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Fallopian organoids promising for ovarian cancer prediction in women with BRCA mutations

Cell Reports
Reuters Health - 05/01/2022 - Fallopian tube organoids hold the potential for predicting the development of ovarian cancer years in advance, researchers say.

"There are new induced pluripotent stem cell (iPSC) technologies coming that will allow clinicians to know if a patient is highly likely to get certain types of cancer, enabling drug treatment very early - just like (a statin) to prevent plaque build-up and heart disease," Dr. Clive Svendsen of Cedars-Sinai Medical Center in Los Angeles told Reuters Health.

For the current study, published in Cell Reports, Dr. Svendsen and colleagues generated iPSCs from healthy individuals and young ovarian cancer patients with germline pathogenic BRCA1 mutations (BRCA1mut).

Following differentiation into fallopian tube epithelial (FTE) organoids, compared to controls, the BRCA1mut lines exhibited cellular abnormalities consistent with cancer development.

Following transplantation in mice, the BRCA1mut organoids showed an increased production of cancer-specific proteins, with organoids from women with the most aggressive ovarian cancer showing the greatest pathology. This finding suggests the potential ability to predict clinical severity prior to disease onset, according to the authors.

"These human FTE organoids from BRCA1mut carriers provide a faithful physiological in vitro model of FTE lesion generation and early carcinogenesis," the authors state. "This platform can be used for personalized mechanistic and drug screening studies."

Dr. Svendsen said, "We are going to make another 20 iPSC lines from patients with a range of different types of cancer onset to see if this model can predict the onset of disease, then test a variety of drugs to see which are effective in both the model and the patient."

Dr. Elizabeth Swisher, Director, Division of Gynecologic Oncology at UW Medicine and Co-Leader, Breast and Ovarian Cancer Research Program at Seattle Cancer Care Alliance, called the preclinical models "promising."

"However," she told Reuters Health by email, "all of the BRCA1 mutated samples come from younger women with ovarian cancer and all were derived from lymphoblasts. That makes it impossible to tell if the differences they observed were really due to the heterozygous BRCA1 mutation...or from other differences between the groups, such as the different starting cell type or because the BRCA1 mutated cells came from patients with ovarian cancer or from younger patients."

"There may have also been other differences," she said, "such as did the cancer patients have chemotherapy exposure before lymphoblast collection?"

"I did not find it convincing that the nodules in mice contained cancers based on the supplemental data shown," she noted. "I would be more convinced if the tissue had pathological evidence of invasion or loss of the BRCA wildtype allele and a pathogenic TP53 mutation. The same goes for the claim that the BRCA1mut organoids developed into serous tubal intraepithelial carcinoma (STIC)."

"I would like to see them repeat these experiments using the same starting material (i.e., lymphoblasts) in all cases and controls," she said. "Then I would want to include BRCA wildtype patients with and without cancer and patients with BRCA1 mutations with and without cancer, preferably matched for age and prior chemo exposure."

Dr. Ronny Drapkin, Director of the Ovarian Cancer Research Center and of the Gynecologic Cancer Research, Basser Center for BRCA, at Penn Medicine in Philadelphia, also commented in an email to Reuters Health.

"The study provides a path towards being able to generate fallopian tube cell lines from BRCA1/2 mutation carriers," he said. "Until now, this was very difficult because pathologists needed to examine that tissue for evidence of early cancers...The ability to circumvent this barrier by using iPSCs from BRCA mutation carriers is a significant breakthrough."

Like Dr. Swisher, he noted that the authors could have considered controls from BRCA 1/2 mutation carriers without cancer.

Further, he noted, "Unexpectedly, the fallopian tube organoids from the BRCA1 mutation carriers formed structures that resemble early tubal precursors, namely STICs, after long-term culture (four months). This is surprising, given that a BRCA1 mutation on its own would not be expected to do this in the absence of other mutations, especially a mutation in the TP53 gene (the earliest somatic mutation in these early cancers), and loss (or methylation) of the other BRCA1 allele."

"While the authors carefully characterized the morphologic features of these organoids, probed for the expression of cancer-related genes, and clearly show the malignant features of the organoids, they did not perform DNA sequencing of these cells to see whether other alterations were acquired during culture that could explain the phenotype," he added. "This remains an open question."

"An interesting feature of this model system is that iPSCs-modeling may predict the severity of disease in BRCA1 patients with cancer," he said. "The authors showed that the organoid cultures of a BRCA1 patient with stage IIIC cancer were more aggressive than those from a BRCA1 patient with stage IIC disease. This is an exciting possibility, although as the authors note, a much larger cohort of samples need to be studied."

SOURCE: https://bit.ly/3JI11YH Cell Reports, online December 28, 2021.

By Marilynn Larkin

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