title: Rapid phenotypic and genomic change in response to therapeutic pressure in prostate cancer inferred by high content analysis of single circulating tumor cells.
abstract: Timely characterization of a cancer's evolution is required to predict treatment efficacy and to detect resistance early. High content analysis of single Circulating Tumor Cells (CTCs) enables sequential characterization of genotypic, morphometric and protein expression alterations in real time over the course of cancer treatment. This concept was investigated in a patient with castrate-resistant prostate cancer progressing through both chemotherapy and targeted therapy. In this case study, we integrate across four timepoints 41 genome-wide copy number variation (CNV) profiles plus morphometric parameters and androgen receptor (AR) protein levels. Remarkably, little change was observed in response to standard chemotherapy, evidenced by the fact that a unique clone (A), exhibiting highly rearranged CNV profiles and AR+ phenotype was found circulating before and after treatment. However, clinical response and subsequent progression after targeted therapy was associated with the drastic depletion of clone A, followed by the sequential emergence of two distinct CTC sub-populations that differed in both AR genotype and expression phenotype. While AR- cells with flat or pseudo-diploid CNV profiles (clone B) were identified at the time of response, a new tumor lineage of AR+ cells (clone C) with CNV altered profiles was detected during relapse. We showed that clone C, despite phylogenetically related to clone A, possessed a unique set of somatic CNV alterations, including MYC amplification, an event linked to hormone escape. Interesting, we showed that both clones acquired AR gene amplification by deploying different evolutionary paths. Overall, these data demonstrate the timeframe of tumor evolution in response to therapy and provide a framework for the multi-scale analysis of fluid biopsies to quantify and monitor disease evolution in individual patients.
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Angel E
authors.initials: AE
authors.lastname: Dago
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America; Skyline Genomics, Roslyn Heights, New York, United States of America.
authors.forename: Asya
authors.initials: A
authors.lastname: Stepansky
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Anders
authors.initials: A
authors.lastname: Carlsson
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Madelyn
authors.initials: M
authors.lastname: Luttgen
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America; Skyline Genomics, Roslyn Heights, New York, United States of America.
authors.forename: Jude
authors.initials: J
authors.lastname: Kendall
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America; Department of Molecular and Cellular Biology, Stony Brook University, Stony Brook, New York, United States of America.
authors.forename: Timour
authors.initials: T
authors.lastname: Baslan
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Anand
authors.initials: A
authors.lastname: Kolatkar
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Wigler
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America; Department of Pathology, Scripps Clinic, La Jolla, California, United States of America.
authors.forename: Kelly
authors.initials: K
authors.lastname: Bethel
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Gross
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Hicks
authors.affiliation: Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Kuhn
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002869:Chromosome Aberrations; D060965:Clonal Evolution; D056915:DNA Copy Number Variations; D023281:Genomics; D006801:Humans; D007150:Immunohistochemistry; D042541:Intracellular Space; D008297:Male; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D064129:Prostatic Neoplasms, Castration-Resistant; D021381:Protein Transport; D011944:Receptors, Androgen / Q000378:metabolism; D059010:Single-Cell Analysis
chemical_list: C410798:AR protein, human; D011944:Receptors, Androgen
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