Browsing by Author "Coffey, Donna M."

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    Cell Origins of High-Grade Serous Ovarian Cancer
    (MDPI, 2018-11) Kim, Jaeyeon; Park, Eun Young; Kim, Olga; Schilder, Jeanne M.; Coffey, Donna M.; Cho, Chi-Heum; Bast, Robert C.; Biochemistry and Molecular Biology, School of Medicine
    High-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), is the most common and deadliest type of ovarian cancer. HGSC appears to arise from the ovary, fallopian tube, or peritoneum. As most HGSC cases present with widespread peritoneal metastases, it is often not clear where HGSC truly originates. Traditionally, the ovarian surface epithelium (OSE) was long believed to be the origin of HGSC. Since the late 1990s, the fallopian tube epithelium has emerged as a potential primary origin of HGSC. Particularly, serous tubal intraepithelial carcinoma (STIC), a noninvasive tumor lesion formed preferentially in the distal fallopian tube epithelium, was proposed as a precursor for HGSC. It was hypothesized that STIC lesions would progress, over time, to malignant and metastatic HGSC, arising from the fallopian tube or after implanting on the ovary or peritoneum. Many clinical studies and several mouse models support the fallopian tube STIC origin of HGSC. Current evidence indicates that STIC may serve as a precursor for HGSC in high-risk women carrying germline BRCA1 or 2 mutations. Yet not all STIC lesions appear to progress to clinical HGSCs, nor would all HGSCs arise from STIC lesions, even in high-risk women. Moreover, the clinical importance of STIC remains less clear in women in the general population, in which 85–90% of all HGSCs arise. Recently, increasing attention has been brought to the possibility that many potential precursor or premalignant lesions, though composed of microscopically—and genetically—cancerous cells, do not advance to malignant tumors or lethal malignancies. Hence, rigorous causal evidence would be crucial to establish that STIC is a bona fide premalignant lesion for metastatic HGSC. While not all STICs may transform into malignant tumors, these lesions are clearly associated with increased risk for HGSC. Identification of the molecular characteristics of STICs that predict their malignant potential and clinical behavior would bolster the clinical importance of STIC. Also, as STIC lesions alone cannot account for all HGSCs, other potential cellular origins of HGSC need to be investigated. The fallopian tube stroma in mice, for instance, has been shown to be capable of giving rise to metastatic HGSC, which faithfully recapitulates the clinical behavior and molecular aspect of human HGSC. Elucidating the precise cell(s) of origin of HGSC will be critical for improving the early detection and prevention of ovarian cancer, ultimately reducing ovarian cancer mortality.
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    In vivo modeling of metastatic human high-grade serous ovarian cancer in mice
    (PLOS, 2020-06-04) Kim, Olga; Park, Eun Young; Klinkebiel, David L.; Pack, Svetlana D.; Shin, Yong-Hyun; Abdullaev, Zied; Emerson, Robert E.; Coffey, Donna M.; Kwon, Sun Young; Creighton, Chad J.; Kwon, Sanghoon; Chang, Edmund C.; Chiang, Theodore; Yatsenko, Alexander N.; Chien, Jeremy; Cheon, Dong-Joo; Yang-Hartwich, Yang; Nakshatri, Harikrishna; Nephew, Kenneth P.; Behringer, Richard R.; Fernández, Facundo M.; Cho, Chi-Heum; Vanderhyden, Barbara; Drapkin, Ronny; Bast, Robert C., Jr.; Miller, Kathy D.; Karpf, Adam R.; Kim, Jaeyeon; Biochemistry and Molecular Biology, School of Medicine
    Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies.
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    Targeting progesterone signaling prevents metastatic ovarian cancer
    (National Academy of Science, 2020-12-15) Kim, Olga; Park, Eun Young; Kwon, Sun Young; Shin, Sojin; Emerson, Robert E.; Shin, Yong-Hyun; DeMayo, Francesco J.; Lydon, John P.; Coffey, Donna M.; Hawkins, Shannon M.; Quilliam, Lawrence A.; Cheon, Dong-Joo; Fernández, Facundo M.; Nephew, Kenneth P.; Karpf, Adam R.; Widschwendter, Martin; Sood, Anil K.; Bast, Robert C., Jr.; Godwin, Andrew K.; Miller, Kathy D.; Cho, Chi-Heum; Kim, Jaeyeon; Biochemistry and Molecular Biology, School of Medicine
    Effective cancer prevention requires the discovery and intervention of a factor critical to cancer development. Here we show that ovarian progesterone is a crucial endogenous factor inducing the development of primary tumors progressing to metastatic ovarian cancer in a mouse model of high-grade serous carcinoma (HGSC), the most common and deadliest ovarian cancer type. Blocking progesterone signaling by the pharmacologic inhibitor mifepristone or by genetic deletion of the progesterone receptor (PR) effectively suppressed HGSC development and its peritoneal metastases. Strikingly, mifepristone treatment profoundly improved mouse survival (∼18 human years). Hence, targeting progesterone/PR signaling could offer an effective chemopreventive strategy, particularly in high-risk populations of women carrying a deleterious mutation in the BRCA gene.