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The DNA damage response (DDR) system is critical to maintain genomic integrity and guard against DNA damages. DDR alterations, resulting from DDR gene mutations or epigenetic modifications, have been involved in cancer initiation, progression, and treatment response. However, the role of DDR alterations in cancer metastasis has not been well characterized. Recently, there is increasing evidence of an important role of DDR in regulating multiple facets of cancer metastatic process. In this chapter, we summarize current knowledge of the interplay among DDR alterations, tumor genomic evolution, tumor microenvironment remodeling and emergence of treatment resistance, which ultimately leads to tumor progression and metastasis development. We discuss several pre-clinical models of DDR gene alterations and cancer metastatic predisposition, and clinical evidence of potential DDR involvement in metastasis. We further discuss its clinical relevance in metastatic cancer management, such as the utilization of DDR defects as a biomarker and therapeutic target.
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