Oncostatin M Receptor-Targeted Antibodies Suppress STAT3 Signaling and Inhibit Ovarian Cancer Growth
Although patients with advanced ovarian cancer may respond initially to treatment, disease relapse is common, and nearly 50% of patients do not survive beyond five years, indicating an urgent need for improved therapies. To identify new therapeutic targets, we performed single-cell and nuclear RNA-s...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2021-10, Vol.81 (20), p.5336-5352 |
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| creator | Geethadevi, Anjali Nair, Ajay Parashar, Deepak Ku, Zhiqiang Xiong, Wei Deng, Hui Li, Yongsheng George, Jasmine McAllister, Donna M Sun, Yunguang Kadamberi, Ishaque P Gupta, Prachi Dwinell, Michael B Bradley, William H Rader, Janet S Rui, Hallgeir Schwabe, Robert F Zhang, Ningyan Pradeep, Sunila An, Zhiqiang Chaluvally-Raghavan, Pradeep |
| description | Although patients with advanced ovarian cancer may respond initially to treatment, disease relapse is common, and nearly 50% of patients do not survive beyond five years, indicating an urgent need for improved therapies. To identify new therapeutic targets, we performed single-cell and nuclear RNA-seq data set analyses on 17 human ovarian cancer specimens, revealing the oncostatin M receptor (OSMR) as highly expressed in ovarian cancer cells. Conversely, oncostatin M (OSM), the ligand of OSMR, was highly expressed by tumor-associated macrophages and promoted proliferation and metastasis in cancer cells. Ovarian cancer cell lines and additional patient samples also exhibited elevated levels of OSMR when compared with other cell types in the tumor microenvironment or to normal ovarian tissue samples. OSMR was found to be important for ovarian cancer cell proliferation and migration. Binding of OSM to OSMR caused OSMR-IL6ST dimerization, which is required to produce oncogenic signaling cues for prolonged STAT3 activation. Human monoclonal antibody clones B14 and B21 directed to the extracellular domain of OSMR abrogated OSM-induced OSMR-IL6ST heterodimerization, promoted the internalization and degradation of OSMR, and effectively blocked OSMR-mediated signaling
. Importantly, these antibody clones inhibited the growth of ovarian cancer cells
and
by suppressing oncogenic signaling through OSMR and STAT3 activation. Collectively, this study provides a proof of principle that anti-OSMR antibody can mediate disruption of OSM-induced OSMR-IL6ST dimerization and oncogenic signaling, thus documenting the preclinical therapeutic efficacy of human OSMR antagonist antibodies for immunotherapy in ovarian cancer. SIGNIFICANCE: This study uncovers a role for OSMR in promoting ovarian cancer cell proliferation and metastasis by activating STAT3 signaling and demonstrates the preclinical efficacy of antibody-based OSMR targeting for ovarian cancer treatment. |
| doi_str_mv | 10.1158/0008-5472.CAN-21-0483 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8530981</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2560835870</sourcerecordid><originalsourceid>FETCH-LOGICAL-c477t-f79a23f2b3c3a990318b16904398c0f3de9dd61ddf7aea8b9ddd3e6a0f6cc5733</originalsourceid><addsrcrecordid>eNpVUcFO3DAQtaqisgU-AeRjL6F2Jk6cC9JqRSkSZSVYztbEdnaNsnawvVT9-2YFXdHTzGjeezN6j5Bzzi45F_I7Y0wWomrKy8X8vih5wSoJn8iMC5BFU1XiM5kdMMfka0rP0yg4E1_IMVQgWQ0wI2bpdUgZs_P0F32w2o45xGKFcW2zNXTus-uCcTbRx904RpumZjVfAX10a4-D82uK3tBbv3Gdy3T5itGhpwv02kZ6E8PvvDklRz0OyZ691xPy9ON6tfhZ3C1vbhfzu0JXTZOLvmmxhL7sQAO2LQMuO163rIJWataDsa0xNTemb9Ci7KbJgK2R9bXWogE4IVdvuuOu21qjrc8RBzVGt8X4RwV06v-Ndxu1Dq9KCmCt5JPAt3eBGF52NmW1dUnbYUBvwy6pUtRMgpANm6DiDapjSCna_nCGM7VPSO3dV3v31ZSQKrnaJzTxLj7-eGD9iwT-AmVSjpY</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2560835870</pqid></control><display><type>article</type><title>Oncostatin M Receptor-Targeted Antibodies Suppress STAT3 Signaling and Inhibit Ovarian Cancer Growth</title><source>MEDLINE</source><source>American Association for Cancer Research</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Geethadevi, Anjali ; Nair, Ajay ; Parashar, Deepak ; Ku, Zhiqiang ; Xiong, Wei ; Deng, Hui ; Li, Yongsheng ; George, Jasmine ; McAllister, Donna M ; Sun, Yunguang ; Kadamberi, Ishaque P ; Gupta, Prachi ; Dwinell, Michael B ; Bradley, William H ; Rader, Janet S ; Rui, Hallgeir ; Schwabe, Robert F ; Zhang, Ningyan ; Pradeep, Sunila ; An, Zhiqiang ; Chaluvally-Raghavan, Pradeep</creator><creatorcontrib>Geethadevi, Anjali ; Nair, Ajay ; Parashar, Deepak ; Ku, Zhiqiang ; Xiong, Wei ; Deng, Hui ; Li, Yongsheng ; George, Jasmine ; McAllister, Donna M ; Sun, Yunguang ; Kadamberi, Ishaque P ; Gupta, Prachi ; Dwinell, Michael B ; Bradley, William H ; Rader, Janet S ; Rui, Hallgeir ; Schwabe, Robert F ; Zhang, Ningyan ; Pradeep, Sunila ; An, Zhiqiang ; Chaluvally-Raghavan, Pradeep</creatorcontrib><description>Although patients with advanced ovarian cancer may respond initially to treatment, disease relapse is common, and nearly 50% of patients do not survive beyond five years, indicating an urgent need for improved therapies. To identify new therapeutic targets, we performed single-cell and nuclear RNA-seq data set analyses on 17 human ovarian cancer specimens, revealing the oncostatin M receptor (OSMR) as highly expressed in ovarian cancer cells. Conversely, oncostatin M (OSM), the ligand of OSMR, was highly expressed by tumor-associated macrophages and promoted proliferation and metastasis in cancer cells. Ovarian cancer cell lines and additional patient samples also exhibited elevated levels of OSMR when compared with other cell types in the tumor microenvironment or to normal ovarian tissue samples. OSMR was found to be important for ovarian cancer cell proliferation and migration. Binding of OSM to OSMR caused OSMR-IL6ST dimerization, which is required to produce oncogenic signaling cues for prolonged STAT3 activation. Human monoclonal antibody clones B14 and B21 directed to the extracellular domain of OSMR abrogated OSM-induced OSMR-IL6ST heterodimerization, promoted the internalization and degradation of OSMR, and effectively blocked OSMR-mediated signaling
. Importantly, these antibody clones inhibited the growth of ovarian cancer cells
and
by suppressing oncogenic signaling through OSMR and STAT3 activation. Collectively, this study provides a proof of principle that anti-OSMR antibody can mediate disruption of OSM-induced OSMR-IL6ST dimerization and oncogenic signaling, thus documenting the preclinical therapeutic efficacy of human OSMR antagonist antibodies for immunotherapy in ovarian cancer. SIGNIFICANCE: This study uncovers a role for OSMR in promoting ovarian cancer cell proliferation and metastasis by activating STAT3 signaling and demonstrates the preclinical efficacy of antibody-based OSMR targeting for ovarian cancer treatment.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-21-0483</identifier><identifier>PMID: 34380633</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Antibodies, Monoclonal - pharmacology ; Apoptosis ; Biomarkers, Tumor - genetics ; Biomarkers, Tumor - metabolism ; Cancer-Associated Fibroblasts - immunology ; Cell Proliferation ; Cytokine Receptor gp130 - genetics ; Cytokine Receptor gp130 - metabolism ; Female ; Gene Expression Regulation, Neoplastic - drug effects ; Humans ; Mice ; Mice, Nude ; Neoplasm Metastasis ; Oncostatin M - genetics ; Oncostatin M - metabolism ; Oncostatin M Receptor beta Subunit - antagonists & inhibitors ; Oncostatin M Receptor beta Subunit - immunology ; Oncostatin M Receptor beta Subunit - metabolism ; Ovarian Neoplasms - immunology ; Ovarian Neoplasms - metabolism ; Ovarian Neoplasms - pathology ; Ovarian Neoplasms - prevention & control ; Prognosis ; STAT3 Transcription Factor - antagonists & inhibitors ; STAT3 Transcription Factor - genetics ; STAT3 Transcription Factor - metabolism ; Tumor Cells, Cultured ; Tumor Microenvironment ; Xenograft Model Antitumor Assays</subject><ispartof>Cancer research (Chicago, Ill.), 2021-10, Vol.81 (20), p.5336-5352</ispartof><rights>2021 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c477t-f79a23f2b3c3a990318b16904398c0f3de9dd61ddf7aea8b9ddd3e6a0f6cc5733</citedby><cites>FETCH-LOGICAL-c477t-f79a23f2b3c3a990318b16904398c0f3de9dd61ddf7aea8b9ddd3e6a0f6cc5733</cites><orcidid>0000-0003-4004-9514 ; 0000-0001-7332-1292 ; 0000-0002-8268-3460 ; 0000-0001-7031-3385 ; 0000-0003-4521-5614 ; 0000-0003-1914-0727 ; 0000-0001-5486-7919 ; 0000-0002-4348-2180 ; 0000-0002-5062-8950 ; 0000-0003-2441-7727</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34380633$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Geethadevi, Anjali</creatorcontrib><creatorcontrib>Nair, Ajay</creatorcontrib><creatorcontrib>Parashar, Deepak</creatorcontrib><creatorcontrib>Ku, Zhiqiang</creatorcontrib><creatorcontrib>Xiong, Wei</creatorcontrib><creatorcontrib>Deng, Hui</creatorcontrib><creatorcontrib>Li, Yongsheng</creatorcontrib><creatorcontrib>George, Jasmine</creatorcontrib><creatorcontrib>McAllister, Donna M</creatorcontrib><creatorcontrib>Sun, Yunguang</creatorcontrib><creatorcontrib>Kadamberi, Ishaque P</creatorcontrib><creatorcontrib>Gupta, Prachi</creatorcontrib><creatorcontrib>Dwinell, Michael B</creatorcontrib><creatorcontrib>Bradley, William H</creatorcontrib><creatorcontrib>Rader, Janet S</creatorcontrib><creatorcontrib>Rui, Hallgeir</creatorcontrib><creatorcontrib>Schwabe, Robert F</creatorcontrib><creatorcontrib>Zhang, Ningyan</creatorcontrib><creatorcontrib>Pradeep, Sunila</creatorcontrib><creatorcontrib>An, Zhiqiang</creatorcontrib><creatorcontrib>Chaluvally-Raghavan, Pradeep</creatorcontrib><title>Oncostatin M Receptor-Targeted Antibodies Suppress STAT3 Signaling and Inhibit Ovarian Cancer Growth</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Although patients with advanced ovarian cancer may respond initially to treatment, disease relapse is common, and nearly 50% of patients do not survive beyond five years, indicating an urgent need for improved therapies. To identify new therapeutic targets, we performed single-cell and nuclear RNA-seq data set analyses on 17 human ovarian cancer specimens, revealing the oncostatin M receptor (OSMR) as highly expressed in ovarian cancer cells. Conversely, oncostatin M (OSM), the ligand of OSMR, was highly expressed by tumor-associated macrophages and promoted proliferation and metastasis in cancer cells. Ovarian cancer cell lines and additional patient samples also exhibited elevated levels of OSMR when compared with other cell types in the tumor microenvironment or to normal ovarian tissue samples. OSMR was found to be important for ovarian cancer cell proliferation and migration. Binding of OSM to OSMR caused OSMR-IL6ST dimerization, which is required to produce oncogenic signaling cues for prolonged STAT3 activation. Human monoclonal antibody clones B14 and B21 directed to the extracellular domain of OSMR abrogated OSM-induced OSMR-IL6ST heterodimerization, promoted the internalization and degradation of OSMR, and effectively blocked OSMR-mediated signaling
. Importantly, these antibody clones inhibited the growth of ovarian cancer cells
and
by suppressing oncogenic signaling through OSMR and STAT3 activation. Collectively, this study provides a proof of principle that anti-OSMR antibody can mediate disruption of OSM-induced OSMR-IL6ST dimerization and oncogenic signaling, thus documenting the preclinical therapeutic efficacy of human OSMR antagonist antibodies for immunotherapy in ovarian cancer. SIGNIFICANCE: This study uncovers a role for OSMR in promoting ovarian cancer cell proliferation and metastasis by activating STAT3 signaling and demonstrates the preclinical efficacy of antibody-based OSMR targeting for ovarian cancer treatment.</description><subject>Animals</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Apoptosis</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Cancer-Associated Fibroblasts - immunology</subject><subject>Cell Proliferation</subject><subject>Cytokine Receptor gp130 - genetics</subject><subject>Cytokine Receptor gp130 - metabolism</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Neoplasm Metastasis</subject><subject>Oncostatin M - genetics</subject><subject>Oncostatin M - metabolism</subject><subject>Oncostatin M Receptor beta Subunit - antagonists & inhibitors</subject><subject>Oncostatin M Receptor beta Subunit - immunology</subject><subject>Oncostatin M Receptor beta Subunit - metabolism</subject><subject>Ovarian Neoplasms - immunology</subject><subject>Ovarian Neoplasms - metabolism</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Ovarian Neoplasms - prevention & control</subject><subject>Prognosis</subject><subject>STAT3 Transcription Factor - antagonists & inhibitors</subject><subject>STAT3 Transcription Factor - genetics</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Tumor Cells, Cultured</subject><subject>Tumor Microenvironment</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUcFO3DAQtaqisgU-AeRjL6F2Jk6cC9JqRSkSZSVYztbEdnaNsnawvVT9-2YFXdHTzGjeezN6j5Bzzi45F_I7Y0wWomrKy8X8vih5wSoJn8iMC5BFU1XiM5kdMMfka0rP0yg4E1_IMVQgWQ0wI2bpdUgZs_P0F32w2o45xGKFcW2zNXTus-uCcTbRx904RpumZjVfAX10a4-D82uK3tBbv3Gdy3T5itGhpwv02kZ6E8PvvDklRz0OyZ691xPy9ON6tfhZ3C1vbhfzu0JXTZOLvmmxhL7sQAO2LQMuO163rIJWataDsa0xNTemb9Ci7KbJgK2R9bXWogE4IVdvuuOu21qjrc8RBzVGt8X4RwV06v-Ndxu1Dq9KCmCt5JPAt3eBGF52NmW1dUnbYUBvwy6pUtRMgpANm6DiDapjSCna_nCGM7VPSO3dV3v31ZSQKrnaJzTxLj7-eGD9iwT-AmVSjpY</recordid><startdate>20211015</startdate><enddate>20211015</enddate><creator>Geethadevi, Anjali</creator><creator>Nair, Ajay</creator><creator>Parashar, Deepak</creator><creator>Ku, Zhiqiang</creator><creator>Xiong, Wei</creator><creator>Deng, Hui</creator><creator>Li, Yongsheng</creator><creator>George, Jasmine</creator><creator>McAllister, Donna M</creator><creator>Sun, Yunguang</creator><creator>Kadamberi, Ishaque P</creator><creator>Gupta, Prachi</creator><creator>Dwinell, Michael B</creator><creator>Bradley, William H</creator><creator>Rader, Janet S</creator><creator>Rui, Hallgeir</creator><creator>Schwabe, Robert F</creator><creator>Zhang, Ningyan</creator><creator>Pradeep, Sunila</creator><creator>An, Zhiqiang</creator><creator>Chaluvally-Raghavan, Pradeep</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4004-9514</orcidid><orcidid>https://orcid.org/0000-0001-7332-1292</orcidid><orcidid>https://orcid.org/0000-0002-8268-3460</orcidid><orcidid>https://orcid.org/0000-0001-7031-3385</orcidid><orcidid>https://orcid.org/0000-0003-4521-5614</orcidid><orcidid>https://orcid.org/0000-0003-1914-0727</orcidid><orcidid>https://orcid.org/0000-0001-5486-7919</orcidid><orcidid>https://orcid.org/0000-0002-4348-2180</orcidid><orcidid>https://orcid.org/0000-0002-5062-8950</orcidid><orcidid>https://orcid.org/0000-0003-2441-7727</orcidid></search><sort><creationdate>20211015</creationdate><title>Oncostatin M Receptor-Targeted Antibodies Suppress STAT3 Signaling and Inhibit Ovarian Cancer Growth</title><author>Geethadevi, Anjali ; Nair, Ajay ; Parashar, Deepak ; Ku, Zhiqiang ; Xiong, Wei ; Deng, Hui ; Li, Yongsheng ; George, Jasmine ; McAllister, Donna M ; Sun, Yunguang ; Kadamberi, Ishaque P ; Gupta, Prachi ; Dwinell, Michael B ; Bradley, William H ; Rader, Janet S ; Rui, Hallgeir ; Schwabe, Robert F ; Zhang, Ningyan ; Pradeep, Sunila ; An, Zhiqiang ; Chaluvally-Raghavan, Pradeep</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c477t-f79a23f2b3c3a990318b16904398c0f3de9dd61ddf7aea8b9ddd3e6a0f6cc5733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Apoptosis</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Cancer-Associated Fibroblasts - immunology</topic><topic>Cell Proliferation</topic><topic>Cytokine Receptor gp130 - genetics</topic><topic>Cytokine Receptor gp130 - metabolism</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Neoplasm Metastasis</topic><topic>Oncostatin M - genetics</topic><topic>Oncostatin M - metabolism</topic><topic>Oncostatin M Receptor beta Subunit - antagonists & inhibitors</topic><topic>Oncostatin M Receptor beta Subunit - immunology</topic><topic>Oncostatin M Receptor beta Subunit - metabolism</topic><topic>Ovarian Neoplasms - immunology</topic><topic>Ovarian Neoplasms - metabolism</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Ovarian Neoplasms - prevention & control</topic><topic>Prognosis</topic><topic>STAT3 Transcription Factor - antagonists & inhibitors</topic><topic>STAT3 Transcription Factor - genetics</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Tumor Cells, Cultured</topic><topic>Tumor Microenvironment</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Geethadevi, Anjali</creatorcontrib><creatorcontrib>Nair, Ajay</creatorcontrib><creatorcontrib>Parashar, Deepak</creatorcontrib><creatorcontrib>Ku, Zhiqiang</creatorcontrib><creatorcontrib>Xiong, Wei</creatorcontrib><creatorcontrib>Deng, Hui</creatorcontrib><creatorcontrib>Li, Yongsheng</creatorcontrib><creatorcontrib>George, Jasmine</creatorcontrib><creatorcontrib>McAllister, Donna M</creatorcontrib><creatorcontrib>Sun, Yunguang</creatorcontrib><creatorcontrib>Kadamberi, Ishaque P</creatorcontrib><creatorcontrib>Gupta, Prachi</creatorcontrib><creatorcontrib>Dwinell, Michael B</creatorcontrib><creatorcontrib>Bradley, William H</creatorcontrib><creatorcontrib>Rader, Janet S</creatorcontrib><creatorcontrib>Rui, Hallgeir</creatorcontrib><creatorcontrib>Schwabe, Robert F</creatorcontrib><creatorcontrib>Zhang, Ningyan</creatorcontrib><creatorcontrib>Pradeep, Sunila</creatorcontrib><creatorcontrib>An, Zhiqiang</creatorcontrib><creatorcontrib>Chaluvally-Raghavan, Pradeep</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Geethadevi, Anjali</au><au>Nair, Ajay</au><au>Parashar, Deepak</au><au>Ku, Zhiqiang</au><au>Xiong, Wei</au><au>Deng, Hui</au><au>Li, Yongsheng</au><au>George, Jasmine</au><au>McAllister, Donna M</au><au>Sun, Yunguang</au><au>Kadamberi, Ishaque P</au><au>Gupta, Prachi</au><au>Dwinell, Michael B</au><au>Bradley, William H</au><au>Rader, Janet S</au><au>Rui, Hallgeir</au><au>Schwabe, Robert F</au><au>Zhang, Ningyan</au><au>Pradeep, Sunila</au><au>An, Zhiqiang</au><au>Chaluvally-Raghavan, Pradeep</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Oncostatin M Receptor-Targeted Antibodies Suppress STAT3 Signaling and Inhibit Ovarian Cancer Growth</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2021-10-15</date><risdate>2021</risdate><volume>81</volume><issue>20</issue><spage>5336</spage><epage>5352</epage><pages>5336-5352</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><abstract>Although patients with advanced ovarian cancer may respond initially to treatment, disease relapse is common, and nearly 50% of patients do not survive beyond five years, indicating an urgent need for improved therapies. To identify new therapeutic targets, we performed single-cell and nuclear RNA-seq data set analyses on 17 human ovarian cancer specimens, revealing the oncostatin M receptor (OSMR) as highly expressed in ovarian cancer cells. Conversely, oncostatin M (OSM), the ligand of OSMR, was highly expressed by tumor-associated macrophages and promoted proliferation and metastasis in cancer cells. Ovarian cancer cell lines and additional patient samples also exhibited elevated levels of OSMR when compared with other cell types in the tumor microenvironment or to normal ovarian tissue samples. OSMR was found to be important for ovarian cancer cell proliferation and migration. Binding of OSM to OSMR caused OSMR-IL6ST dimerization, which is required to produce oncogenic signaling cues for prolonged STAT3 activation. Human monoclonal antibody clones B14 and B21 directed to the extracellular domain of OSMR abrogated OSM-induced OSMR-IL6ST heterodimerization, promoted the internalization and degradation of OSMR, and effectively blocked OSMR-mediated signaling
. Importantly, these antibody clones inhibited the growth of ovarian cancer cells
and
by suppressing oncogenic signaling through OSMR and STAT3 activation. Collectively, this study provides a proof of principle that anti-OSMR antibody can mediate disruption of OSM-induced OSMR-IL6ST dimerization and oncogenic signaling, thus documenting the preclinical therapeutic efficacy of human OSMR antagonist antibodies for immunotherapy in ovarian cancer. SIGNIFICANCE: This study uncovers a role for OSMR in promoting ovarian cancer cell proliferation and metastasis by activating STAT3 signaling and demonstrates the preclinical efficacy of antibody-based OSMR targeting for ovarian cancer treatment.</abstract><cop>United States</cop><pmid>34380633</pmid><doi>10.1158/0008-5472.CAN-21-0483</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0003-4004-9514</orcidid><orcidid>https://orcid.org/0000-0001-7332-1292</orcidid><orcidid>https://orcid.org/0000-0002-8268-3460</orcidid><orcidid>https://orcid.org/0000-0001-7031-3385</orcidid><orcidid>https://orcid.org/0000-0003-4521-5614</orcidid><orcidid>https://orcid.org/0000-0003-1914-0727</orcidid><orcidid>https://orcid.org/0000-0001-5486-7919</orcidid><orcidid>https://orcid.org/0000-0002-4348-2180</orcidid><orcidid>https://orcid.org/0000-0002-5062-8950</orcidid><orcidid>https://orcid.org/0000-0003-2441-7727</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0008-5472 |
| ispartof | Cancer research (Chicago, Ill.), 2021-10, Vol.81 (20), p.5336-5352 |
| issn | 0008-5472 1538-7445 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8530981 |
| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Antibodies, Monoclonal - pharmacology Apoptosis Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Cancer-Associated Fibroblasts - immunology Cell Proliferation Cytokine Receptor gp130 - genetics Cytokine Receptor gp130 - metabolism Female Gene Expression Regulation, Neoplastic - drug effects Humans Mice Mice, Nude Neoplasm Metastasis Oncostatin M - genetics Oncostatin M - metabolism Oncostatin M Receptor beta Subunit - antagonists & inhibitors Oncostatin M Receptor beta Subunit - immunology Oncostatin M Receptor beta Subunit - metabolism Ovarian Neoplasms - immunology Ovarian Neoplasms - metabolism Ovarian Neoplasms - pathology Ovarian Neoplasms - prevention & control Prognosis STAT3 Transcription Factor - antagonists & inhibitors STAT3 Transcription Factor - genetics STAT3 Transcription Factor - metabolism Tumor Cells, Cultured Tumor Microenvironment Xenograft Model Antitumor Assays |
| title | Oncostatin M Receptor-Targeted Antibodies Suppress STAT3 Signaling and Inhibit Ovarian Cancer Growth |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T14%3A35%3A53IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Oncostatin%20M%20Receptor-Targeted%20Antibodies%20Suppress%20STAT3%20Signaling%20and%20Inhibit%20Ovarian%20Cancer%20Growth&rft.jtitle=Cancer%20research%20(Chicago,%20Ill.)&rft.au=Geethadevi,%20Anjali&rft.date=2021-10-15&rft.volume=81&rft.issue=20&rft.spage=5336&rft.epage=5352&rft.pages=5336-5352&rft.issn=0008-5472&rft.eissn=1538-7445&rft_id=info:doi/10.1158/0008-5472.CAN-21-0483&rft_dat=%3Cproquest_pubme%3E2560835870%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2560835870&rft_id=info:pmid/34380633&rfr_iscdi=true |