Maheswaran

Maheswaran Lab

Research topics in the Maheswaran Lab include: tumorigenesis, breast cancer and cancer genetics.

Overview

Shyamala Maheswaran, PhD
Associate Professor of Surgery
Harvard Medical School

Assistant Molecular Biologist
Center for Cancer Research

Research Summary

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.

Read the Maheswaran Lab's Annual Report in Full

Group Members

Maheswaran Laboratory*

Shyamala Maheswaran, PhD
Principal Investigator

Group Members*

  • Katherine Broderick
  • Valentine Comaills, PhD
  • Taronish Dubash, PhD
  • Richard Ebright**
  • Erin Emmons
  • Xin Hong, PhD
  • Mark Kalinich, MD**
  • Michael Koulopoulos
  • Laura Libby
  • Joseph LiCausi
  • Andy Mai
  • Dieuwke Marvin, PhD
  • Douglas Micalizzi, MD
  • John Milner
  • David Miyamoto, MD, PhD
  • Kira Niederhoffer
  • Shiwei Pan
  • Erin Silva
  • Talik Sundaresan, MD
  • Tanya Todorova, PhD
  • Nicole Vincent Jordan, PhD
  • Toshifumi Yae, PhD
  • Marcus Zachariah, MD
  • Yu (Eric) Zheng, PhD


* co-directed with Daniel Haber, MD, PhD

** PhD Candidates

Research Projects

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.

Publications

View a list of publications by researchers at the Maheswaran Laboratory

Selected Publications

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 (in press)

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.

*co-corresponding authors

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