Breastcanceristhemostprevalentcanceramongwomenandleadstoabout40,000metastaticrelateddeaths annuallyintheUnitedStates.Circulatingtumorcells(CTCs)shedfromtheprimarytumorintothecirculatory system.TheseCTCsarethendisplacedindistantorganswheremetastatictumorseventuallyarise.Distinctive breastcancerCTCsareassumedtoresultfromdiscretepatternsofmutatedcancergenes.Nonetheless,the contribution of epigenetic changes to the development of individual CTC characteristics is unknown. DNA methylationatcytosinesinCpGdinucleotidesiscriticalinprogramminggeneexpressionanditsdisruptionisa typical hallmark of cancer. Vertebrate CpG islands are short spreads of DNA sequences that differ from the typicalgenomicpatternbybeingGC-richandpredominantlyunmethylated.Incancercells,someCpGislands becomestronglymethylated,whichresultsinrepressionofgenetranscription.Additionally,partiallymethylated domains(PMDs)arefoundingenepoorregionswhichcorrespondtolamina-attachmentdomains.PMDsare thoughttobelinkedtogeneexpression,butnotenoughisknownaboutwhytheircorrespondingdomainsexist orabouttheirsinglecellcomposition.Methylomeshavealsobeenlinkedtoenhancersthatcontrolacohortof gene expression. Our lab has established several patient-derived CTC lines, allowing me to analyze the methylomes in CTCs for the first time. By studying the methylomes of CTCs using whole genome bisulfite sequencing (WGBS), I hope to understand if methylation patterns in CTCs are heterogeneous and how this variationcontributestometastasis.FindingsfromWGBSanalysishavedemonstratedthattheCTClinesBrx50 andBrx61appeartobelessmethylatedwhencomparedtotheCTClinesBrx07andBrx68.Intriguingly,Brx07 andBrx68aremoremetastaticwhencomparedtoBrx50andBrx61.Thesespecificareasthatvarybetweenthe CTCs?methylomescouldbepotentialareasofinterestformetastasis.
PublicHealthRelevanceStatement CTCs hold the key to understanding the biology of metastasis and provides a biomarker to noninvasively measuretheevolutionoftumorgenotypesduringtreatmentanddiseaseprogressionofbreastcancer,therefore makingthemtargetsforthepreventionofmetastasis.IdentifyingDNAmethylationsignaturesinCTCswillextend our ability to classify breast cancer and to predict the prognosis by using methylation patterns, an outcome beyondwhatiscurrentlypossible.
| Ortiz, Veronica; Yu, Min (2018) Analyzing Circulating Tumor Cells One at a Time. Trends Cell Biol 28:764-775 |
