Peritoneal Spread of Ovarian Cancer Harbors Therapeutic Vulnerabilities Regulated by FOXM1 and EGFR/ERBB2 Signaling
Peritoneal spread is the primary mechanism of metastasis of ovarian cancer, and survival of ovarian cancer cells in the peritoneal cavity as nonadherent spheroids and their adherence to the mesothelium of distant organs lead to cancer progression, metastasis, and mortality. However, the mechanisms t...
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| Vydáno v: | Cancer research (Chicago, Ill.) Ročník 80; číslo 24; s. 5554 |
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| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
15.12.2020
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| ISSN: | 1538-7445, 1538-7445 |
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| Abstract | Peritoneal spread is the primary mechanism of metastasis of ovarian cancer, and survival of ovarian cancer cells in the peritoneal cavity as nonadherent spheroids and their adherence to the mesothelium of distant organs lead to cancer progression, metastasis, and mortality. However, the mechanisms that govern this metastatic process in ovarian cancer cells remain poorly understood. In this study, we cultured ovarian cancer cell lines in adherent and nonadherent conditions
and analyzed changes in mRNA and protein levels to identify mechanisms of tumor cell survival and proliferation in adherent and nonadherent cells. EGFR or ERBB2 upregulated ZEB1 in nonadherent cells, which caused resistance to cell death and increased tumor-initiating capacity. Conversely, Forkhead box M1 (FOXM1) was required for the induction of integrin β1, integrin-α V, and integrin-α 5 for adhesion of cancer cells. FOXM1 also upregulated ZEB1, which could act as a feedback inhibitor of FOXM1, and caused the transition of adherent cells to nonadherent cells. Strikingly, the combinatorial treatment with lapatinib [dual kinase inhibitor of EGFR (ERBB1) and ERBB2] and thiostrepton (FOXM1 inhibitor) reduced growth and peritoneal spread of ovarian cancer cells more effectively than either single-agent treatment
. In conclusion, these results demonstrate that FOXM1 and EGFR/ERBB2 pathways are key points of vulnerability for therapy to disrupt peritoneal spread and adhesion of ovarian cancer cells. SIGNIFICANCE: This study describes the mechanism exhibited by ovarian cancer cells required for adherent cell transition to nonadherent form during peritoneal spread and metastasis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/24/5554/F1.large.jpg. |
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| AbstractList | Peritoneal spread is the primary mechanism of metastasis of ovarian cancer, and survival of ovarian cancer cells in the peritoneal cavity as nonadherent spheroids and their adherence to the mesothelium of distant organs lead to cancer progression, metastasis, and mortality. However, the mechanisms that govern this metastatic process in ovarian cancer cells remain poorly understood. In this study, we cultured ovarian cancer cell lines in adherent and nonadherent conditions
and analyzed changes in mRNA and protein levels to identify mechanisms of tumor cell survival and proliferation in adherent and nonadherent cells. EGFR or ERBB2 upregulated ZEB1 in nonadherent cells, which caused resistance to cell death and increased tumor-initiating capacity. Conversely, Forkhead box M1 (FOXM1) was required for the induction of integrin β1, integrin-α V, and integrin-α 5 for adhesion of cancer cells. FOXM1 also upregulated ZEB1, which could act as a feedback inhibitor of FOXM1, and caused the transition of adherent cells to nonadherent cells. Strikingly, the combinatorial treatment with lapatinib [dual kinase inhibitor of EGFR (ERBB1) and ERBB2] and thiostrepton (FOXM1 inhibitor) reduced growth and peritoneal spread of ovarian cancer cells more effectively than either single-agent treatment
. In conclusion, these results demonstrate that FOXM1 and EGFR/ERBB2 pathways are key points of vulnerability for therapy to disrupt peritoneal spread and adhesion of ovarian cancer cells. SIGNIFICANCE: This study describes the mechanism exhibited by ovarian cancer cells required for adherent cell transition to nonadherent form during peritoneal spread and metastasis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/24/5554/F1.large.jpg. Peritoneal spread is the primary mechanism of metastasis of ovarian cancer, and survival of ovarian cancer cells in the peritoneal cavity as nonadherent spheroids and their adherence to the mesothelium of distant organs lead to cancer progression, metastasis, and mortality. However, the mechanisms that govern this metastatic process in ovarian cancer cells remain poorly understood. In this study, we cultured ovarian cancer cell lines in adherent and nonadherent conditions in vitro and analyzed changes in mRNA and protein levels to identify mechanisms of tumor cell survival and proliferation in adherent and nonadherent cells. EGFR or ERBB2 upregulated ZEB1 in nonadherent cells, which caused resistance to cell death and increased tumor-initiating capacity. Conversely, Forkhead box M1 (FOXM1) was required for the induction of integrin β1, integrin-α V, and integrin-α 5 for adhesion of cancer cells. FOXM1 also upregulated ZEB1, which could act as a feedback inhibitor of FOXM1, and caused the transition of adherent cells to nonadherent cells. Strikingly, the combinatorial treatment with lapatinib [dual kinase inhibitor of EGFR (ERBB1) and ERBB2] and thiostrepton (FOXM1 inhibitor) reduced growth and peritoneal spread of ovarian cancer cells more effectively than either single-agent treatment in vivo. In conclusion, these results demonstrate that FOXM1 and EGFR/ERBB2 pathways are key points of vulnerability for therapy to disrupt peritoneal spread and adhesion of ovarian cancer cells. SIGNIFICANCE: This study describes the mechanism exhibited by ovarian cancer cells required for adherent cell transition to nonadherent form during peritoneal spread and metastasis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/24/5554/F1.large.jpg.Peritoneal spread is the primary mechanism of metastasis of ovarian cancer, and survival of ovarian cancer cells in the peritoneal cavity as nonadherent spheroids and their adherence to the mesothelium of distant organs lead to cancer progression, metastasis, and mortality. However, the mechanisms that govern this metastatic process in ovarian cancer cells remain poorly understood. In this study, we cultured ovarian cancer cell lines in adherent and nonadherent conditions in vitro and analyzed changes in mRNA and protein levels to identify mechanisms of tumor cell survival and proliferation in adherent and nonadherent cells. EGFR or ERBB2 upregulated ZEB1 in nonadherent cells, which caused resistance to cell death and increased tumor-initiating capacity. Conversely, Forkhead box M1 (FOXM1) was required for the induction of integrin β1, integrin-α V, and integrin-α 5 for adhesion of cancer cells. FOXM1 also upregulated ZEB1, which could act as a feedback inhibitor of FOXM1, and caused the transition of adherent cells to nonadherent cells. Strikingly, the combinatorial treatment with lapatinib [dual kinase inhibitor of EGFR (ERBB1) and ERBB2] and thiostrepton (FOXM1 inhibitor) reduced growth and peritoneal spread of ovarian cancer cells more effectively than either single-agent treatment in vivo. In conclusion, these results demonstrate that FOXM1 and EGFR/ERBB2 pathways are key points of vulnerability for therapy to disrupt peritoneal spread and adhesion of ovarian cancer cells. SIGNIFICANCE: This study describes the mechanism exhibited by ovarian cancer cells required for adherent cell transition to nonadherent form during peritoneal spread and metastasis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/24/5554/F1.large.jpg. |
| Author | Tsaih, Shirng-Wern Kadamberi, Ishaque P Ramchandran, Ramani Ram, Prahlad T Gopinadhan Nair, Gopa Kumar Lu, Yiling Geethadevi, Anjali Chaluvally-Raghavan, Pradeep Nair, Bindu Uyar, Denise S Pradeep, Sunila Nair, Ajay Parashar, Deepak George, Jasmine Mills, Gordon B Rader, Janet S |
| Author_xml | – sequence: 1 givenname: Deepak orcidid: 0000-0002-5062-8950 surname: Parashar fullname: Parashar, Deepak organization: Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin – sequence: 2 givenname: Bindu orcidid: 0000-0003-4521-5614 surname: Nair fullname: Nair, Bindu organization: Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin – sequence: 3 givenname: Anjali orcidid: 0000-0001-5486-7919 surname: Geethadevi fullname: Geethadevi, Anjali organization: Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin – sequence: 4 givenname: Jasmine surname: George fullname: George, Jasmine organization: Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin – sequence: 5 givenname: Ajay orcidid: 0000-0003-4521-5614 surname: Nair fullname: Nair, Ajay organization: Department of Systems Biology, Columbia University, New York, New York – sequence: 6 givenname: Shirng-Wern orcidid: 0000-0002-9836-4659 surname: Tsaih fullname: Tsaih, Shirng-Wern organization: Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin – sequence: 7 givenname: Ishaque P surname: Kadamberi fullname: Kadamberi, Ishaque P organization: Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin – sequence: 8 givenname: Gopa Kumar orcidid: 0000-0002-2694-8401 surname: Gopinadhan Nair fullname: Gopinadhan Nair, Gopa Kumar organization: Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin – sequence: 9 givenname: Yiling surname: Lu fullname: Lu, Yiling organization: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 10 givenname: Ramani orcidid: 0000-0002-3555-6119 surname: Ramchandran fullname: Ramchandran, Ramani organization: Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin – sequence: 11 givenname: Denise S orcidid: 0000-0002-6081-0799 surname: Uyar fullname: Uyar, Denise S organization: Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin – sequence: 12 givenname: Janet S orcidid: 0000-0001-7031-3385 surname: Rader fullname: Rader, Janet S organization: Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin – sequence: 13 givenname: Prahlad T surname: Ram fullname: Ram, Prahlad T organization: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 14 givenname: Gordon B orcidid: 0000-0002-0144-9614 surname: Mills fullname: Mills, Gordon B organization: Department of Developmental and Cancer Biology, Knight Cancer Institute Oregon Health Science University, Oregon, Portland, Oregon – sequence: 15 givenname: Sunila orcidid: 0000-0003-2441-7727 surname: Pradeep fullname: Pradeep, Sunila email: pchaluvally@mcw.edu, spradeep@mcw.edu organization: Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin – sequence: 16 givenname: Pradeep surname: Chaluvally-Raghavan fullname: Chaluvally-Raghavan, Pradeep email: pchaluvally@mcw.edu, spradeep@mcw.edu organization: Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin |
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| SubjectTerms | Animals Cell Line, Tumor Cell Proliferation - drug effects Cell Proliferation - genetics Cell Survival - drug effects Cell Survival - genetics Disease Models, Animal ErbB Receptors - antagonists & inhibitors ErbB Receptors - genetics ErbB Receptors - metabolism Female Forkhead Box Protein M1 - antagonists & inhibitors Forkhead Box Protein M1 - genetics Forkhead Box Protein M1 - metabolism Gene Knockdown Techniques Humans Lapatinib - pharmacology Lapatinib - therapeutic use Mice Ovarian Neoplasms - metabolism Ovarian Neoplasms - pathology Peritoneal Neoplasms - metabolism Peritoneal Neoplasms - prevention & control Peritoneal Neoplasms - secondary Receptor, ErbB-2 - antagonists & inhibitors Receptor, ErbB-2 - genetics Receptor, ErbB-2 - metabolism Signal Transduction - drug effects Signal Transduction - genetics Thiostrepton - pharmacology Thiostrepton - therapeutic use Transfection |
| Title | Peritoneal Spread of Ovarian Cancer Harbors Therapeutic Vulnerabilities Regulated by FOXM1 and EGFR/ERBB2 Signaling |
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