Matthew Ramsey Email & Phone Number

Boston, Ma, Us

Boston, Ma, Us

Cambridge, Cambridgeshire, Gb

Boston, Ma, Us

Boston, Ma, Us

Boston, Ma, Us

Boston, Ma, Us

Us

In the Ramsey laboratory, we are exploring how alterations in transcriptional programs contribute to the development and progression of Squamous Cell Carcinoma, with the goal of identifying new therapeutic targets that can move from the bench to the bedside. Members of the laboratory employ a variety of classical phenotypic assays (colony forming assays, soft agar assays, trans-well invasion, scratch assays, proliferation/apoptosis analysis by FACS), whole-genome analysis (RNA-seq, ChIP-seq) and biochemical methods (Immunoprecipitation, Chromatin Immunoprecipitation) to dissect transcriptional and signaling pathways regulating key aspects of tumor progression, and to identify potential new therapeutic targets. We also have extensive expertise in the use of in vitro genetic tools including CRISPR/Cas9 (single gene editing, genome-wide screening), shRNA, chemical inhibitors, ORF expression, site-directed mutagenesis, generation of deletion mutants, and luciferase reporter assays, which allow us to carefully dissect gene functions. These tools are complemented by a variety of in vivo pre-clinical systems including CRISPR/Cas9 gene edited models, germline knock-out, conditional knock-out, and transgenic models, orthotopic transplants, carcinogen-induced models, and Xenografts, which allow us to assess the translational potential of our discoveries.

Boston, Ma, Us

A major goal of my postdoctoral research was to understand the in vivo requirement for the transcription factor p63 in Squamous Cell Carcinoma maintenance. I combined a chemical carcinogenesis model with temporally controlled conditional excision of p63 in SCC tumor cells and demonstrated an absolute requirement for p63 in tumor maintenance. I then developed an orthotopic SCC tumor model and identified FGFR signaling as a key p63-regulated pathway, which was activated by release of FGF ligands by fibroblasts in the tumor microenvironment. Finally, I demonstrated the therapeutic efficacy of blocking this pathway in SCC using the FGFR inhibitor AZD4547 in an endogenous tumor model. This work was selected from the submitted abstracts for platform presentations at the 2011 "Mechanisms and Models of Cancer" conference at the Salk Institute for Biological Sciences and at the 2012 "Mechanisms and Models of Cancer" conference at Cold Spring Harbor Laboratories.

Boston, Ma, Us

During my postdoctoral fellowship in the laboratory of Leif Ellisen, I worked to elucidate the mechanisms by which the transcription factor p63 controlled gene expression in Squamous Cell Carcinoma. I developed a Tandem Affinity Purification (TAP) system in SCC cells and identified multiple p63-interacting proteins, including HDAC1/2. I employed co-immunoprecipitation, glycerol gradient fractionation, and deletion mapping to validate the p63-HDAC1/2 interactions. I employed Chromatin Immunoprecipitation (ChIP), luciferase reporters, HDAC inhibitors (TSA, Vorinostat), and shRNA to demonstrate that HDAC1/2 are required for proper repression of p63 target genes, particularly pro-apoptotic target genes such as Puma. I then demonstrated that HDAC inhibition slows SCC tumor growth, and sensitivity to HDAC inhibition was strongly correlated with p63 levels, suggesting that p63 levels could serve as a biomarker of response to HDAC inhibitors. In addition to HDAC1/2, my TAP studies identified members of the SRCAP co-repressor complex as p63-interacting proteins, and we engaged in a collaborative study to demonstrate that the p63-SRCAP complex mediates H2A.Z deposition in the chromatin of p63-repressed genes, further elucidating the mechanisms of p63-dependent transcriptional repression.

Us

As a research technician in the laboratory of James Rheinwald, I worked to understand the mechanisms controlling senescence and immortalization in cultured keratinocytes. I performed lifespan analysis of keratinocytes with mutations in the p53 and Rb pathways, and examined changes in cell cycle inhibitors such as p16INK4a during passage by western blotting and immunohistochemistry. In addition, I compared the effects of defined media and feeder layer systems on lifespan and immortalization potential. This work allowed us to identify telomere-independent roles of p53 and p16INK4a in limiting keratinocyte lifespan. In addition, I was responsible for growing, maintaining, freezing, and distributing cell lines in the Rhienwald Cell Culture Core, which consisted of over 70 unique primary and immortalized keratinocyte, fibroblast, and mesothelial cell lines, as well as multiple SCC cell lines.

Ph.D., Genetics And Molecular Biology

B.S., Biology