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p73 isoforms meet evolution of metastasis

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Abstract

Cancer largely adheres to Darwinian selection. Evolutionary forces are prominent during metastasis, the final and incurable disease stage, where cells acquire combinations of advantageous phenotypic features and interact with a dynamically changing microenvironment, in order to overcome the metastatic bottlenecks, while therapy exerts additional selective pressures. As a strategy to increase their fitness, tumors often co-opt developmental and tissue-homeostasis programs. Herein, 25 years after its discovery, we review TP73, a sibling of the cardinal tumor-suppressor TP53, through the lens of cancer evolution. The TP73 gene regulates a wide range of processes in embryonic development, tissue homeostasis and cancer via an overwhelming number of functionally divergent isoforms. We suggest that TP73 neither merely mimics TP53 via its p53-like tumor-suppressive functions, nor has black-or-white-type effects, as inferred by the antagonism between several of its isoforms in processes like apoptosis and DNA damage response. Rather, under dynamic conditions of selective pressure, the various p73 isoforms which are often co-expressed within the same cancer cells may work towards a common goal by simultaneously activating isoform-specific transcriptional and non-transcriptional programs. Combinatorial co-option of these programs offers selective advantages that overall increase the likelihood for successfully surpassing the barriers of the metastatic cascade. The p73 functional pleiotropy-based capabilities might be present in subclonal populations and expressed dynamically under changing microenvironmental conditions, thereby supporting clonal expansion and propelling evolution of metastasis. Deciphering the critical p73 isoform patterns along the spatiotemporal axes of tumor evolution could identify strategies to target TP73 for prevention and therapy of cancer metastasis.

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Acknowledgements

All figures presented in this work were created using BioRender (biorender.com). AGG acknowledges Deutscher Akademischer Austauschdienst “Hochschulpartnerschaften mit Griechenland” (No. 57513880) and “DNA Damage and Repair and Their Relevance to Carcinogenesis” (No. 57339330).

Funding

This work was supported by Deutsche Forschungsgemeinschaft, TRR81/3 109546710 Project A10 to TS.

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Authors and Affiliations

  1. DNA Damage Laboratory, Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), 15780, Zografou, Greece

    Stella Logotheti & Alexandros G. Georgakilas

  2. Izmir Biomedicine and Genome Center (IBG), 35340, Balcova, Izmir, Turkey

    Athanasia Pavlopoulou & Işıl Takan

  3. Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, 35340, Balcova, Izmir, Turkey

    Athanasia Pavlopoulou & Işıl Takan

  4. Institute of Translational Medicine for Health Care Systems, Medical School Berlin, Hochschule Für Gesundheit Und Medizin, 14197, Berlin, Germany

    Stephan Marquardt

  5. Institute of Molecular Oncology, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps-University, Marburg, Germany

    Thorsten Stiewe

  6. Institute of Lung Health, Giessen, Germany

    Thorsten Stiewe

  7. German Center for Lung Research (DZL), Philipps-University, Marburg, Germany

    Thorsten Stiewe

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  1. Stella Logotheti
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Logotheti, S., Pavlopoulou, A., Marquardt, S. et al. p73 isoforms meet evolution of metastasis. Cancer Metastasis Rev 41, 853–869 (2022). https://doi.org/10.1007/s10555-022-10057-z

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