BRCA1mut and potentially other high-risk mutations.”

“This study represents an exciting use of IPSCs, bringing us closer than ever to significantly improving the outcomes for women with this common type of ovarian cancer,” said Jeffrey Golden, MD, vice dean of Research and Graduate Education and director of the Burns and Allen Research Institute at Cedars-Sinai. “Building on these findings may one day allow us to provide early, lifesaving detection of ovarian cancer in women who carry the BRCA-1 mutation and create effective, individualized prevention and, if necessary, treatment strategies.”

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