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