SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer
Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. We use in vitro and in vivo human prostate cancer models to show that these tumors can...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2017-01, Vol.355 (6320), p.84-88 |
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| creator | Mu, Ping Zhang, Zeda Benelli, Matteo Karthaus, Wouter R. Hoover, Elizabeth Chen, Chi-Chao Wongvipat, John Ku, Sheng-Yu Gao, Dong Cao, Zhen Shah, Neel Adams, Elizabeth J. Abida, Wassim Watson, Philip A. Prandi, Davide Huang, Chun-Hao de Stanchina, Elisa Lowe, Scott W. Ellis, Leigh Beltran, Himisha Rubin, Mark A. Goodrich, David W. Demichelis, Francesca Sawyers, Charles L. |
| description | Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. We use in vitro and in vivo human prostate cancer models to show that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR)–dependent luminal epithelial cells to AR-independent basal-like cells. This lineage plasticity is enabled by the loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2, and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching. |
| doi_str_mv | 10.1126/science.aah4307 |
| format | Article |
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We use in vitro and in vivo human prostate cancer models to show that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR)–dependent luminal epithelial cells to AR-independent basal-like cells. This lineage plasticity is enabled by the loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2, and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.aah4307</identifier><identifier>PMID: 28059768</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Androgen Antagonists - therapeutic use ; Androgen receptors ; Androgens ; Benzamides ; Cancer ; Cell Line, Tumor ; Cell Lineage ; Cell Plasticity ; Deprivation ; Drug resistance ; Drugs ; Epigenetics ; Gene expression ; Hormones ; Humans ; In vitro methods and tests ; Male ; Mathematical models ; Mutation ; Nitriles ; Phenylthiohydantoin - analogs & derivatives ; Phenylthiohydantoin - therapeutic use ; Plastic foam ; Plastic properties ; Plasticity ; Prostate ; Prostate cancer ; Prostatic Neoplasms - drug therapy ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - pathology ; Retinoblastoma ; Retinoblastoma Binding Proteins - genetics ; Sox2 protein ; SOXB1 Transcription Factors - genetics ; SOXB1 Transcription Factors - metabolism ; Suppressors ; Switching ; Therapy ; Tumor suppressor genes ; Tumor Suppressor Protein p53 - genetics ; Tumors ; Ubiquitin-Protein Ligases - genetics</subject><ispartof>Science (American Association for the Advancement of Science), 2017-01, Vol.355 (6320), p.84-88</ispartof><rights>Copyright © 2016 American Association for the Advancement of Science</rights><rights>Copyright © 2017, American Association for the Advancement of Science.</rights><rights>Copyright © 2017, American Association for the Advancement of Science</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c522t-4a0f4e238140439474fcf52d79c2794984ca5160723a5b2cd9cba2df6c49efe33</citedby><cites>FETCH-LOGICAL-c522t-4a0f4e238140439474fcf52d79c2794984ca5160723a5b2cd9cba2df6c49efe33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/24917839$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/24917839$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,776,780,799,881,2871,2872,27901,27902,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28059768$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mu, Ping</creatorcontrib><creatorcontrib>Zhang, Zeda</creatorcontrib><creatorcontrib>Benelli, Matteo</creatorcontrib><creatorcontrib>Karthaus, Wouter R.</creatorcontrib><creatorcontrib>Hoover, Elizabeth</creatorcontrib><creatorcontrib>Chen, Chi-Chao</creatorcontrib><creatorcontrib>Wongvipat, John</creatorcontrib><creatorcontrib>Ku, Sheng-Yu</creatorcontrib><creatorcontrib>Gao, Dong</creatorcontrib><creatorcontrib>Cao, Zhen</creatorcontrib><creatorcontrib>Shah, Neel</creatorcontrib><creatorcontrib>Adams, Elizabeth J.</creatorcontrib><creatorcontrib>Abida, Wassim</creatorcontrib><creatorcontrib>Watson, Philip A.</creatorcontrib><creatorcontrib>Prandi, Davide</creatorcontrib><creatorcontrib>Huang, Chun-Hao</creatorcontrib><creatorcontrib>de Stanchina, Elisa</creatorcontrib><creatorcontrib>Lowe, Scott W.</creatorcontrib><creatorcontrib>Ellis, Leigh</creatorcontrib><creatorcontrib>Beltran, Himisha</creatorcontrib><creatorcontrib>Rubin, Mark A.</creatorcontrib><creatorcontrib>Goodrich, David W.</creatorcontrib><creatorcontrib>Demichelis, Francesca</creatorcontrib><creatorcontrib>Sawyers, Charles L.</creatorcontrib><title>SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. We use in vitro and in vivo human prostate cancer models to show that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR)–dependent luminal epithelial cells to AR-independent basal-like cells. This lineage plasticity is enabled by the loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2, and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching.</description><subject>Androgen Antagonists - therapeutic use</subject><subject>Androgen receptors</subject><subject>Androgens</subject><subject>Benzamides</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Cell Lineage</subject><subject>Cell Plasticity</subject><subject>Deprivation</subject><subject>Drug resistance</subject><subject>Drugs</subject><subject>Epigenetics</subject><subject>Gene expression</subject><subject>Hormones</subject><subject>Humans</subject><subject>In vitro methods and tests</subject><subject>Male</subject><subject>Mathematical models</subject><subject>Mutation</subject><subject>Nitriles</subject><subject>Phenylthiohydantoin - analogs & derivatives</subject><subject>Phenylthiohydantoin - therapeutic use</subject><subject>Plastic foam</subject><subject>Plastic properties</subject><subject>Plasticity</subject><subject>Prostate</subject><subject>Prostate cancer</subject><subject>Prostatic Neoplasms - drug therapy</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Prostatic Neoplasms - pathology</subject><subject>Retinoblastoma</subject><subject>Retinoblastoma Binding Proteins - genetics</subject><subject>Sox2 protein</subject><subject>SOXB1 Transcription Factors - genetics</subject><subject>SOXB1 Transcription Factors - metabolism</subject><subject>Suppressors</subject><subject>Switching</subject><subject>Therapy</subject><subject>Tumor suppressor genes</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumors</subject><subject>Ubiquitin-Protein Ligases - genetics</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1vVCEUxYnR2LG6dqV5iRs3r4ULPGBjok39SJrUaE3cEYZ335TJm8cUGJP-9-U5Y_1YuSB3cX4cDvcQ8pzRE8agO80-4OTxxLlrwal6QBaMGtkaoPwhWVDKu1ZTJY_Ik5zXlFbN8MfkCDSVRnV6QVZfL79Ds01xEwvmZgwTuhU229HlEnwot42b-npKqDPFFU5NwhxycfXZJkzN1WfJ25_Ql3es7XEIc6QyW1aoYONnMj0ljwY3Znx2mMfk2_vzq7OP7cXlh09nby9aLwFKKxwdBALXTFDBjVBi8IOEXhkPygijhXeSdVQBd3IJvjd-6aAfOi8MDsj5MXmz993ulhvsfY2S3Gi3KWxcurXRBfu3MoVru4o_rAShlIBq8PpgkOLNDnOxm5A9jqObMO6yZVpTCtAp_h-o7KQBoLPrq3_QddylqW6iUkpyDZ2YDU_3lK_LywmH-9yM2rlve-jbHvquN17--d17_lfBFXixB9a5xPRbF4YpzQ2_A3z7slQ</recordid><startdate>20170106</startdate><enddate>20170106</enddate><creator>Mu, Ping</creator><creator>Zhang, Zeda</creator><creator>Benelli, Matteo</creator><creator>Karthaus, Wouter R.</creator><creator>Hoover, Elizabeth</creator><creator>Chen, Chi-Chao</creator><creator>Wongvipat, John</creator><creator>Ku, Sheng-Yu</creator><creator>Gao, Dong</creator><creator>Cao, Zhen</creator><creator>Shah, Neel</creator><creator>Adams, Elizabeth J.</creator><creator>Abida, Wassim</creator><creator>Watson, Philip A.</creator><creator>Prandi, Davide</creator><creator>Huang, Chun-Hao</creator><creator>de Stanchina, Elisa</creator><creator>Lowe, Scott W.</creator><creator>Ellis, Leigh</creator><creator>Beltran, Himisha</creator><creator>Rubin, Mark A.</creator><creator>Goodrich, David W.</creator><creator>Demichelis, Francesca</creator><creator>Sawyers, Charles L.</creator><general>American Association for the Advancement of Science</general><general>The American Association for the Advancement of Science</general><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>7QF</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QQ</scope><scope>7QR</scope><scope>7SC</scope><scope>7SE</scope><scope>7SN</scope><scope>7SP</scope><scope>7SR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7TK</scope><scope>7TM</scope><scope>7U5</scope><scope>7U9</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>H94</scope><scope>JG9</scope><scope>JQ2</scope><scope>K9.</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170106</creationdate><title>SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer</title><author>Mu, Ping ; Zhang, Zeda ; Benelli, Matteo ; Karthaus, Wouter R. ; Hoover, Elizabeth ; Chen, Chi-Chao ; Wongvipat, John ; Ku, Sheng-Yu ; Gao, Dong ; Cao, Zhen ; Shah, Neel ; Adams, Elizabeth J. ; Abida, Wassim ; Watson, Philip A. ; Prandi, Davide ; Huang, Chun-Hao ; de Stanchina, Elisa ; Lowe, Scott W. ; Ellis, Leigh ; Beltran, Himisha ; Rubin, Mark A. ; Goodrich, David W. ; Demichelis, Francesca ; Sawyers, Charles L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c522t-4a0f4e238140439474fcf52d79c2794984ca5160723a5b2cd9cba2df6c49efe33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Androgen Antagonists - therapeutic use</topic><topic>Androgen receptors</topic><topic>Androgens</topic><topic>Benzamides</topic><topic>Cancer</topic><topic>Cell Line, Tumor</topic><topic>Cell Lineage</topic><topic>Cell Plasticity</topic><topic>Deprivation</topic><topic>Drug resistance</topic><topic>Drugs</topic><topic>Epigenetics</topic><topic>Gene expression</topic><topic>Hormones</topic><topic>Humans</topic><topic>In vitro methods and tests</topic><topic>Male</topic><topic>Mathematical models</topic><topic>Mutation</topic><topic>Nitriles</topic><topic>Phenylthiohydantoin - analogs & derivatives</topic><topic>Phenylthiohydantoin - therapeutic use</topic><topic>Plastic foam</topic><topic>Plastic properties</topic><topic>Plasticity</topic><topic>Prostate</topic><topic>Prostate cancer</topic><topic>Prostatic Neoplasms - drug therapy</topic><topic>Prostatic Neoplasms - genetics</topic><topic>Prostatic Neoplasms - pathology</topic><topic>Retinoblastoma</topic><topic>Retinoblastoma Binding Proteins - genetics</topic><topic>Sox2 protein</topic><topic>SOXB1 Transcription Factors - genetics</topic><topic>SOXB1 Transcription Factors - metabolism</topic><topic>Suppressors</topic><topic>Switching</topic><topic>Therapy</topic><topic>Tumor suppressor genes</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumors</topic><topic>Ubiquitin-Protein Ligases - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mu, Ping</creatorcontrib><creatorcontrib>Zhang, Zeda</creatorcontrib><creatorcontrib>Benelli, Matteo</creatorcontrib><creatorcontrib>Karthaus, Wouter R.</creatorcontrib><creatorcontrib>Hoover, Elizabeth</creatorcontrib><creatorcontrib>Chen, Chi-Chao</creatorcontrib><creatorcontrib>Wongvipat, John</creatorcontrib><creatorcontrib>Ku, Sheng-Yu</creatorcontrib><creatorcontrib>Gao, Dong</creatorcontrib><creatorcontrib>Cao, Zhen</creatorcontrib><creatorcontrib>Shah, Neel</creatorcontrib><creatorcontrib>Adams, Elizabeth J.</creatorcontrib><creatorcontrib>Abida, Wassim</creatorcontrib><creatorcontrib>Watson, Philip A.</creatorcontrib><creatorcontrib>Prandi, Davide</creatorcontrib><creatorcontrib>Huang, Chun-Hao</creatorcontrib><creatorcontrib>de Stanchina, Elisa</creatorcontrib><creatorcontrib>Lowe, Scott W.</creatorcontrib><creatorcontrib>Ellis, Leigh</creatorcontrib><creatorcontrib>Beltran, Himisha</creatorcontrib><creatorcontrib>Rubin, Mark A.</creatorcontrib><creatorcontrib>Goodrich, David W.</creatorcontrib><creatorcontrib>Demichelis, Francesca</creatorcontrib><creatorcontrib>Sawyers, Charles L.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Aluminium Industry Abstracts</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Ceramic Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Computer and Information Systems Abstracts</collection><collection>Corrosion Abstracts</collection><collection>Ecology Abstracts</collection><collection>Electronics & Communications Abstracts</collection><collection>Engineered Materials Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Materials Business File</collection><collection>Mechanical & Transportation Engineering Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ANTE: Abstracts in New Technology & Engineering</collection><collection>Engineering Research Database</collection><collection>Aerospace Database</collection><collection>Copper Technical Reference Library</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Materials Research Database</collection><collection>ProQuest Computer Science Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Civil Engineering Abstracts</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>Computer and Information Systems Abstracts Academic</collection><collection>Computer and Information Systems Abstracts Professional</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science (American Association for the Advancement of Science)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mu, Ping</au><au>Zhang, Zeda</au><au>Benelli, Matteo</au><au>Karthaus, Wouter R.</au><au>Hoover, Elizabeth</au><au>Chen, Chi-Chao</au><au>Wongvipat, John</au><au>Ku, Sheng-Yu</au><au>Gao, Dong</au><au>Cao, Zhen</au><au>Shah, Neel</au><au>Adams, Elizabeth J.</au><au>Abida, Wassim</au><au>Watson, Philip A.</au><au>Prandi, Davide</au><au>Huang, Chun-Hao</au><au>de Stanchina, Elisa</au><au>Lowe, Scott W.</au><au>Ellis, Leigh</au><au>Beltran, Himisha</au><au>Rubin, Mark A.</au><au>Goodrich, David W.</au><au>Demichelis, Francesca</au><au>Sawyers, Charles L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2017-01-06</date><risdate>2017</risdate><volume>355</volume><issue>6320</issue><spage>84</spage><epage>88</epage><pages>84-88</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><abstract>Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. We use in vitro and in vivo human prostate cancer models to show that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR)–dependent luminal epithelial cells to AR-independent basal-like cells. This lineage plasticity is enabled by the loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2, and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching.</abstract><cop>United States</cop><pub>American Association for the Advancement of Science</pub><pmid>28059768</pmid><doi>10.1126/science.aah4307</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 2017-01, Vol.355 (6320), p.84-88 |
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| language | eng |
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| source | American Association for the Advancement of Science; Jstor Complete Legacy; MEDLINE |
| subjects | Androgen Antagonists - therapeutic use Androgen receptors Androgens Benzamides Cancer Cell Line, Tumor Cell Lineage Cell Plasticity Deprivation Drug resistance Drugs Epigenetics Gene expression Hormones Humans In vitro methods and tests Male Mathematical models Mutation Nitriles Phenylthiohydantoin - analogs & derivatives Phenylthiohydantoin - therapeutic use Plastic foam Plastic properties Plasticity Prostate Prostate cancer Prostatic Neoplasms - drug therapy Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology Retinoblastoma Retinoblastoma Binding Proteins - genetics Sox2 protein SOXB1 Transcription Factors - genetics SOXB1 Transcription Factors - metabolism Suppressors Switching Therapy Tumor suppressor genes Tumor Suppressor Protein p53 - genetics Tumors Ubiquitin-Protein Ligases - genetics |
| title | SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer |
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