The present thesis focuses on the characterization and exploration of the specificities of the CTCs, which, as precursors of metastasis, provide important models to identify and understand key pathways that underlie their ability to disseminate and form metastases. This thesis presents two projects concerning CTCs in the context of prostate and breast cancer. In prostate cancer, we studied the hypomethylation-associated silencing of large chromatin domains, whose contribution to tumorigenesis is uncertain. Through high-resolution genome-wide single-cell DNA methylation sequencing, we identified 40 core domains that are uniformly hypomethylated from the earliest detectable stages of prostate malignancy through metastatic CTCs. Nested among these repressive domains are smaller loci with preserved methylation that escape silencing and are enriched for cell proliferation genes. Transcriptionally silenced genes within the core hypomethylated domains are. enriched for immune-related genes; prominent among these is, single gene cluster harboring all five CDI genes that present lipid antigens to NKT cells and four IFI16-related interferon-inducible genes Implicated in innate immunity. The restoration of CDl or IFII6 murine orthologs in immuno-competent mice abrogates tumorigenesis, accompanied by the activation of antitumor immunity. Thus, early epigenetic changes may shape tumorigenesis, targeting collocated genes within defined chromosomal loci. Hypomethylation domains are detectable in blood specimens enriched for CTCs. In breast cancer, we studied genes that restrain tumor progression by conducted a genome wide CRISPR loss-of-function screen and identified HECTD4, a poorly characterized E3 ubiquitin ligase, as highly enriched. Consistent with a tumor suppressive role of the gene, both in-vitro anchorage-independent assays and mouse xenografts models demonstrated a striking growth advantage by HECTD4-depleted cells. ln reconstitution assays, HECTD4 demonstrated ubiquitination enzymatic activity and unbiased proteomics screening identified COX-2 as a major ubiquitination target. HECTD4 controls CAX-} protein levels by directly mediating its degradation, as well as by regulating its transcriptional induction through its regulatory kinase MKK7, which is also a HECTD4 target gene. Suppression of COX-2