Maheswaran Lab

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 laboratory has uncovered novel tumor cell characteristics that promote metastasis in breast cancer patients. Our 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. We intend to define the functional and molecular properties of 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 heterogeneous cancer cell populations to metastasis and their significance as biomarkers and therapeutic targets.

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, 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 to cellular states including: epithelial to mesenchymal plasticity, senescence, and how these aspects of tumor heterogeneity influence cancer progression and therapeutic responses.

Oncogenic and Epigenetic Cues in Senescence

Senescence, a state of prolonged growth arrest induced by stress, contributes to aging and age-related degenerative diseases. It is an important tumor suppressor mechanism in premalignant tumors, which override this safeguard machinery through the loss of the tumor suppressors RB and p53 and progress to become malignant tumors. Senescence is also an alternative cellular response to chemo- and radiation therapies, from which a few rare cells escape and exhibit highly drug resistant phenotypes. Taken together, there is a critical need to identify mechanisms that induce and maintain senescence independent of the RB and p53 signaling axes, which are often inactivated in cancers. Identification of druggable targets that can induce and maintain senescence as future therapies complementing current therapeutic interventions is an unmet need that is gaining significant attention from a clinical perspective. Based on our published work on SETD1A, we are investigating (a) the functional and mechanistic roles of SETD1A in cells, the deregulation of which induces senescence. (b) the role of SETD1A in maintaining the cellular equilibrium between proliferation, senescence and escape from senescence and (c) how SETD1AKD- induced senescent cells remodel the microenvironment and its impact on tumor progression and drug responses. The longterm goal of this work is to ultimately exploit SETD1A, a druggable enzyme, to unleash the tumor suppressor effects of senescence and curtail cancer progression, drug resistance and possibly age-related diseases.

Publications

View a list of publications by researchers at the Maheswaran Laboratory

Selected Publications

Tajima K, Matsuda S, Yae T, Drapkin B, Morris R, Boukhali M, Niederhoffer K, Comaills V, Dubash T, Nieman L, Guo H, Magnus NKC, Dyson N, Shioda T, Haas W, Haber DA, Maheswaran S. SETD1A protects from senescence through regulation of the mitotic gene expression program. Nature Comm. 2019 Jun 28;10(1):2854.

Kwan TT, Bardia A, Spring LM, Giobbie-Hurder A, Kalinich M, Dubash T, Sundaresan T, Hong X, LiCausi JA, Ho U, Silva EJ, Wittner BS, Sequist LV, Kapur R, Miyamoto DT, Toner M, Haber DA, Maheswaran S. A digital RNA signature of Circulating Tumor Cells predicting early therapeutic response in localized and metastatic breast cancer. Cancer Discov. 2018 Aug 13

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.

*co-corresponding authors

Our Researchers

Shyamala Maheswaran, PhD

Group Members*

• Risa Burr, PhD
• Dante Che
• Charles Dai, PhD
• Douglas Fox, PhD
• Sarah Guay
• Hongshan Guo, PhD
• Elad Horwitz, PhD
• Shih-Bo Huang, PhD
• Justin Kelly
• Laura Libby
• Douglas Micalizzi, MD
• Ajinkya Revandkar, PhD
• Hunter Russell
• Karsen Seeger
• Joanna Vuille**
• Devon Wiley
• Ben Wittner, PhD

* Co-directed with Daniel Haber, MD, PhD
** Graduate student