The integrative genomic and functional immunological analyses of colorectal cancer initiating cells to modulate stemness properties and the susceptibility to immune responses
Abstract Background Colorectal cancer (CRC) initiating cells (CICs) possess self-renewal capabilities and are pivotal in tumor recurrence and resistance to conventional therapies, including immunotherapy. The mechanisms underlying their interaction with immune cells remain unclear. Methods We conduc...
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2025-02-01
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| author | Issam Tout Salim Bougarn Mohammed Toufiq Neha Gopinath Ola Hussein Abbirami Sathappan Evonne Chin-Smith Fazulur Rehaman Rebecca Mathew Lisa Mathew Kun Wang Li Liu Abdulrahman Salhab Oleksandr Soloviov Sara Tomei Waseem Hasan Sahar Da’as Yosra Bejaoui Nady El Hajj Karama Makni Maalej Said Dermime Kakil Rasul Paolo Dellabona Giulia Casorati Alice Turdo Matilde Todaro Giorgio Stassi Soldano Ferrone Xinhui Wang Cristina Maccalli |
| author_facet | Issam Tout Salim Bougarn Mohammed Toufiq Neha Gopinath Ola Hussein Abbirami Sathappan Evonne Chin-Smith Fazulur Rehaman Rebecca Mathew Lisa Mathew Kun Wang Li Liu Abdulrahman Salhab Oleksandr Soloviov Sara Tomei Waseem Hasan Sahar Da’as Yosra Bejaoui Nady El Hajj Karama Makni Maalej Said Dermime Kakil Rasul Paolo Dellabona Giulia Casorati Alice Turdo Matilde Todaro Giorgio Stassi Soldano Ferrone Xinhui Wang Cristina Maccalli |
| author_sort | Issam Tout |
| collection | DOAJ |
| description | Abstract Background Colorectal cancer (CRC) initiating cells (CICs) possess self-renewal capabilities and are pivotal in tumor recurrence and resistance to conventional therapies, including immunotherapy. The mechanisms underlying their interaction with immune cells remain unclear. Methods We conducted a multi-omics analysis—encompassing DNA methylation, total RNA sequencing, and microRNAs (miRNAs; N = 800) profiling on primary CICs and differentiated tumor cell lines, including autologous pairs. Functional immunological assays were performed to assess the impact of miRNA modulation. Results CICs exhibited distinct methylation patterns, transcriptomic profiles, and miRNA expressions compared to differentiated tumor cells (p < 0.05 or 0.01). Notably, miRNA-15a and -196a were implicated in regulating tumorigenic pathways, such as epithelial-to-mesenchymal transition (EMT), TGF-β signaling, and immune modulation. The transfection of CICs with miRNA mimics led to the downregulation of oncogenic EMT markers (CRKL, lncRNA SOX2-OT, JUNB, SMAD3) and TGF-β pathway, resulting in a significant reduction of the in vitro proliferation and the tumorigenicity and migration in a zebrafish xenograft model. Additionally, miRNA-15a enhanced the expression of antigen processing machinery and decreased the expression of immune checkpoints (PD-L1, PD-L2, CTLA-4) and immunosuppressive cytokines (IL-4). The co-culture of HLA-matched lymphocytes with CICs overexpressing the miRNA-15a, elicited robust tumor-specific immune responses, characterized by a shift toward central and effector memory T cell phenotypes and prevented their terminal differentiation and exhaustion. The combination of miRNA modulation with Indoleamine 2,3-dioxygenase blockade and immunomodulating agents further potentiated these effects. Conclusions Our study demonstrates that the modulation of miRNA-15a in CICs not only suppresses the tumorigenic properties but also enhances their visibility to the immune system by upregulating antigen presentation and reducing immunomodulatory molecules. These findings suggest that combining miRNA modulation with epigenetic or immunomodulatory agents holds significant promise for overcoming treatment resistance in CRC. Graphical Abstract |
| format | Article |
| id | doaj-art-f6261c3f95e24e7a8f60d995b4ab1cb0 |
| institution | DOAJ |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
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| series | Journal of Translational Medicine |
| spelling | doaj-art-f6261c3f95e24e7a8f60d995b4ab1cb02025-08-20T03:11:09ZengBMCJournal of Translational Medicine1479-58762025-02-0123112410.1186/s12967-025-06176-0The integrative genomic and functional immunological analyses of colorectal cancer initiating cells to modulate stemness properties and the susceptibility to immune responsesIssam Tout0Salim Bougarn1Mohammed Toufiq2Neha Gopinath3Ola Hussein4Abbirami Sathappan5Evonne Chin-Smith6Fazulur Rehaman7Rebecca Mathew8Lisa Mathew9Kun Wang10Li Liu11Abdulrahman Salhab12Oleksandr Soloviov13Sara Tomei14Waseem Hasan15Sahar Da’as16Yosra Bejaoui17Nady El Hajj18Karama Makni Maalej19Said Dermime20Kakil Rasul21Paolo Dellabona22Giulia Casorati23Alice Turdo24Matilde Todaro25Giorgio Stassi26Soldano Ferrone27Xinhui Wang28Cristina Maccalli29Laboratory of Immune Biological Therapy, Division of Translational Medicine, Research Branch, Sidra MedicineLaboratory of Immune Biological Therapy, Division of Translational Medicine, Research Branch, Sidra MedicineJackson Laboratory for Genomic MedicineLaboratory of Immune Biological Therapy, Division of Translational Medicine, Research Branch, Sidra MedicineLaboratory of Immune Biological Therapy, Division of Translational Medicine, Research Branch, Sidra MedicineAdvanced Imaging Core, Research Branch, Sidra MedicineLaboratory of Immune Biological Therapy, Division of Translational Medicine, Research Branch, Sidra MedicineIntegrated Genomics Services, Research Branch, Sidra MedicineIntegrated Genomics Services, Research Branch, Sidra MedicineIntegrated Genomics Services, Research Branch, Sidra MedicineIntegrated Genomics Services, Research Branch, Sidra MedicineIntegrated Genomics Services, Research Branch, Sidra MedicineIntegrated Genomics Services, Research Branch, Sidra MedicineIntegrated Genomics Services, Research Branch, Sidra MedicineIntegrated Genomics Services, Research Branch, Sidra MedicineZebrafish Functional Genomics Core, Research Department, Sidra MedicineZebrafish Functional Genomics Core, Research Department, Sidra MedicineCollege of Health and Life Science, Hamad Bin Khalifa UniversityCollege of Health and Life Science, Hamad Bin Khalifa UniversityTranslational Cancer Research Facility, Hamad Medical CorporationTranslational Cancer Research Facility, Hamad Medical CorporationNational Center for Cancer Care and Research, Hamad Medical CorporationExperimental Immunology Unit, Department of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele HospitalExperimental Immunology Unit, Department of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele HospitalDepartment of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of PalermoDepartment of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of PalermoDepartment of Precision Medicine in Medical, Surgical and Critical Care, University of PalermoDepartment of Surgery, Massachusetts General Hospital, Harvard Medical SchoolDepartment of Surgery, Massachusetts General Hospital, Harvard Medical SchoolLaboratory of Immune Biological Therapy, Division of Translational Medicine, Research Branch, Sidra MedicineAbstract Background Colorectal cancer (CRC) initiating cells (CICs) possess self-renewal capabilities and are pivotal in tumor recurrence and resistance to conventional therapies, including immunotherapy. The mechanisms underlying their interaction with immune cells remain unclear. Methods We conducted a multi-omics analysis—encompassing DNA methylation, total RNA sequencing, and microRNAs (miRNAs; N = 800) profiling on primary CICs and differentiated tumor cell lines, including autologous pairs. Functional immunological assays were performed to assess the impact of miRNA modulation. Results CICs exhibited distinct methylation patterns, transcriptomic profiles, and miRNA expressions compared to differentiated tumor cells (p < 0.05 or 0.01). Notably, miRNA-15a and -196a were implicated in regulating tumorigenic pathways, such as epithelial-to-mesenchymal transition (EMT), TGF-β signaling, and immune modulation. The transfection of CICs with miRNA mimics led to the downregulation of oncogenic EMT markers (CRKL, lncRNA SOX2-OT, JUNB, SMAD3) and TGF-β pathway, resulting in a significant reduction of the in vitro proliferation and the tumorigenicity and migration in a zebrafish xenograft model. Additionally, miRNA-15a enhanced the expression of antigen processing machinery and decreased the expression of immune checkpoints (PD-L1, PD-L2, CTLA-4) and immunosuppressive cytokines (IL-4). The co-culture of HLA-matched lymphocytes with CICs overexpressing the miRNA-15a, elicited robust tumor-specific immune responses, characterized by a shift toward central and effector memory T cell phenotypes and prevented their terminal differentiation and exhaustion. The combination of miRNA modulation with Indoleamine 2,3-dioxygenase blockade and immunomodulating agents further potentiated these effects. Conclusions Our study demonstrates that the modulation of miRNA-15a in CICs not only suppresses the tumorigenic properties but also enhances their visibility to the immune system by upregulating antigen presentation and reducing immunomodulatory molecules. These findings suggest that combining miRNA modulation with epigenetic or immunomodulatory agents holds significant promise for overcoming treatment resistance in CRC. Graphical Abstracthttps://doi.org/10.1186/s12967-025-06176-0Colorectal cancerCancer initiating cellsMicroRNAsT-cell responsesCombination therapies |
| spellingShingle | Issam Tout Salim Bougarn Mohammed Toufiq Neha Gopinath Ola Hussein Abbirami Sathappan Evonne Chin-Smith Fazulur Rehaman Rebecca Mathew Lisa Mathew Kun Wang Li Liu Abdulrahman Salhab Oleksandr Soloviov Sara Tomei Waseem Hasan Sahar Da’as Yosra Bejaoui Nady El Hajj Karama Makni Maalej Said Dermime Kakil Rasul Paolo Dellabona Giulia Casorati Alice Turdo Matilde Todaro Giorgio Stassi Soldano Ferrone Xinhui Wang Cristina Maccalli The integrative genomic and functional immunological analyses of colorectal cancer initiating cells to modulate stemness properties and the susceptibility to immune responses Journal of Translational Medicine Colorectal cancer Cancer initiating cells MicroRNAs T-cell responses Combination therapies |
| title | The integrative genomic and functional immunological analyses of colorectal cancer initiating cells to modulate stemness properties and the susceptibility to immune responses |
| title_full | The integrative genomic and functional immunological analyses of colorectal cancer initiating cells to modulate stemness properties and the susceptibility to immune responses |
| title_fullStr | The integrative genomic and functional immunological analyses of colorectal cancer initiating cells to modulate stemness properties and the susceptibility to immune responses |
| title_full_unstemmed | The integrative genomic and functional immunological analyses of colorectal cancer initiating cells to modulate stemness properties and the susceptibility to immune responses |
| title_short | The integrative genomic and functional immunological analyses of colorectal cancer initiating cells to modulate stemness properties and the susceptibility to immune responses |
| title_sort | integrative genomic and functional immunological analyses of colorectal cancer initiating cells to modulate stemness properties and the susceptibility to immune responses |
| topic | Colorectal cancer Cancer initiating cells MicroRNAs T-cell responses Combination therapies |
| url | https://doi.org/10.1186/s12967-025-06176-0 |
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