TY - JOUR
T1 - Epithelial/mesenchymal heterogeneity of high-grade serous ovarian carcinoma samples correlates with miRNA let-7 levels and predicts tumor growth and metastasis
AU - Chirshev, Evgeny
AU - Hojo, Nozomi
AU - Bertucci, Antonella
AU - Sanderman, Linda
AU - Nguyen, Anthony
AU - Wang, Hanmin
AU - Suzuki, Tise
AU - Brito, Emmanuel
AU - Martinez, Shannalee R.
AU - Castañón, Christine
AU - Mirshahidi, Saied
AU - Vazquez, Marcelo E.
AU - Wat, Pamela
AU - Oberg, Kerby C.
AU - Ioffe, Yevgeniya J.
AU - Unternaehrer, Juli J.
N1 - Publisher Copyright:
© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - Patient-derived samples present an advantage over current cell line models of high-grade serous ovarian cancer (HGSOC) that are not always reliable and phenotypically faithful models of in vivo HGSOC. To improve upon cell line models of HGSOC, we set out to characterize a panel of patient-derived cells and determine their epithelial and mesenchymal characteristics. We analyzed RNA and protein expression levels in patient-derived xenograft (PDX) models of HGSOC, and functionally characterized these models using flow cytometry, wound healing assays, invasion assays, and spheroid cultures. Besides in vitro work, we also evaluated the growth characteristics of PDX in vivo (orthotopic PDX). We found that all samples had hybrid characteristics, covering a spectrum from an epithelial-to-mesenchymal state. Samples with a stronger epithelial phenotype were more active in self-renewal assays and more tumorigenic in orthotopic xenograft models as compared to samples with a stronger mesenchymal phenotype, which were more migratory and invasive. Additionally, we observed an inverse association between microRNA let-7 (lethal-7) expression and stemness, consistent with the loss of let-7 being an important component of the cancer stem cell phenotype. We observed that lower let-7 levels were associated with the epithelial state and a lower epithelial mesenchymal transition (EMT) score, more efficient spheroid and tumor formation, and increased sensitivity to platinum-based chemotherapy. Surprisingly, in these HGSOC cells, stemness could be dissociated from invasiveness: Cells with lower let-7 levels were more tumorigenic, but less migratory, and with a lower EMT score, than those with higher let-7 levels. We conclude that let-7 expression and epithelial/mesenchymal state are valuable predictors of HGSOC proliferation, in vitro self-renewal, and tumor burden in vivo.
AB - Patient-derived samples present an advantage over current cell line models of high-grade serous ovarian cancer (HGSOC) that are not always reliable and phenotypically faithful models of in vivo HGSOC. To improve upon cell line models of HGSOC, we set out to characterize a panel of patient-derived cells and determine their epithelial and mesenchymal characteristics. We analyzed RNA and protein expression levels in patient-derived xenograft (PDX) models of HGSOC, and functionally characterized these models using flow cytometry, wound healing assays, invasion assays, and spheroid cultures. Besides in vitro work, we also evaluated the growth characteristics of PDX in vivo (orthotopic PDX). We found that all samples had hybrid characteristics, covering a spectrum from an epithelial-to-mesenchymal state. Samples with a stronger epithelial phenotype were more active in self-renewal assays and more tumorigenic in orthotopic xenograft models as compared to samples with a stronger mesenchymal phenotype, which were more migratory and invasive. Additionally, we observed an inverse association between microRNA let-7 (lethal-7) expression and stemness, consistent with the loss of let-7 being an important component of the cancer stem cell phenotype. We observed that lower let-7 levels were associated with the epithelial state and a lower epithelial mesenchymal transition (EMT) score, more efficient spheroid and tumor formation, and increased sensitivity to platinum-based chemotherapy. Surprisingly, in these HGSOC cells, stemness could be dissociated from invasiveness: Cells with lower let-7 levels were more tumorigenic, but less migratory, and with a lower EMT score, than those with higher let-7 levels. We conclude that let-7 expression and epithelial/mesenchymal state are valuable predictors of HGSOC proliferation, in vitro self-renewal, and tumor burden in vivo.
KW - epithelial/mesenchymal transition
KW - high-grade serous ovarian cancer
KW - microRNA
KW - orthotopic patient-derived xenografts
KW - stem cells
KW - transcriptional regulation
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U2 - 10.1002/1878-0261.12762
DO - 10.1002/1878-0261.12762
M3 - Article
C2 - 32652647
SN - 1574-7891
VL - 14
SP - 2796
EP - 2813
JO - Molecular Oncology
JF - Molecular Oncology
IS - 11
ER -