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 and therapeutic vulnerabilities in breast cancer patients. Further, tumor microenvironmental factors contribute to tumor cell plasticity leading to multiple cell states creating extensive tumor heterogeneity. These altered cells states dictate the interaction of tumor cells with the non-tumor cell populations in the tumor microenvironment leading to tumor progression. Our goal is to define these interactions and to identify druggable nodes resulting from the interaction of tumor cells and their environment. These investigations will provide insight into the contribution of heterogeneous cancer cell populations to tumor progression and 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.

Naturally occurring senescence induced by microenvironmental factors

Senescence is associated with the secretion of bioactive molecules - the senescenceassociated secretory phenotype (SASP). SASP, which is context dependent, remodels the cellular microenvironment and contributes to many age-related diseases. Senolytic compounds, that eliminate senescent cells, alleviate these age-related conditions in preclinical models and in clinical trials; thus, senescence is a druggable cell state. TGFß, prevalent in the hypoxic tumor microenvironment, induces senescence in cancers, rendering it a physiological tumor cell state. In an immunecompetent mouse lung cancer model, suppressing TGFß signaling, specifically in the tumor cells, ablated senescent cells in tumors and mitigated immune suppressive immune infiltration. In a therapeutic setting, non-small cell lung cancers with high TGFß/ hypoxia-signaling and increased senescence - exhibit poor progression-free survival upon receiving immune checkpoint inhibitors (ICI). We are now exploring whether microenvironmental hypoxia-TGFß-induced physiological senescence and SASP are exploited by tumors to mount an innate resistance to ICIs, and how we can exploit this phenotype to improve ICI responses.

Publications

View a list of publications by researchers at the Maheswaran Laboratory

Selected Publications

Matsuda S. Revandkar A, Dubash TD, Ravi A, Wittner BS, Lin M, Morris R, Burr R, Guo H, Seeger K, Szabolcs A, Che D, Nieman L, Getz GA, DT, Lawrence MS, Gainor J, Haber DA, Maheswaran S TGFß in the microenvironment induces a physiologically occurring immune suppressive senescent state. Cell Reports 2023 Mar 28;42(3):112129.

Karabacak, NM, Zheng Y, Dubash TD, Burr R, Micalizzi DS, Wittner BS, Lin M, Wiley D, Comaills V, Emmons E, Niederhoffer K, Ho U, Ukleja J, Che D, Stowe H, Nieman L, Haas W, Stott SL, Lawrence MS, Ting DT, Miyamoto DT, Haber DA, Toner M, Maheswaran S Differential kinase activity across prostate tumor compartments defines sensitivity to target inhibition. Cancer Research 2022 15;82(6):1084-1097.

Ebright RY, Zachariah MA, Micalizzi DS, Wittner BS, Niederhoffer KL, Nieman LT, Chirn B, Wiley DF, Wesley B, Shaw B, NieblasBedolla E, Atlas L, Szabolcs A, Iafrate AJ, Toner M, Ting DT, Brastianos PK, Haber DA, Maheswaran S. HIF1A signaling selectively supports proliferation of breast cancer in the brain. Nat Commun. 2020 Dec 9;11(1):6311.

Ebright RY, Lee S, Wittner BS, Niederhoffer KL, Nicholson BT, Bardia A, Truesdell S, Wiley DF, Wesley B, Li S, Mai A, Aceto N, Vincent-Jordan N, Szabolcs A, Chirn B, Kreuzer J, Comaills V, Kalinich M, Haas W, Ting DT, Toner M, Vasudevan S, Haber DA, Maheswaran S* Micalizzi DS Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis. Science. 2020; 367(6485):14.

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.

*co-corresponding authors

Our Researchers

Shyamala Maheswaran, PhD

Group Members*

• Ezgi Antmen, PhD
• Risa Burr, PhD
• Charles Dai, PhD
• Yan Fang, PhD
• Douglas Fox, PhD
• Sarah Guay
• Megan Honeywell, PhD
• Elad Horwitz, PhD
• Shih-Bo Huang, PhD
• Ji Eun Kwak
• Laura Libby
• Zachary Nicolson
• Ajinkya Revandkar, PhD
• Weikun Xia, PhD
• Min Yang, PhD

* Co-directed with Daniel A. Haber, MD, PhD