PEBC Report - Programa de Epigenética y Biología del Cáncer

Thea Tlsty
Thea Tlsty, PhD, is a Professor in
the Department of Pathology,
Director of the Program in Cell
Cycling and Signaling in the UCSF
Comprehensive Cancer Center
and Director of the Center for
Translational Research in the
Molecular Genetics of Cancer at
the University of California, San
Francisco, School of Medicine,
San Francisco, CA. She received a Ph.D. in Molecular
Biology from Washington University. Dr. Tlsty trained with
Dr. Robert Schimke at Stanford University as a
Postdoctoral Fellow and Senior Research Associate in the
Department of Biological Sciences before she was
recruited to the University of North Carolina as Assistant
Professor of Pathology and Member of the UNC
Lineberger Comprehensive Cancer Center. In 1994 she
joined the faculty at UCSF.
Dr. Tlsty studies genetic, epigenetic and functional
changes involved in the earliest steps of epithelial cancers
and how interactions between stromal components and
epithelial cells collaborate to moderate carcinogenesis.
Her research studies of human epithelial cells from healthy
individuals are providing novel insights into how early
molecular events affect genomic integrity and fuel carcinogenesis.
Prior work from her laboratory has shown
that surrounding stroma can dramatically influence
tumorigenesis. She investigates how these changes are
initiated and moderated, as well as their consequences
for clinical disease. These insights are applied in risk
assessment, early detection, and prognostic studies.
Areas of particular interest include human breast carcinogenesis
and the role of tumor suppressor genes in regulating
premalignant phenotypes. Her studies use molecular,
biochemical and cellular analyses to evaluate primary
human cells, develop recombinant models of cell-cell
interactions and apply novel information to intact human
tissue.
Re-programming the Epigenome in
Carcinogenesis
The active acquisition of epigenetic changes is a poorly
understood but important process in development, differentiation,
and disease. Our work has shown that repression of
the p16/pRb pathway in human epithelial cells, a condition
common to stem cells and many tumor cells, induces
dynamic epigenetic remodeling resulting in the targeted
methylation of a selected group of CpG islands. We hypothesized
that cells in this epigenetically plastic state could be
programmed by the microenvironment to acquire epigenetic
changes associated with tumorigenesis. Here, we
describe an in vitro model system where epigenetically plastic
cells were placed in an environment that induced epithelial
to mesenchymal transition (EMT) and led to a program of
acquired de novo DNA methylation at targeted sites. In this
model, we found that repression of E-cadherin transcription
preceded the subsequent acquisition of methylated CpG
sites. Furthermore, the induction of EMT was accompanied
by de novo methylation of several other gene promoters,
including those of the estrogen receptor and Twist. These
data demonstrate that signals from the microenvironment
can induce phenotypic and gene expression changes associated
with targeted de novo epigenetic alterations important
in tumor progression, and that these alterations occur
through a deterministic, rather than stochastic, mechanism.
Given the dynamic epigenetic reprogramming that occurs in
these cells, DNA methylation profiles observed in human
tumors may reflect the history of environmental exposures
during the genesis of a tumor.
Department of Pathology
UCSF Comprehensive Cancer Center,
University of California, San Francisco,
CA, USA
Cancer Epigenetics and Biology Symposium
28 28, 29 May 2009, Barcelona