Shyamala Maheswaran, PhD
Associate Professor of Surgery
Harvard Medical School
Assistant Molecular Biologist
Center for Cancer Research
Metastasis, the leading cause of cancer related mortality, is a highly orchestrated process involving angiogenesis, invasion, intravasation and survival in the vasculature, and extravasation and growth at distal sites. The Maheswaran lab 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. The expression of HOXB9, a transcription factor, and BTG2, its binding partner, is deregulated in a subset of aggressive breast cancer leading to tumoral expression of several growth factors which modify the tumor microenvironment. Using breast cancer cells with modulated expression of HOXB9 and BTG2 as model systems, we intend to gain insight into the pathways that drive tumor progression and thus render tumor cells susceptible to targeted therapeutic intervention.
Shyamala Maheswaran, PhD
Principal InvestigatorGroup Members*
* co-directed with Daniel Haber, MD, PhD
Elucidating the mechanism of tumor metastasis using HOXB9 and BTG2 expressing breast cancers as a model system
My research goal is to understand the biology of breast cancer metastasis using cell culture and animal models and to validate these findings in clinical specimens. 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 aberrations 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. In mouse models, breast tumor xenografts in which HOXB9 is overexpressed or BTG2 is suppressed are more sensitive to drugs that target the HER pathway and tumor angiogenesis.
The goals of the lab are:
1) to identify the mechanisms by which these molecular aberrations alter the tumor microenvironment and to delineate the autocrine and paracrine mechanisms that influence tumor progression,
2) to identify the pathways that can be targeted either alone or in combination to suppress tumor progression and metastasis in this setting, and
3) to determine whether gain of HOXB9 and/or loss of BTG2 can be used as markers to identify patients who will be responsive/resistant to breast cancer therapies.
By modulating HOXB9 and BTG2 expression in breast cancer cells, we intend to identify the molecular mechanisms that will render this subset of aggressive breast cancers susceptible to therapies that target these pathways.
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, prostate, pancreatic and lung 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.