Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy
Bone metastasis is a major health threat to breast cancer patients. Tumor-derived Jagged1 represents a central node in mediating tumor-stromal interactions that promote osteolytic bone metastasis. Here, we report the development of a highly effective fully human monoclonal antibody against Jagged1 (...
Gespeichert in:
| Veröffentlicht in: | Cancer cell 2017-12, Vol.32 (6), p.731-747.e6 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 747.e6 |
|---|---|
| container_issue | 6 |
| container_start_page | 731 |
| container_title | Cancer cell |
| container_volume | 32 |
| creator | Zheng, Hanqiu Bae, Yangjin Kasimir-Bauer, Sabine Tang, Rebecca Chen, Jin Ren, Guangwen Yuan, Min Esposito, Mark Li, Wenyang Wei, Yong Shen, Minhong Zhang, Lanjing Tupitsyn, Nikolai Pantel, Klaus King, Chadwick Sun, Jan Moriguchi, Jodi Jun, Helen Toni Coxon, Angela Lee, Brendan Kang, Yibin |
| description | Bone metastasis is a major health threat to breast cancer patients. Tumor-derived Jagged1 represents a central node in mediating tumor-stromal interactions that promote osteolytic bone metastasis. Here, we report the development of a highly effective fully human monoclonal antibody against Jagged1 (clone 15D11). In addition to its inhibitory effect on bone metastasis of Jagged1-expressing tumor cells, 15D11 dramatically sensitizes bone metastasis to chemotherapy, which induces Jagged1 expression in osteoblasts to provide a survival niche for cancer cells. We further confirm the bone metastasis-promoting function of osteoblast-derived Jagged1 using osteoblast-specific Jagged1 transgenic mouse model. These findings establish 15D11 as a potential therapeutic agent for the prevention or treatment of bone metastasis.
[Display omitted]
•Jagged1 antibody 15D11 reduces bone metastasis without significant side effects•Chemotherapy induces tumor-protecting Jagged1 in osteoblasts•Transgenic expression of Jagged1 in osteoblasts promotes bone metastasis•15D11 sensitizes bone metastasis to chemotherapy
Zheng et al. develop 15D11, a fully human monoclonal antibody to Jagged1, which inhibits Jagged1 on breast cancer cells as well as blocking metastasis-promoting effects of osteoblast-derived Jagged1 induced by chemotherapy. 15D11 reduces bone metastasis and sensitizes metastases to chemotherapy in mouse models of breast cancer. |
| doi_str_mv | 10.1016/j.ccell.2017.11.002 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5729937</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S1535610817304725</els_id><sourcerecordid>1976440575</sourcerecordid><originalsourceid>FETCH-LOGICAL-c459t-56c8fbca28c4775850097de1db50b5c2b357fb05f401de73cf51596da95db0f93</originalsourceid><addsrcrecordid>eNp9kc1u1DAUhS0EoqXwBEjISzYJthPH8QKkMvyr0AXD2nLsm4xHSTy1nUHD0-PplAo2rK6l-51zrHsQek5JSQltXm1LY2AcS0aoKCktCWEP0DltRVtUTds8zG9e8aKhpD1DT2LckqyiQj5GZ0yyinHOztHP9QaC3sGSnMGXc3Kdtwe81mGA5OYBr5fJhwLr2eLrmMB3o45H9JszGyjeQXB7sPiLHgawFH-HObrkfkHEb_0M-CukjOvoIk4erzYw-XSbd3iKHvV6jPDsbl6gHx_er1efiqvrj59Xl1eFqblMBW9M23dGs9bUQvCWEyKFBWo7TjpuWFdx0XeE9zWhFkRlek65bKyW3Hakl9UFenPy3S3dBNbAnIIe1S64SYeD8tqpfzez26jB7xUXTMpKZIOXdwbB3ywQk5pcPN5dz-CXqKgUTV0TLnhGqxNqgo8xQH8fQ4k6Vqa26rYydaxMUapyZVn14u8f3mv-dJSB1ycA8p32DoKKxsFswLoAJinr3X8DfgP9b6uo</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1976440575</pqid></control><display><type>article</type><title>Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy</title><source>MEDLINE</source><source>Cell Press Free Archives</source><source>Elsevier ScienceDirect Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Zheng, Hanqiu ; Bae, Yangjin ; Kasimir-Bauer, Sabine ; Tang, Rebecca ; Chen, Jin ; Ren, Guangwen ; Yuan, Min ; Esposito, Mark ; Li, Wenyang ; Wei, Yong ; Shen, Minhong ; Zhang, Lanjing ; Tupitsyn, Nikolai ; Pantel, Klaus ; King, Chadwick ; Sun, Jan ; Moriguchi, Jodi ; Jun, Helen Toni ; Coxon, Angela ; Lee, Brendan ; Kang, Yibin</creator><creatorcontrib>Zheng, Hanqiu ; Bae, Yangjin ; Kasimir-Bauer, Sabine ; Tang, Rebecca ; Chen, Jin ; Ren, Guangwen ; Yuan, Min ; Esposito, Mark ; Li, Wenyang ; Wei, Yong ; Shen, Minhong ; Zhang, Lanjing ; Tupitsyn, Nikolai ; Pantel, Klaus ; King, Chadwick ; Sun, Jan ; Moriguchi, Jodi ; Jun, Helen Toni ; Coxon, Angela ; Lee, Brendan ; Kang, Yibin</creatorcontrib><description>Bone metastasis is a major health threat to breast cancer patients. Tumor-derived Jagged1 represents a central node in mediating tumor-stromal interactions that promote osteolytic bone metastasis. Here, we report the development of a highly effective fully human monoclonal antibody against Jagged1 (clone 15D11). In addition to its inhibitory effect on bone metastasis of Jagged1-expressing tumor cells, 15D11 dramatically sensitizes bone metastasis to chemotherapy, which induces Jagged1 expression in osteoblasts to provide a survival niche for cancer cells. We further confirm the bone metastasis-promoting function of osteoblast-derived Jagged1 using osteoblast-specific Jagged1 transgenic mouse model. These findings establish 15D11 as a potential therapeutic agent for the prevention or treatment of bone metastasis.
[Display omitted]
•Jagged1 antibody 15D11 reduces bone metastasis without significant side effects•Chemotherapy induces tumor-protecting Jagged1 in osteoblasts•Transgenic expression of Jagged1 in osteoblasts promotes bone metastasis•15D11 sensitizes bone metastasis to chemotherapy
Zheng et al. develop 15D11, a fully human monoclonal antibody to Jagged1, which inhibits Jagged1 on breast cancer cells as well as blocking metastasis-promoting effects of osteoblast-derived Jagged1 induced by chemotherapy. 15D11 reduces bone metastasis and sensitizes metastases to chemotherapy in mouse models of breast cancer.</description><identifier>ISSN: 1535-6108</identifier><identifier>EISSN: 1878-3686</identifier><identifier>DOI: 10.1016/j.ccell.2017.11.002</identifier><identifier>PMID: 29232552</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Antibodies, Monoclonal - pharmacology ; Antineoplastic Agents - pharmacology ; bone metastasis ; Bone Neoplasms - drug therapy ; Bone Neoplasms - secondary ; breast cancer ; chemoresistance ; Humans ; Jagged-1 Protein - antagonists & inhibitors ; Jagged1 ; Mice ; Mice, Transgenic ; neutralizing antibody ; osteoblastic niche ; osteoblasts ; Osteoblasts - drug effects ; Xenograft Model Antitumor Assays</subject><ispartof>Cancer cell, 2017-12, Vol.32 (6), p.731-747.e6</ispartof><rights>2017 Elsevier Inc.</rights><rights>Copyright © 2017 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c459t-56c8fbca28c4775850097de1db50b5c2b357fb05f401de73cf51596da95db0f93</citedby><cites>FETCH-LOGICAL-c459t-56c8fbca28c4775850097de1db50b5c2b357fb05f401de73cf51596da95db0f93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ccell.2017.11.002$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,777,781,882,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29232552$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zheng, Hanqiu</creatorcontrib><creatorcontrib>Bae, Yangjin</creatorcontrib><creatorcontrib>Kasimir-Bauer, Sabine</creatorcontrib><creatorcontrib>Tang, Rebecca</creatorcontrib><creatorcontrib>Chen, Jin</creatorcontrib><creatorcontrib>Ren, Guangwen</creatorcontrib><creatorcontrib>Yuan, Min</creatorcontrib><creatorcontrib>Esposito, Mark</creatorcontrib><creatorcontrib>Li, Wenyang</creatorcontrib><creatorcontrib>Wei, Yong</creatorcontrib><creatorcontrib>Shen, Minhong</creatorcontrib><creatorcontrib>Zhang, Lanjing</creatorcontrib><creatorcontrib>Tupitsyn, Nikolai</creatorcontrib><creatorcontrib>Pantel, Klaus</creatorcontrib><creatorcontrib>King, Chadwick</creatorcontrib><creatorcontrib>Sun, Jan</creatorcontrib><creatorcontrib>Moriguchi, Jodi</creatorcontrib><creatorcontrib>Jun, Helen Toni</creatorcontrib><creatorcontrib>Coxon, Angela</creatorcontrib><creatorcontrib>Lee, Brendan</creatorcontrib><creatorcontrib>Kang, Yibin</creatorcontrib><title>Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><description>Bone metastasis is a major health threat to breast cancer patients. Tumor-derived Jagged1 represents a central node in mediating tumor-stromal interactions that promote osteolytic bone metastasis. Here, we report the development of a highly effective fully human monoclonal antibody against Jagged1 (clone 15D11). In addition to its inhibitory effect on bone metastasis of Jagged1-expressing tumor cells, 15D11 dramatically sensitizes bone metastasis to chemotherapy, which induces Jagged1 expression in osteoblasts to provide a survival niche for cancer cells. We further confirm the bone metastasis-promoting function of osteoblast-derived Jagged1 using osteoblast-specific Jagged1 transgenic mouse model. These findings establish 15D11 as a potential therapeutic agent for the prevention or treatment of bone metastasis.
[Display omitted]
•Jagged1 antibody 15D11 reduces bone metastasis without significant side effects•Chemotherapy induces tumor-protecting Jagged1 in osteoblasts•Transgenic expression of Jagged1 in osteoblasts promotes bone metastasis•15D11 sensitizes bone metastasis to chemotherapy
Zheng et al. develop 15D11, a fully human monoclonal antibody to Jagged1, which inhibits Jagged1 on breast cancer cells as well as blocking metastasis-promoting effects of osteoblast-derived Jagged1 induced by chemotherapy. 15D11 reduces bone metastasis and sensitizes metastases to chemotherapy in mouse models of breast cancer.</description><subject>Animals</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>bone metastasis</subject><subject>Bone Neoplasms - drug therapy</subject><subject>Bone Neoplasms - secondary</subject><subject>breast cancer</subject><subject>chemoresistance</subject><subject>Humans</subject><subject>Jagged-1 Protein - antagonists & inhibitors</subject><subject>Jagged1</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>neutralizing antibody</subject><subject>osteoblastic niche</subject><subject>osteoblasts</subject><subject>Osteoblasts - drug effects</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1u1DAUhS0EoqXwBEjISzYJthPH8QKkMvyr0AXD2nLsm4xHSTy1nUHD0-PplAo2rK6l-51zrHsQek5JSQltXm1LY2AcS0aoKCktCWEP0DltRVtUTds8zG9e8aKhpD1DT2LckqyiQj5GZ0yyinHOztHP9QaC3sGSnMGXc3Kdtwe81mGA5OYBr5fJhwLr2eLrmMB3o45H9JszGyjeQXB7sPiLHgawFH-HObrkfkHEb_0M-CukjOvoIk4erzYw-XSbd3iKHvV6jPDsbl6gHx_er1efiqvrj59Xl1eFqblMBW9M23dGs9bUQvCWEyKFBWo7TjpuWFdx0XeE9zWhFkRlek65bKyW3Hakl9UFenPy3S3dBNbAnIIe1S64SYeD8tqpfzez26jB7xUXTMpKZIOXdwbB3ywQk5pcPN5dz-CXqKgUTV0TLnhGqxNqgo8xQH8fQ4k6Vqa26rYydaxMUapyZVn14u8f3mv-dJSB1ycA8p32DoKKxsFswLoAJinr3X8DfgP9b6uo</recordid><startdate>20171211</startdate><enddate>20171211</enddate><creator>Zheng, Hanqiu</creator><creator>Bae, Yangjin</creator><creator>Kasimir-Bauer, Sabine</creator><creator>Tang, Rebecca</creator><creator>Chen, Jin</creator><creator>Ren, Guangwen</creator><creator>Yuan, Min</creator><creator>Esposito, Mark</creator><creator>Li, Wenyang</creator><creator>Wei, Yong</creator><creator>Shen, Minhong</creator><creator>Zhang, Lanjing</creator><creator>Tupitsyn, Nikolai</creator><creator>Pantel, Klaus</creator><creator>King, Chadwick</creator><creator>Sun, Jan</creator><creator>Moriguchi, Jodi</creator><creator>Jun, Helen Toni</creator><creator>Coxon, Angela</creator><creator>Lee, Brendan</creator><creator>Kang, Yibin</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><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></search><sort><creationdate>20171211</creationdate><title>Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy</title><author>Zheng, Hanqiu ; Bae, Yangjin ; Kasimir-Bauer, Sabine ; Tang, Rebecca ; Chen, Jin ; Ren, Guangwen ; Yuan, Min ; Esposito, Mark ; Li, Wenyang ; Wei, Yong ; Shen, Minhong ; Zhang, Lanjing ; Tupitsyn, Nikolai ; Pantel, Klaus ; King, Chadwick ; Sun, Jan ; Moriguchi, Jodi ; Jun, Helen Toni ; Coxon, Angela ; Lee, Brendan ; Kang, Yibin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c459t-56c8fbca28c4775850097de1db50b5c2b357fb05f401de73cf51596da95db0f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>bone metastasis</topic><topic>Bone Neoplasms - drug therapy</topic><topic>Bone Neoplasms - secondary</topic><topic>breast cancer</topic><topic>chemoresistance</topic><topic>Humans</topic><topic>Jagged-1 Protein - antagonists & inhibitors</topic><topic>Jagged1</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>neutralizing antibody</topic><topic>osteoblastic niche</topic><topic>osteoblasts</topic><topic>Osteoblasts - drug effects</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zheng, Hanqiu</creatorcontrib><creatorcontrib>Bae, Yangjin</creatorcontrib><creatorcontrib>Kasimir-Bauer, Sabine</creatorcontrib><creatorcontrib>Tang, Rebecca</creatorcontrib><creatorcontrib>Chen, Jin</creatorcontrib><creatorcontrib>Ren, Guangwen</creatorcontrib><creatorcontrib>Yuan, Min</creatorcontrib><creatorcontrib>Esposito, Mark</creatorcontrib><creatorcontrib>Li, Wenyang</creatorcontrib><creatorcontrib>Wei, Yong</creatorcontrib><creatorcontrib>Shen, Minhong</creatorcontrib><creatorcontrib>Zhang, Lanjing</creatorcontrib><creatorcontrib>Tupitsyn, Nikolai</creatorcontrib><creatorcontrib>Pantel, Klaus</creatorcontrib><creatorcontrib>King, Chadwick</creatorcontrib><creatorcontrib>Sun, Jan</creatorcontrib><creatorcontrib>Moriguchi, Jodi</creatorcontrib><creatorcontrib>Jun, Helen Toni</creatorcontrib><creatorcontrib>Coxon, Angela</creatorcontrib><creatorcontrib>Lee, Brendan</creatorcontrib><creatorcontrib>Kang, Yibin</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><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 cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zheng, Hanqiu</au><au>Bae, Yangjin</au><au>Kasimir-Bauer, Sabine</au><au>Tang, Rebecca</au><au>Chen, Jin</au><au>Ren, Guangwen</au><au>Yuan, Min</au><au>Esposito, Mark</au><au>Li, Wenyang</au><au>Wei, Yong</au><au>Shen, Minhong</au><au>Zhang, Lanjing</au><au>Tupitsyn, Nikolai</au><au>Pantel, Klaus</au><au>King, Chadwick</au><au>Sun, Jan</au><au>Moriguchi, Jodi</au><au>Jun, Helen Toni</au><au>Coxon, Angela</au><au>Lee, Brendan</au><au>Kang, Yibin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy</atitle><jtitle>Cancer cell</jtitle><addtitle>Cancer Cell</addtitle><date>2017-12-11</date><risdate>2017</risdate><volume>32</volume><issue>6</issue><spage>731</spage><epage>747.e6</epage><pages>731-747.e6</pages><issn>1535-6108</issn><eissn>1878-3686</eissn><abstract>Bone metastasis is a major health threat to breast cancer patients. Tumor-derived Jagged1 represents a central node in mediating tumor-stromal interactions that promote osteolytic bone metastasis. Here, we report the development of a highly effective fully human monoclonal antibody against Jagged1 (clone 15D11). In addition to its inhibitory effect on bone metastasis of Jagged1-expressing tumor cells, 15D11 dramatically sensitizes bone metastasis to chemotherapy, which induces Jagged1 expression in osteoblasts to provide a survival niche for cancer cells. We further confirm the bone metastasis-promoting function of osteoblast-derived Jagged1 using osteoblast-specific Jagged1 transgenic mouse model. These findings establish 15D11 as a potential therapeutic agent for the prevention or treatment of bone metastasis.
[Display omitted]
•Jagged1 antibody 15D11 reduces bone metastasis without significant side effects•Chemotherapy induces tumor-protecting Jagged1 in osteoblasts•Transgenic expression of Jagged1 in osteoblasts promotes bone metastasis•15D11 sensitizes bone metastasis to chemotherapy
Zheng et al. develop 15D11, a fully human monoclonal antibody to Jagged1, which inhibits Jagged1 on breast cancer cells as well as blocking metastasis-promoting effects of osteoblast-derived Jagged1 induced by chemotherapy. 15D11 reduces bone metastasis and sensitizes metastases to chemotherapy in mouse models of breast cancer.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>29232552</pmid><doi>10.1016/j.ccell.2017.11.002</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1535-6108 |
| ispartof | Cancer cell, 2017-12, Vol.32 (6), p.731-747.e6 |
| issn | 1535-6108 1878-3686 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5729937 |
| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Antibodies, Monoclonal - pharmacology Antineoplastic Agents - pharmacology bone metastasis Bone Neoplasms - drug therapy Bone Neoplasms - secondary breast cancer chemoresistance Humans Jagged-1 Protein - antagonists & inhibitors Jagged1 Mice Mice, Transgenic neutralizing antibody osteoblastic niche osteoblasts Osteoblasts - drug effects Xenograft Model Antitumor Assays |
| title | Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-21T05%3A46%3A45IST&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=Therapeutic%20Antibody%20Targeting%20Tumor-%20and%20Osteoblastic%20Niche-Derived%20Jagged1%20Sensitizes%20Bone%20Metastasis%20to%20Chemotherapy&rft.jtitle=Cancer%20cell&rft.au=Zheng,%20Hanqiu&rft.date=2017-12-11&rft.volume=32&rft.issue=6&rft.spage=731&rft.epage=747.e6&rft.pages=731-747.e6&rft.issn=1535-6108&rft.eissn=1878-3686&rft_id=info:doi/10.1016/j.ccell.2017.11.002&rft_dat=%3Cproquest_pubme%3E1976440575%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=1976440575&rft_id=info:pmid/29232552&rft_els_id=S1535610817304725&rfr_iscdi=true |