Epithelial/mesenchymal heterogeneity of high‐grade serous ovarian carcinoma samples correlates with miRNA let‐7 levels and predicts tumor growth and metastasis

Chirshev, Evgeny; Hojo, Nozomi; Bertucci, Antonella; Sanderman, Linda; Nguyen, Anthony; Wang, Hanmin; Suzuki, Tise; Brito, Emmanuel; Martinez, Shannalee R.; Castañón, Christine; Mirshahidi, Saied; Vazquez, Marcelo E.; Wat, Pamela; Oberg, Kerby C.; Ioffe, Yevgeniya; Unternaehrer, Juli

doi:10.1002/1878-0261.12762

Cited by 23 publications

(43 citation statements)

References 90 publications

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“…To examine first the signaling response of HGSC cells to in vivo-like, physiological low and high stiffness range reported in HGSC omental metastasis tissues (0.40-33.13 kPa) 16 , we used soft (2 kPa) and stiff (21 kPa) polyacrylamide hydrogels functionalized for cell adhesion with covalently bound COL1. As relevant cell models for the heterogeneous HGSC cell phenotypes, we used relatively platinumsensitive, epithelial (CDH1 + , CDH2 low ) OVCAR4, more resistant and mesenchymal (CDH1 − , CDH2 + ) OVCAR8, and the platinum-sensitive, mesenchymal (CDH1 − , CDH2 low ) TYK-nu, all of HGSC origin and harboring TP53 mutations 19,[21][22][23] (see Supplementary Fig. 6a for corresponding platinum sensitivities in our standard two-dimensional (2D) culture).…”

Section: Resultsmentioning

confidence: 99%

Co-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance

et al. 2021

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Due to its dynamic nature, the evolution of cancer cell-extracellular matrix (ECM) crosstalk, critically affecting metastasis and treatment resistance, remains elusive. Our results show that platinum-chemotherapy itself enhances resistance by progressively changing the cancer cell-intrinsic adhesion signaling and cell-surrounding ECM. Examining ovarian high-grade serous carcinoma (HGSC) transcriptome and histology, we describe the fibrotic ECM heterogeneity at primary tumors and distinct metastatic sites, prior and after chemotherapy. Using cell models from systematic ECM screen to collagen-based 2D and 3D cultures, we demonstrate that both specific ECM substrates and stiffness increase resistance to platinum-mediated, apoptosis-inducing DNA damage via FAK and β1 integrin-pMLC-YAP signaling. Among such substrates around metastatic HGSCs, COL6 was upregulated by chemotherapy and enhanced the resistance of relapse, but not treatment-naïve, HGSC organoids. These results identify matrix adhesion as an adaptive response, driving HGSC aggressiveness via co-evolving ECM composition and sensing, suggesting stromal and tumor strategies for ECM pathway targeting.

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Section: Resultsmentioning

confidence: 99%

Co-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance

et al. 2021

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“…MCF-7 and PANC-1 cells were treated with TGFB1 (10 ng/mL), OVCAR8 and OVSAHO cells were treated with EGF (100 ng/mL). PDX6, a HGSOC chemotherapy naïve sample, was obtained as described [ 22 ]. Deidentified fresh ovarian cancer ascites samples was provided by the LLU Biospecimen Laboratory and were processed by centrifuging.…”

Section: Methodsmentioning

confidence: 99%

“…Let-7 is frequently reduced in many types of cancer [ 13 ]. Let-7 loss correlates with poor prognosis, functions as a biomarker for less differentiated cancer [ 13 , 19 , 20 , 21 ], and predicts tumor growth and metastasis [ 22 ]. Mechanisms for its loss are incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

The Epithelial–Mesenchymal Transcription Factor SNAI1 Represses Transcription of the Tumor Suppressor miRNA let-7 in Cancer

Wang

Chirshev

Hojo

et al. 2021

Cancers

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We aimed to determine the mechanism of epithelial–mesenchymal transition (EMT)-induced stemness in cancer cells. Cancer relapse and metastasis are caused by rare stem-like cells within tumors. Studies of stem cell reprogramming have linked let-7 repression and acquisition of stemness with the EMT factor, SNAI1. The mechanisms for the loss of let-7 in cancer cells are incompletely understood. In four carcinoma cell lines from breast cancer, pancreatic cancer, and ovarian cancer and in ovarian cancer patient-derived cells, we analyzed stem cell phenotype and tumor growth via mRNA, miRNA, and protein expression, spheroid formation, and growth in patient-derived xenografts. We show that treatment with EMT-promoting growth factors or SNAI1 overexpression increased stemness and reduced let-7 expression, while SNAI1 knockdown reduced stemness and restored let-7 expression. Rescue experiments demonstrate that the pro-stemness effects of SNAI1 are mediated via let-7. In vivo, nanoparticle-delivered siRNA successfully knocked down SNAI1 in orthotopic patient-derived xenografts, accompanied by reduced stemness and increased let-7 expression, and reduced tumor burden. Chromatin immunoprecipitation demonstrated that SNAI1 binds the promoters of various let-7 family members, and luciferase assays revealed that SNAI1 represses let-7 transcription. In conclusion, the SNAI1/let-7 axis is an important component of stemness pathways in cancer cells, and this study provides a rationale for future work examining this axis as a potential target for cancer stem cell-specific therapies.

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“…MCF-7 and PANC-1 cells were treated with TGFB1 (10 ng/ml), OVCAR8 and OVSAHO cells were treated with EGF (100 ng/ml). PDX6, a HGSOC chemotherapy naïve sample, was obtained as described 20 . All studies were approved by the Loma Linda University (LLU) institutional review board (IRB).…”

Section: Methodsmentioning

confidence: 99%

“…Let-7 is frequently reduced in many types of cancer 13 . Let-7 loss correlates with poor prognosis, and is a biomarker for less differentiated cancer 13,19 , and predicts tumor growth and metastasis 20 . Mechanisms for its loss are incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

The epithelial-mesenchymal transcription factorSNAI1represses transcription of the tumor suppressor miRNAlet-7in cancer

Wang

Chirshev

Hojo

et al. 2020

Preprint

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We aimed to determine the mechanism of epithelial-mesenchymal transition (EMT)-induced stemness in cancer cells. Cancer relapse and metastasis are caused by rare stem-like cells within tumors. Studies of stem cell reprogramming have linked let-7 repression and acquisition of stemness with the EMT factor, SNAI1. The mechanisms for the loss of let-7 in cancer cells are incompletely understood. In four carcinoma cell lines from breast cancer, pancreatic cancer and ovarian cancer and in ovarian cancer patient-derived cells, we analyzed stem cell phenotype and tumor growth via mRNA, miRNA, and protein expression, spheroid formation, and growth in patient-derived xenografts. We show that treatment with EMT-promoting growth factors or SNAI1 overexpression increased stemness and reduced let-7 expression, while SNAI1 knockdown reduced stemness and restored let-7 expression. Rescue experiments demonstrate that the pro-stemness effects of SNAI1 are mediated via let-7. In vivo, nanoparticle-delivered siRNA successfully knocked down SNAI1 in orthotopic patient-derived xenografts, accompanied by reduced stemness and increased let-7 expression, and reduced tumor burden. Chromatin immunoprecipitation demonstrated that SNAI1 binds the promoters of various let-7 family members, and luciferase assays revealed that SNAI1 represses let-7 transcription. In conclusion, the SNAI1/let-7 axis is an important component of stemness pathways in cancer cells, and this study provides a rationale for future work examining this axis as a potential target for cancer stem cell-specific therapies.

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Epithelial/mesenchymal heterogeneity of high‐grade serous ovarian carcinoma samples correlates with miRNA let‐7 levels and predicts tumor growth and metastasis

Cited by 23 publications

References 90 publications

Co-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance

Co-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance

The Epithelial–Mesenchymal Transcription Factor SNAI1 Represses Transcription of the Tumor Suppressor miRNA let-7 in Cancer

The epithelial-mesenchymal transcription factorSNAI1represses transcription of the tumor suppressor miRNAlet-7in cancer

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