Profiling of Circulating Tumor Cells for Screening of Selective Inhibitors of Tumor‐Initiating Stem‐Like Cells
Abstract A critical barrier to effective cancer therapy is the improvement of drug selectivity, toxicity, and reduced recurrence of tumors expanded from tumor‐initiating stem‐like cells (TICs). The aim is to identify circulating tumor cell (CTC)‐biomarkers and to identify an effective combination of...
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| Format: | Article |
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Wiley
2023-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202206812 |
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| author | Chia‐Lin Chen Juan Carlos Hernandez Dinesh Babu Uthaya Kumar Tatsuya Machida Stanley M. Tahara Anthony El‐Khoueiry Meng Li Vasu Punj Suresh Kumar Swaminathan Ameya Kirtane Yibu Chen Jayanth Panyam Keigo Machida |
| author_facet | Chia‐Lin Chen Juan Carlos Hernandez Dinesh Babu Uthaya Kumar Tatsuya Machida Stanley M. Tahara Anthony El‐Khoueiry Meng Li Vasu Punj Suresh Kumar Swaminathan Ameya Kirtane Yibu Chen Jayanth Panyam Keigo Machida |
| author_sort | Chia‐Lin Chen |
| collection | DOAJ |
| description | Abstract A critical barrier to effective cancer therapy is the improvement of drug selectivity, toxicity, and reduced recurrence of tumors expanded from tumor‐initiating stem‐like cells (TICs). The aim is to identify circulating tumor cell (CTC)‐biomarkers and to identify an effective combination of TIC‐specific, repurposed federal drug administration (FDA)‐approved drugs. Three different types of high‐throughput screens targeting the TIC population are employed: these include a CD133 (+) cell viability screen, a NANOG expression screen, and a drug combination screen. When combined in a refined secondary screening approach that targets Nanog expression with the same FDA‐approved drug library, histone deacetylase (HDAC) inhibitor(s) combined with all‐trans retinoic acid (ATRA) demonstrate the highest efficacy for inhibition of TIC growth in vitro and in vivo. Addition of immune checkpoint inhibitor further decreases recurrence and extends PDX mouse survival. RNA‐seq analysis of TICs reveals that combined drug treatment reduces many Toll‐like receptors (TLR) and stemness genes through repression of the lncRNA MIR22HG. This downregulation induces PTEN and TET2, leading to loss of the self‐renewal property of TICs. Thus, CTC biomarker analysis would predict the prognosis and therapy response to this drug combination. In general, biomarker‐guided stratification of HCC patients and TIC‐targeted therapy should eradicate TICs to extend HCC patient survival. |
| format | Article |
| id | doaj-art-999c7bce83734a00a201565cd6d18f4d |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2023-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-999c7bce83734a00a201565cd6d18f4d2025-08-20T03:36:57ZengWileyAdvanced Science2198-38442023-05-011014n/an/a10.1002/advs.202206812Profiling of Circulating Tumor Cells for Screening of Selective Inhibitors of Tumor‐Initiating Stem‐Like CellsChia‐Lin Chen0Juan Carlos Hernandez1Dinesh Babu Uthaya Kumar2Tatsuya Machida3Stanley M. Tahara4Anthony El‐Khoueiry5Meng Li6Vasu Punj7Suresh Kumar Swaminathan8Ameya Kirtane9Yibu Chen10Jayanth Panyam11Keigo Machida12Departments of Molecular Microbiology and Immunology University of Southern California Los Angeles CA 90033 USADepartments of Molecular Microbiology and Immunology University of Southern California Los Angeles CA 90033 USADepartments of Molecular Microbiology and Immunology University of Southern California Los Angeles CA 90033 USADepartments of Molecular Microbiology and Immunology University of Southern California Los Angeles CA 90033 USADepartments of Molecular Microbiology and Immunology University of Southern California Los Angeles CA 90033 USANorris Comprehensive Cancer Center University of Southern California Keck School of Medicine Los Angeles CA 90033 USANorris Medical Library 2003 Zonal Ave Los Angeles CA 90089 USADepartment of Medicine University of Southern California Keck School of Medicine and Norris Comprehensive Cancer Center Los Angeles CA 90089 USADepartment of Pharmaceutics University of Minnesota Minneapolis MN 55455 USADepartment of Pharmaceutics University of Minnesota Minneapolis MN 55455 USANorris Medical Library 2003 Zonal Ave Los Angeles CA 90089 USADepartment of Pharmaceutics University of Minnesota Minneapolis MN 55455 USADepartments of Molecular Microbiology and Immunology University of Southern California Los Angeles CA 90033 USAAbstract A critical barrier to effective cancer therapy is the improvement of drug selectivity, toxicity, and reduced recurrence of tumors expanded from tumor‐initiating stem‐like cells (TICs). The aim is to identify circulating tumor cell (CTC)‐biomarkers and to identify an effective combination of TIC‐specific, repurposed federal drug administration (FDA)‐approved drugs. Three different types of high‐throughput screens targeting the TIC population are employed: these include a CD133 (+) cell viability screen, a NANOG expression screen, and a drug combination screen. When combined in a refined secondary screening approach that targets Nanog expression with the same FDA‐approved drug library, histone deacetylase (HDAC) inhibitor(s) combined with all‐trans retinoic acid (ATRA) demonstrate the highest efficacy for inhibition of TIC growth in vitro and in vivo. Addition of immune checkpoint inhibitor further decreases recurrence and extends PDX mouse survival. RNA‐seq analysis of TICs reveals that combined drug treatment reduces many Toll‐like receptors (TLR) and stemness genes through repression of the lncRNA MIR22HG. This downregulation induces PTEN and TET2, leading to loss of the self‐renewal property of TICs. Thus, CTC biomarker analysis would predict the prognosis and therapy response to this drug combination. In general, biomarker‐guided stratification of HCC patients and TIC‐targeted therapy should eradicate TICs to extend HCC patient survival.https://doi.org/10.1002/advs.202206812alcoholhepatocellular carcinoma (HCC)tumor‐initiating stem‐like cells (TIC) |
| spellingShingle | Chia‐Lin Chen Juan Carlos Hernandez Dinesh Babu Uthaya Kumar Tatsuya Machida Stanley M. Tahara Anthony El‐Khoueiry Meng Li Vasu Punj Suresh Kumar Swaminathan Ameya Kirtane Yibu Chen Jayanth Panyam Keigo Machida Profiling of Circulating Tumor Cells for Screening of Selective Inhibitors of Tumor‐Initiating Stem‐Like Cells Advanced Science alcohol hepatocellular carcinoma (HCC) tumor‐initiating stem‐like cells (TIC) |
| title | Profiling of Circulating Tumor Cells for Screening of Selective Inhibitors of Tumor‐Initiating Stem‐Like Cells |
| title_full | Profiling of Circulating Tumor Cells for Screening of Selective Inhibitors of Tumor‐Initiating Stem‐Like Cells |
| title_fullStr | Profiling of Circulating Tumor Cells for Screening of Selective Inhibitors of Tumor‐Initiating Stem‐Like Cells |
| title_full_unstemmed | Profiling of Circulating Tumor Cells for Screening of Selective Inhibitors of Tumor‐Initiating Stem‐Like Cells |
| title_short | Profiling of Circulating Tumor Cells for Screening of Selective Inhibitors of Tumor‐Initiating Stem‐Like Cells |
| title_sort | profiling of circulating tumor cells for screening of selective inhibitors of tumor initiating stem like cells |
| topic | alcohol hepatocellular carcinoma (HCC) tumor‐initiating stem‐like cells (TIC) |
| url | https://doi.org/10.1002/advs.202206812 |
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