The absence of telomerase leads to immune response and tumor regression in zebrafish melanoma
Most cancers re-activate telomerase to maintain telomere length and thus acquire immortality. Activating telomerase promoter mutations are found in many cancers, including melanoma. However, it is unclear when and if telomerase is strictly required during tumorigenesis. We combined the telomerase mutant (tert<sup>-/-</sup>) with two established zebrafish melanoma models. We show that tert<sup>-/-</sup> melanomas initially develop with similar incidence and invasiveness to tert<sup>+/+</sup> tumors. However, they eventually decline in growth and regress. Late tert<sup>-/-</sup> tumors exhibit reduced cell proliferation, increased apoptosis, and melanocyte differentiation. Notably, these tumors show enhanced immune cell infiltration and can resume growth when transplanted into immunocompromised hosts. We propose that telomerase is required for melanoma in zebrafish, albeit at later stages of progression, to sustain tumor growth while avoiding immune rejection and regression. Thus, the absence of telomerase restricts melanoma through tumor-autonomous mechanisms (cell-cycle arrest, apoptosis, and melanocyte differentiation) and a non-tumor-autonomous mechanism (immune rejection).
Authors
- Giulia Allavena (ORCID: https://orcid.org/0000-0003-3267-175X)
- Malia Bird (ORCID: https://orcid.org/0000-0001-8871-155X)
- Da Kang
- Bruno Lopes-Bastos (ORCID: https://orcid.org/0000-0002-0517-9455)
- Mounir El Maï (ORCID: https://orcid.org/0000-0002-7528-2474)
- Jia‐Xing Yue (ORCID: https://orcid.org/0000-0002-2122-9221)
- Tânia Ferreira (ORCID: https://orcid.org/0000-0002-4175-9684)
- Gianni Liti (ORCID: https://orcid.org/0000-0002-2318-0775)
- Seniye Targen (ORCID: https://orcid.org/0000-0002-8957-9359)
- Joana Nabais (ORCID: https://orcid.org/0000-0003-3645-8278)
- Tânia Carvalho (ORCID: https://orcid.org/0000-0002-5283-5013)
- Lorenzo Tattini (ORCID: https://orcid.org/0000-0002-5477-084X)
- Miguel Godinho Ferreira (ORCID: https://orcid.org/0000-0002-8363-7183)
Institutions
- Champalimaud Foundation (PT)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Sun Yat-sen University (CN)
- Institut de Recherche sur le Cancer et le Vieillissement de Nice (FR)
- Sun Yat-sen University Cancer Center (CN)
- Instituto Gulbenkian de Ciência (PT)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.115035
- Citations
- 1
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 0.33
Funders
- Infrastructures en Biologie Santé et Agronomie
- University of Oxford
- Institut National de la Santé et de la Recherche Médicale
- University of Toronto
- Fondation ARC pour la Recherche sur le Cancer
- Centre National de la Recherche Scientifique
- Institut National Du Cancer
- Fundação para a Ciência e a Tecnologia
- European Regional Development Fund