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Epigenetic Regulation of Cancer Dormancy as a Plasticity Mechanism for Metastasis Initiation

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Tumor Dormancy and Recurrence

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Metastasis is responsible for the vast majority of cancer-related deaths. However, our understanding of this complex process is still vastly limited, as is the ability to prevent metastasis. Paradoxically, while clinical trials are commonly performed in patients with advanced metastatic disease, disseminated residual disease is rarely targeted. This eliminates a critical window of opportunity to prevent metastasis. Disseminated tumor cells (DTCs) that seed metastases can remain undetected years to decades after treatment of the primary tumor. Late relapse may be due to the ability of DTCs to survive in a quiescent or dormant state and evade therapies. Quiescence, a reversible growth arrest coupled to robust survival, has emerged as a fitting biological definition for dormancy of single DTCs, but these mechanisms remain as one of the least understood “black boxes” in cancer biology. Because of the reversible nature of dormancy, it has been proposed that epigenetic changes are key in regulating the onset, maintenance and reactivation from this state. This is mediated by the post-translational modification of histones (PTMs), ATP-dependent chromatin remodeling, DNA methylation, and the incorporation of specialized histone variants into chromatin. Many morphogenetic and micro-environmental cues like retinoic acid, TGFβs, hematopoietic stem cell dormancy regulating cues and BMPs are known to cause chromatin modifications that dictate cell fate; these same cues were linked to the induction of cancer cell dormancy. Despite progress in understanding cancer cell dormancy, key questions remain open regarding its epigenetic nature. In this chapter we attempt to address key questions related to this topic using available data or hypothetical scenarios to build a model to further dissect how cancer cell dormancy can be manipulated epigenetically as a therapeutic strategy.

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Authors and Affiliations

  1. Department of Pharmacological Sciences, Laboratory of Cancer Metastasis, Mount Sinai School of Medicine, New York, NY, 10029, USA

    Maria Soledad Sosa

  2. Tisch Cancer Institute, Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, NY, 10029, USA

    Maria Soledad Sosa, Emily Bernstein & Julio A. Aguirre-Ghiso

  3. Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY, 10029, USA

    Emily Bernstein & Julio A. Aguirre-Ghiso

  4. Division of Hematology and Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY, 10029, USA

    Julio A. Aguirre-Ghiso

  5. Department of Otolaryngology, Mount Sinai School of Medicine, New York, NY, 10029, USA

    Julio A. Aguirre-Ghiso

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  1. Maria Soledad Sosa
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  2. Emily Bernstein
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  3. Julio A. Aguirre-Ghiso
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Correspondence to Maria Soledad Sosa , Emily Bernstein or Julio A. Aguirre-Ghiso .

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Editors and Affiliations

  1. Department of Experimental Therapeutics and Department of Urologic Sciences, BC Cancer Agency and University of British Columbia, Vancouver, British Columbia, Canada

    Yuzhuo Wang

  2. School of Life, Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, Buckinghamshire, United Kingdom

    Francesco Crea

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Sosa, M.S., Bernstein, E., Aguirre-Ghiso, J.A. (2017). Epigenetic Regulation of Cancer Dormancy as a Plasticity Mechanism for Metastasis Initiation. In: Wang, Y., Crea, F. (eds) Tumor Dormancy and Recurrence. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-59242-8_1

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