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Division of Surgical Oncology
Shyamala Maheswaran, PhDAssociate Professor of SurgeryHarvard Medical School
Assistant Molecular BiologistCenter for Cancer Research
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, PhDPrincipal Investigator
* 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 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.
View a list of publications by researchers at the Maheswaran Laboratory
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.
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