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Shyamala Maheswaran, PhDAssociate Professor of SurgeryHarvard Medical School
Assistant Molecular BiologistCenter for Cancer Research
Metastasis, the leading cause of cancer-related deaths, is governed by multiple steps, which are not well understood. Using cell culture and mouse models, as well as patient-derived tumor tissues, and tumor cells circulating in the blood (Circulating Tumor Cells/CTCs), the Maheswaran Lab has uncovered novel tumor cell characteristics that promote metastasis in breast cancer patients. Their findings show that cancer cells exist in multiple cellular states, each state exhibiting different characteristics. As such, each breast cancer patient harbors a mixture of tumor cells with different functional properties. They intend to define the functional and molecular properties of these different subclasses of tumor cells and their contribution to metastasis, tumor evolution and drug sensitivity using appropriate experimental models and patient-derived samples. These findings will provide insight into the contribution of these different cancer cell populations to metastasis and their significance as biomarkers and therapeutic targets.
Shyamala Maheswaran, PhDPrincipal Investigator
* co-directed with Daniel Haber, MD, PhD** PhD Candidates
Mechanisms of Breast Cancer Metastasis
The research in my laboratory is focused on defining the molecular mechanisms that drive breast cancer progression and metastasis. Cancer, initially confined to the primary site, eventually spreads to distal sites, including lung, liver, bone and brain, by invading into the bloodstream. Upon reaching these distal sites, the tumor cells continue to grow and evolve well after removal of the primary tumor resulting in overt metastasis and disease recurrence, the leading causes of cancer-related deaths. Using cell culture and mouse models and patient derived tissues and circulating tumor cells (CTCs) enriched from the blood of women with breast cancer, we characterize the contribution of oncogenic and tumor microenvironment-derived signals, epithelial to mesenchymal transition and tumor heterogeneity to cancer progression and therapeutic responses.
Persistent proliferation of cancer cells during epithelial to mesenchymal transition leads to cytokinesis failure resulting in binucleated cells and chromosome missegregation.
Metastasis through the Prisim of Circulating Tumor Cells
I am also collaborating with Drs. Daniel Haber and Mehmet Toner to define cancer biology across several tumor types including breast, prostate, liver and lung cancers as well as melanoma using CTCs isolated from the blood of cancer patients. CTCs represent an extremely rare population of cells in the blood and their isolation presents a tremendous technical challenge. The CTC-iChip developed in Dr. Mehmet Toner’s laboratory enables enrichment of live CTCs through selective removal of blood components; red and white blood cells as well as platelets. Characterizing CTCs has far-reaching implications for both clinical care and defining cancer biology. They enable real time monitoring of tumor cells during disease progression and therapeutic responses and could possibly be used for early detection of disease. Viable CTCs cultured from patients provide tremendous insight into molecular heterogeneity and cellular plasticity of tumors that govern differential biological characteristics and responses to therapy. Characterization of CTCs ties in well with the overall goal of the lab to study cancer metastasis.
View a list of publications by researchers at the Maheswaran Laboratory
Comaills V, Kabeche L, Morris R, Buisson R, Yu M, Madden MW, LiCausi JA, Boukhali M, Tajima K, Pan S, Aceto N, Sil S, Zheng Y, Sundaresan T, Yae T, Jordan NV, Miyamoto DT, Ting DT, Ramaswamy S, Haas W, Zou L, Haber DA, Maheswaran S. Genomic Instability Induced by Persistent Proliferation of Cells Undergoing Epithelial-to- Mesenchymal Transition. Cell Reports 2016 Dec 6;17(10):2632-2647.
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 6:8257
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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