shyamala maheswaran, phd maheswaran, phd douglas micalizzi, md john milner david miyamoto, md, phd...
TRANSCRIPT
MGH Center For Cancer Research ANNUAL REPORT 2015-201652
. . .Maheswaran Laboratory*
Katherine Broderick
Valentine Comaills, PhD
Rushil Desai
Richard Ebright**
Erin Emmons
Xin Hong, PhD
Sarah Javaid, PhD
Mark Kalinich, MD**
WooJae Kim, PhD
Laura Libby
Joseph LiCausi
Shyamala Maheswaran, PhD
Douglas Micalizzi, MD
John Milner
David Miyamoto, MD, PhD
Shiwei Pan
Erin Silva
Tilak Sundaresan, MD
Nicole Vincent Jordan, PhD
Toshifumi Yae, PhD
Yu (Eric) Zheng, PhD
Marcus Zachariah, MD
*co-directed with Daniel Haber, MD, PhD
** PhD Candidates
Elucidating the role of the tumor microenviroment in breast cancer metastasis
Aberrant expression of transcription
factors, which has been implicated in the
tumorigenesis of several types of cancers,
can constitute a mechanism that induces the
expression of growth and angiogenic factors
in tumors leading to their local increase in
the tumor microenvironment to favor tumor
progression. The transcription factor HOXB9
is overexpressed in a subset of aggressive
breast cancers. Suppression of its partner,
BTG2—a p53 inducible gene—in breast
cancer is also associated with increased
metastasis, recurrence and early death. We
have modeled breast cancer metastasis
using experimental systems that mimic these
molecular aberrations. These model systems
demonstrate that molecular dysfunction
involving gain of HOXB9 expression and
loss of BTG2 expression induce tumoral
secretion of cytokines such as TGFß and
ErbB ligands and angiogenic factors into
the microenvironment. Secretion of these
growth factors induces signaling pathways
that promote tumor cell proliferation,
migration and invasion, angiogenesis, and
distal metastasis. Moreover, they also alter
tumor cell fates, leading to the acquisition of
mesenchymal and stem-like phenotypes which
influence tumor cell responses to radiation
and other therapeutic interventions. Using cell
culture, animal models and patient derived
samples, we will 1) identify the mechanisms
by which these molecular aberrations alter
the tumor microenvironment and delineate
the autocrine and paracrine mechanisms that
influence tumor progression, and 2) identify
the pathways that can be targeted either
alone or in combination to suppress tumor
progression and metastasis in this setting.
Molecular characterization of circulating tumor cells
In collaboration with Drs. Daniel Haber and
Mehmet Toner, I am also interested in the
cellular and molecular characterization of
circulating tumor cells (CTCs). This interest
Metastasis, the leading cause of cancer related mortality, is a highly orchestrated process involving angiogenesis, invasion, intravasation, survival in the vasculature, extravasation and growth at distal sites. The Maheswaran laboratory is focused on understanding the mechanism of this process using in vitro and in vivo model systems and circulating tumor cells, which are putative metastatic precursors. Epithelial to mesenchytmal transition (EMT), an embryonic process reinstated in tumor cells, is a critical modulator of cancer metastasis. EMT is induced by several transcription factors and signaling pathways, and it enhances tumor cell invasion and resistance to apoptosis. We intend to gain greater insight into EMT induced tumor malignancy and identify signaling nodes that render tumor cells susceptible to targeted therapeutic intervention.
Shyamala Maheswaran, PhD
Principal Investigators 53
HOXB9 overexpressing breast tumors produce growth factors that alter the tumor microenvironment.
Selected Publications:
Tajima K, Yae T, Javaid S, Tam O,
Comaills V, Morris R, Wittner BS,
Liu M, Engstrom A, Takahashi F,
Black JC, Ramaswamy S, Shioda T,
Hammell M, Haber DA, Whetstine JR,
Maheswaran S. SETD1A modulates cell
cycle progression through a miRNA
network that regulates p53 target
genes. Nature Comm 2015 (in press).
Aceto N, Bardia A, Miyamoto DT,
Donaldson MC, Wittner BS, Spencer
JA, Yu M, Pely A, Engstrom A, Zhu
H, Brannigan BW, Kapur R, Stott SL,
Shioda T, Ramaswamy S, Ting DT,
Lin CP, Toner M, Haber DA*,
Maheswaran S*. Circulating tumor
cell clusters are oligoclonal precursors
of breast cancer metastasis. Cell. 158(5):1110-22, 2014.
Yu M, Bardia A, Wittner BS, Stott
SL, Smas ME, Ting DT, Isakoff SJ,
Ciciliano JC, Wells MN, Shah AM,
Concannon KF, Donaldson MC, Sequist
MV, Brachtel E, Sgroi D, Baselga J,
Ramaswamy S, Toner M, Haber DA,
Maheswaran S. Circulating Breast
Tumor Cells Exhibit Dynamic Changes
in Epithelial and Mesenchymal
Composition. Science. 339(6119):
580-584, 2013.
Chiba N, Comaills V, Shiotani B,
Takahashi F, Shimada T, Tajima K,
Winokur D, Hayashida T, Willers H,
Brachtel E, Vivanco MD, Haber DA,
Zou L, Maheswaran S. Homeobox B9
induces epithelial-to-mesenchymal
transition-associated radioresistance
by accelerating DNA damage
responses. Proc Natl Acad Sci U S A.
109(8):2760-5, 2012.
*co-corresponding authors
ties in well with the overall goal of the lab,
which is to study cancer metastasis. In cancer
patients, a rare population of tumor-derived
cells is found in the circulation and is likely
the source for distant metastatic disease.
Detecting CTCs has far-reaching implications
for both clinical care and cancer biology.
CTCs are rare, comprising 1 in 109 cells in
the blood of patients with metastatic breast
cancer. This isolation presents a tremendous
technical challenge for existing cell separation
technologies. The microfluidic technology
developed in Dr. Mehmet Toner’s laboratory
enables gentle, efficient and specific isolation
of live CTCs in a single step. CTCs isolated
from breast cancer patients using this cutting
edge technology will be characterized and
standardized to provide a noninvasive tool for
early disease detection and for monitoring
response/resistance to therapy; viable cells
will be cultured to gain insight into the growth,
drug resistance and metastatic properties of
these epithelial cancers.
(invasion)NRG, ERG
AREG(EMT, invasion)TFGß
(vascularization)
Tumor progression
HOXB9
Angiogenic factorsbFGF, VEGF, ANGPTL2, IL8