FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters
The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in...
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| creator | Li, Mengjiao Nishimura, Tatsunori Takeuchi, Yasuto Hongu, Tsunaki Wang, Yuming Shiokawa, Daisuke Wang, Kang Hirose, Haruka Sasahara, Asako Yano, Masao Ishikawa, Satoko Inokuchi, Masafumi Ota, Tetsuo Tanabe, Masahiko Tada, Kei-ichiro Akiyama, Tetsu Cheng, Xi Liu, Chia-Chi Yamashita, Toshinari Sugano, Sumio Uchida, Yutaro Chiba, Tomoki Asahara, Hiroshi Nakagawa, Masahiro Sato, Shinya Miyagi, Yohei Shimamura, Teppei Nagai, Luis Augusto Kanal, Akinori Katoh, Manami Nomura, Seitaro Nakato, Ryuichiro Suzuki, Yutaka Tojo, Arinobu Voon, Dominic C Ogawa, Seishi Okamoto, Koji Foukakis, Theodoros Gotoh, Noriko |
| description | The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain-containing ion transport regulators (FXYD3), a component of the Na+/K+ pump. Accordingly, FXYD3+ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3+ CSCs were persistent during neoadjuvant chemotherapy, hence linkingthem to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3+ CSCs were sensitive to senolytic Na+/K+ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3+ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targetingthe Na+/K+ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis. |
| doi_str_mv | 10.1172/JCI166666. |
| format | Article |
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To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain-containing ion transport regulators (FXYD3), a component of the Na+/K+ pump. Accordingly, FXYD3+ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3+ CSCs were persistent during neoadjuvant chemotherapy, hence linkingthem to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3+ CSCs were sensitive to senolytic Na+/K+ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3+ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targetingthe Na+/K+ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI166666.</identifier><language>eng</language><publisher>Ann Arbor: American Society for Clinical Investigation</publisher><subject>Alveoli ; Biomedical research ; Breast cancer ; Cardiac glycosides ; Chemoresistance ; Chemotherapy ; Drug resistance ; Genomics ; Glycosides ; Kinases ; Medical prognosis ; Na+/K+-exchanging ATPase ; Patients ; Phenotypic plasticity ; Pregnancy ; Stem cells ; Therapeutic targets ; Transcriptomics ; Tumors</subject><ispartof>The Journal of clinical investigation, 2023-11, Vol.133 (22), p.1-18</ispartof><rights>Copyright American Society for Clinical Investigation Nov 2023</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,860,27901,27902</link.rule.ids></links><search><creatorcontrib>Li, Mengjiao</creatorcontrib><creatorcontrib>Nishimura, Tatsunori</creatorcontrib><creatorcontrib>Takeuchi, Yasuto</creatorcontrib><creatorcontrib>Hongu, Tsunaki</creatorcontrib><creatorcontrib>Wang, Yuming</creatorcontrib><creatorcontrib>Shiokawa, Daisuke</creatorcontrib><creatorcontrib>Wang, Kang</creatorcontrib><creatorcontrib>Hirose, Haruka</creatorcontrib><creatorcontrib>Sasahara, Asako</creatorcontrib><creatorcontrib>Yano, Masao</creatorcontrib><creatorcontrib>Ishikawa, Satoko</creatorcontrib><creatorcontrib>Inokuchi, Masafumi</creatorcontrib><creatorcontrib>Ota, Tetsuo</creatorcontrib><creatorcontrib>Tanabe, Masahiko</creatorcontrib><creatorcontrib>Tada, Kei-ichiro</creatorcontrib><creatorcontrib>Akiyama, Tetsu</creatorcontrib><creatorcontrib>Cheng, Xi</creatorcontrib><creatorcontrib>Liu, Chia-Chi</creatorcontrib><creatorcontrib>Yamashita, Toshinari</creatorcontrib><creatorcontrib>Sugano, Sumio</creatorcontrib><creatorcontrib>Uchida, Yutaro</creatorcontrib><creatorcontrib>Chiba, Tomoki</creatorcontrib><creatorcontrib>Asahara, Hiroshi</creatorcontrib><creatorcontrib>Nakagawa, Masahiro</creatorcontrib><creatorcontrib>Sato, Shinya</creatorcontrib><creatorcontrib>Miyagi, Yohei</creatorcontrib><creatorcontrib>Shimamura, Teppei</creatorcontrib><creatorcontrib>Nagai, Luis Augusto</creatorcontrib><creatorcontrib>Kanal, Akinori</creatorcontrib><creatorcontrib>Katoh, Manami</creatorcontrib><creatorcontrib>Nomura, Seitaro</creatorcontrib><creatorcontrib>Nakato, Ryuichiro</creatorcontrib><creatorcontrib>Suzuki, Yutaka</creatorcontrib><creatorcontrib>Tojo, Arinobu</creatorcontrib><creatorcontrib>Voon, Dominic C</creatorcontrib><creatorcontrib>Ogawa, Seishi</creatorcontrib><creatorcontrib>Okamoto, Koji</creatorcontrib><creatorcontrib>Foukakis, Theodoros</creatorcontrib><creatorcontrib>Gotoh, Noriko</creatorcontrib><title>FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters</title><title>The Journal of clinical investigation</title><description>The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain-containing ion transport regulators (FXYD3), a component of the Na+/K+ pump. Accordingly, FXYD3+ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3+ CSCs were persistent during neoadjuvant chemotherapy, hence linkingthem to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3+ CSCs were sensitive to senolytic Na+/K+ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3+ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targetingthe Na+/K+ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis.</description><subject>Alveoli</subject><subject>Biomedical research</subject><subject>Breast cancer</subject><subject>Cardiac glycosides</subject><subject>Chemoresistance</subject><subject>Chemotherapy</subject><subject>Drug resistance</subject><subject>Genomics</subject><subject>Glycosides</subject><subject>Kinases</subject><subject>Medical prognosis</subject><subject>Na+/K+-exchanging ATPase</subject><subject>Patients</subject><subject>Phenotypic plasticity</subject><subject>Pregnancy</subject><subject>Stem cells</subject><subject>Therapeutic targets</subject><subject>Transcriptomics</subject><subject>Tumors</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><recordid>eNqNTstOwzAQtBBIhMeFL1iJc4odJ9Q5FyrKmQOcqq27gVRuHHZtIfh6EokPYDTSSqOZ2VHqxuiFMcvq7nm1MfczFieqME3jSldZd6oKrStTtkvrztWFyEFrU9dNXaif9evbg4UuDz71ccAQvmFPR2SPiQRwmOhJEmOAHRNKAj8rDJLoCJ5CAMm7MY454NwAX336gI4wZZ4KYgd7zu9lioEYhwQjsfRTluVKnXUYhK7_7qW6XT--rJ7KkeNnnn5uDzHzNEm2lWtbaxrtrP2f6xfR5FTX</recordid><startdate>20231101</startdate><enddate>20231101</enddate><creator>Li, Mengjiao</creator><creator>Nishimura, Tatsunori</creator><creator>Takeuchi, Yasuto</creator><creator>Hongu, Tsunaki</creator><creator>Wang, Yuming</creator><creator>Shiokawa, Daisuke</creator><creator>Wang, Kang</creator><creator>Hirose, Haruka</creator><creator>Sasahara, Asako</creator><creator>Yano, Masao</creator><creator>Ishikawa, 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Yuming ; Shiokawa, Daisuke ; Wang, Kang ; Hirose, Haruka ; Sasahara, Asako ; Yano, Masao ; Ishikawa, Satoko ; Inokuchi, Masafumi ; Ota, Tetsuo ; Tanabe, Masahiko ; Tada, Kei-ichiro ; Akiyama, Tetsu ; Cheng, Xi ; Liu, Chia-Chi ; Yamashita, Toshinari ; Sugano, Sumio ; Uchida, Yutaro ; Chiba, Tomoki ; Asahara, Hiroshi ; Nakagawa, Masahiro ; Sato, Shinya ; Miyagi, Yohei ; Shimamura, Teppei ; Nagai, Luis Augusto ; Kanal, Akinori ; Katoh, Manami ; Nomura, Seitaro ; Nakato, Ryuichiro ; Suzuki, Yutaka ; Tojo, Arinobu ; Voon, Dominic C ; Ogawa, Seishi ; Okamoto, Koji ; Foukakis, Theodoros ; Gotoh, Noriko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-proquest_journals_28993150833</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Alveoli</topic><topic>Biomedical research</topic><topic>Breast cancer</topic><topic>Cardiac 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Masahiko</au><au>Tada, Kei-ichiro</au><au>Akiyama, Tetsu</au><au>Cheng, Xi</au><au>Liu, Chia-Chi</au><au>Yamashita, Toshinari</au><au>Sugano, Sumio</au><au>Uchida, Yutaro</au><au>Chiba, Tomoki</au><au>Asahara, Hiroshi</au><au>Nakagawa, Masahiro</au><au>Sato, Shinya</au><au>Miyagi, Yohei</au><au>Shimamura, Teppei</au><au>Nagai, Luis Augusto</au><au>Kanal, Akinori</au><au>Katoh, Manami</au><au>Nomura, Seitaro</au><au>Nakato, Ryuichiro</au><au>Suzuki, Yutaka</au><au>Tojo, Arinobu</au><au>Voon, Dominic C</au><au>Ogawa, Seishi</au><au>Okamoto, Koji</au><au>Foukakis, Theodoros</au><au>Gotoh, Noriko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters</atitle><jtitle>The Journal of clinical 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To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain-containing ion transport regulators (FXYD3), a component of the Na+/K+ pump. Accordingly, FXYD3+ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3+ CSCs were persistent during neoadjuvant chemotherapy, hence linkingthem to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3+ CSCs were sensitive to senolytic Na+/K+ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3+ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targetingthe Na+/K+ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis.</abstract><cop>Ann Arbor</cop><pub>American Society for Clinical Investigation</pub><doi>10.1172/JCI166666.</doi></addata></record> |
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| subjects | Alveoli Biomedical research Breast cancer Cardiac glycosides Chemoresistance Chemotherapy Drug resistance Genomics Glycosides Kinases Medical prognosis Na+/K+-exchanging ATPase Patients Phenotypic plasticity Pregnancy Stem cells Therapeutic targets Transcriptomics Tumors |
| title | FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters |
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