Hypoxia-driven mobilization of altruistic cancer stem cells in platinum-treated head and neck cancer
BackgroundHead and neck cancers harbor dormant cancer stem cells (CSCs). This study explores how platinum therapy impacts these cells in a non-genetic manner and the role of hypoxia in this process. Previously, we identified a novel population of CSCs exhibiting an “altruistic” phenotype, sacrificin...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1336882/full |
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| author | Lekhika Pathak Lekhika Pathak Lekhika Pathak Bidisha Pal Bidisha Pal Joyeeta Talukdar Partha Jyoti Saikia Sorra Sandhya Wale Tasabehji Wale Tasabehji Hong Li Jyotirmoy Phukan Jyotirmoy Phukan Anjan Bhuyan Sanjukta Patra Bikul Das Bikul Das Bikul Das Bikul Das Bikul Das |
| author_facet | Lekhika Pathak Lekhika Pathak Lekhika Pathak Bidisha Pal Bidisha Pal Joyeeta Talukdar Partha Jyoti Saikia Sorra Sandhya Wale Tasabehji Wale Tasabehji Hong Li Jyotirmoy Phukan Jyotirmoy Phukan Anjan Bhuyan Sanjukta Patra Bikul Das Bikul Das Bikul Das Bikul Das Bikul Das |
| author_sort | Lekhika Pathak |
| collection | DOAJ |
| description | BackgroundHead and neck cancers harbor dormant cancer stem cells (CSCs). This study explores how platinum therapy impacts these cells in a non-genetic manner and the role of hypoxia in this process. Previously, we identified a novel population of CSCs exhibiting an “altruistic” phenotype, sacrificing self-renewal to promote niche defense (tumor stemness defense, TSD), potentially protecting a dormant subpopulation of CSCs, the reawakening CSC (R-CSC) retaining stress memory. This TSD phenotype involves the activation of the MYC-HIF2α pathway and, importantly, is linked to a hypoxic tumor microenvironment. We termed these TSD+ CSCs “altruistic cancer stem cells” (A-CSCs). Here we investigated the potential role of tumor hypoxia in the mobilization of TSD+ CSCs to the circulation as a part of niche defense against platinum therapy.MethodsWe isolated CTCs and primary tumor cells from head and neck squamous cell carcinoma (HNSCC) patients undergoing platinum therapy (n = 14). We analyzed the TSD phenotype and markers of hypoxia in these cells. Additionally, we further characterized a previously reported pre-clinical model of platinum-induced tumor stemness to study the link between hypoxia, TSD+ CSC emergence, and mobilization to the circulation and bone marrow.ResultsWe isolated TSD+ CTCs with a hypoxic signature from eight out of 14 HNSCC patients. These cells displayed increased proliferation and invasion upon cisplatin treatment, suggesting a role in niche defense. Our pre-clinical model confirmed that hypoxia directly correlates with the expansion of TSD+ CSCs and their mobilization into the circulation and bone marrow following cisplatin treatment. We demonstrated the protection of R-CSCs by TSD+ CSCs. Notably, inhibiting hypoxia alone with tirapazamine did not reduce TSD+ CSCs, CTCs, or R-CSCs. However, combining tirapazamine with FM19G11, a MYC-HIF2α pathway inhibitor, significantly reduced the platinum-induced expansion of both TSD+ CSCs, CTCs, and the presence of R-CSCs in the bone marrow.ConclusionsThis study reveals that HNSCC patients undergoing platinum therapy can harbor TSD+ CTCs exhibiting an altruistic phenotype and a hypoxic signature. Additionally, the pre-clinical study provides a novel non-genetic mechanism of therapy resistance-the altruistic tumor self-defense. The tumor microenvironment, through the emergence of TSD+ CSCs, appears to act collectively to defend the tumor self-identity by hijacking an altruistic stem cell niche defense mechanism. |
| format | Article |
| id | doaj-art-6c7b21ab2914454a93500e8c6bbc5548 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-6c7b21ab2914454a93500e8c6bbc55482025-02-03T06:33:42ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011510.3389/fimmu.2024.13368821336882Hypoxia-driven mobilization of altruistic cancer stem cells in platinum-treated head and neck cancerLekhika Pathak0Lekhika Pathak1Lekhika Pathak2Bidisha Pal3Bidisha Pal4Joyeeta Talukdar5Partha Jyoti Saikia6Sorra Sandhya7Wale Tasabehji8Wale Tasabehji9Hong Li10Jyotirmoy Phukan11Jyotirmoy Phukan12Anjan Bhuyan13Sanjukta Patra14Bikul Das15Bikul Das16Bikul Das17Bikul Das18Bikul Das19Department of Cancer and Stem Cell Biology, KaviKrishna Laboratory, Indian Institute of Technology Guwahati Research Park, Guwahati, Assam, IndiaDepartment of Medical Oncology, KaviKrishna Telemedicine Care, Sualkuchi, Assam, IndiaSchool of Agro and Rural Technology, Indian Institute of Technology, Guwahati, Assam, IndiaDepartment of Experimental Therapeutics, Thoreau Laboratory for Global Health, University of Massachusetts, Lowell, MA, United StatesDepartment of Immunology and Infectious Diseases, Forsyth Institute, Cambridge, MA, United StatesDepartment of Cancer and Stem Cell Biology, KaviKrishna Laboratory, Indian Institute of Technology Guwahati Research Park, Guwahati, Assam, IndiaDepartment of Cancer and Stem Cell Biology, KaviKrishna Laboratory, Indian Institute of Technology Guwahati Research Park, Guwahati, Assam, IndiaDepartment of Cancer and Stem Cell Biology, KaviKrishna Laboratory, Indian Institute of Technology Guwahati Research Park, Guwahati, Assam, IndiaDepartment of Experimental Therapeutics, Thoreau Laboratory for Global Health, University of Massachusetts, Lowell, MA, United StatesDepartment of Immunology and Infectious Diseases, Forsyth Institute, Cambridge, MA, United StatesDepartment of Immunology and Infectious Diseases, Forsyth Institute, Cambridge, MA, United StatesDepartment of Medical Oncology, KaviKrishna Telemedicine Care, Sualkuchi, Assam, IndiaDepartment of Otorhinolaryngology, Guwahati Medical College, Guwahati, Assam, IndiaDepartment of Medical Oncology, KaviKrishna Telemedicine Care, Sualkuchi, Assam, IndiaSchool of Agro and Rural Technology, Indian Institute of Technology, Guwahati, Assam, IndiaDepartment of Cancer and Stem Cell Biology, KaviKrishna Laboratory, Indian Institute of Technology Guwahati Research Park, Guwahati, Assam, IndiaDepartment of Medical Oncology, KaviKrishna Telemedicine Care, Sualkuchi, Assam, IndiaSchool of Agro and Rural Technology, Indian Institute of Technology, Guwahati, Assam, IndiaDepartment of Experimental Therapeutics, Thoreau Laboratory for Global Health, University of Massachusetts, Lowell, MA, United StatesDepartment of Immunology and Infectious Diseases, Forsyth Institute, Cambridge, MA, United StatesBackgroundHead and neck cancers harbor dormant cancer stem cells (CSCs). This study explores how platinum therapy impacts these cells in a non-genetic manner and the role of hypoxia in this process. Previously, we identified a novel population of CSCs exhibiting an “altruistic” phenotype, sacrificing self-renewal to promote niche defense (tumor stemness defense, TSD), potentially protecting a dormant subpopulation of CSCs, the reawakening CSC (R-CSC) retaining stress memory. This TSD phenotype involves the activation of the MYC-HIF2α pathway and, importantly, is linked to a hypoxic tumor microenvironment. We termed these TSD+ CSCs “altruistic cancer stem cells” (A-CSCs). Here we investigated the potential role of tumor hypoxia in the mobilization of TSD+ CSCs to the circulation as a part of niche defense against platinum therapy.MethodsWe isolated CTCs and primary tumor cells from head and neck squamous cell carcinoma (HNSCC) patients undergoing platinum therapy (n = 14). We analyzed the TSD phenotype and markers of hypoxia in these cells. Additionally, we further characterized a previously reported pre-clinical model of platinum-induced tumor stemness to study the link between hypoxia, TSD+ CSC emergence, and mobilization to the circulation and bone marrow.ResultsWe isolated TSD+ CTCs with a hypoxic signature from eight out of 14 HNSCC patients. These cells displayed increased proliferation and invasion upon cisplatin treatment, suggesting a role in niche defense. Our pre-clinical model confirmed that hypoxia directly correlates with the expansion of TSD+ CSCs and their mobilization into the circulation and bone marrow following cisplatin treatment. We demonstrated the protection of R-CSCs by TSD+ CSCs. Notably, inhibiting hypoxia alone with tirapazamine did not reduce TSD+ CSCs, CTCs, or R-CSCs. However, combining tirapazamine with FM19G11, a MYC-HIF2α pathway inhibitor, significantly reduced the platinum-induced expansion of both TSD+ CSCs, CTCs, and the presence of R-CSCs in the bone marrow.ConclusionsThis study reveals that HNSCC patients undergoing platinum therapy can harbor TSD+ CTCs exhibiting an altruistic phenotype and a hypoxic signature. Additionally, the pre-clinical study provides a novel non-genetic mechanism of therapy resistance-the altruistic tumor self-defense. The tumor microenvironment, through the emergence of TSD+ CSCs, appears to act collectively to defend the tumor self-identity by hijacking an altruistic stem cell niche defense mechanism.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1336882/fullcirculating tumor cellshead and neck squamous cell carcinoma (HNSCC)tumor stemness defense (TSD)cancer stem cells (CSCs)tumor hypoxiaplatinum chemotherapy |
| spellingShingle | Lekhika Pathak Lekhika Pathak Lekhika Pathak Bidisha Pal Bidisha Pal Joyeeta Talukdar Partha Jyoti Saikia Sorra Sandhya Wale Tasabehji Wale Tasabehji Hong Li Jyotirmoy Phukan Jyotirmoy Phukan Anjan Bhuyan Sanjukta Patra Bikul Das Bikul Das Bikul Das Bikul Das Bikul Das Hypoxia-driven mobilization of altruistic cancer stem cells in platinum-treated head and neck cancer Frontiers in Immunology circulating tumor cells head and neck squamous cell carcinoma (HNSCC) tumor stemness defense (TSD) cancer stem cells (CSCs) tumor hypoxia platinum chemotherapy |
| title | Hypoxia-driven mobilization of altruistic cancer stem cells in platinum-treated head and neck cancer |
| title_full | Hypoxia-driven mobilization of altruistic cancer stem cells in platinum-treated head and neck cancer |
| title_fullStr | Hypoxia-driven mobilization of altruistic cancer stem cells in platinum-treated head and neck cancer |
| title_full_unstemmed | Hypoxia-driven mobilization of altruistic cancer stem cells in platinum-treated head and neck cancer |
| title_short | Hypoxia-driven mobilization of altruistic cancer stem cells in platinum-treated head and neck cancer |
| title_sort | hypoxia driven mobilization of altruistic cancer stem cells in platinum treated head and neck cancer |
| topic | circulating tumor cells head and neck squamous cell carcinoma (HNSCC) tumor stemness defense (TSD) cancer stem cells (CSCs) tumor hypoxia platinum chemotherapy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1336882/full |
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