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Research at Mass General
Daniel A. Haber, MD, PhDDirectorMassachusetts General Hospital Cancer Center
Kurt J. Isselbacher Professor of OncologyHarvard Medical School
The Haber laboratory focuses on understanding the fundamental genetics of human cancer, from inherited mutations that confer familial predisposition to genetic mutations that are acquired by tumors themselves and may render them susceptible to speciﬁc targeted drug therapies. For example, we have identiﬁed mutations in the EGFR gene that confer dramatic sensitivity of some lung cancers to drugs that inhibit that pathway, pointing toward the importance of genetic classiﬁcation of common epithelial cancers in applying novel targeted therapies.
We have also collaborated with the bioengineering team led by Dr. Mehmet Toner, the molecular biology group of Dr. Shyamala Maheswaran, and the Massachusetts General Hospital Cancer Center clinical disease centers to develop, characterize and apply a microﬂuidic device capable of isolating rare circulating tumor cells (CTCs) in the blood of patients with cancer. This new technology offers the promise of 1) noninvasive monitoring of cancers during their treatment for the emergence of drug resistance; 2) early detection of invasive cancers; and ultimately 3) understanding and preventing blood-borne spread of cancer.
Daniel A. Haber, MD, PhDPrincipal Investigator
* co-directed with Shyamala Maheswaran, PhD
** PhD Candidate
Our laboratory is interested in the genetics of human cancer. Current projects include the use of a microﬂuidic device to capture circulating tumor cells (CTCs) and its application in molecular-directed therapy and in the study of human cancer metastasis.
Circulating Tumor Cells and Molecular Genetics Underlying Targeted Cancer Therapeutics
Activating mutations in the epidermal growth factor receptor (EGFR) were identiﬁed in our laboratory in the subset of non-small cell lung cancer (NSCLC) with dramatic responses to the tyrosine kinase inhibitor geﬁtinib. We have studied mechanisms underlying such oncogene addiction, as well as the pathways that lead to the acquisition of resistance to targeted therapies, including the application of irreversible kinase inhibitors to circumventing mutations that alter drug binding affinity. Following on our efforts to monitor the emergence of drug resistance mutations, we are now collaborating with the Toner and Maheswaran laboratories to characterize novel microﬂuidic devices capable of isolating CTCs from the blood of cancer patients. Our most advanced version of these CTC-Chips relies upon blood ﬂow through a specialized chamber, which allows the high efficiency separation of antibody-tagged leukocytes, thereby identifying intact CTCs without selection bias. In a series of CTC studies, we have shown that the number of captured CTCs correlates with clinical evidence of tumor response, and that the cells can be used to deﬁne molecular markers characteristic of the underlying malignancy, including EGFR mutations and EML4-ALK translocations in lung cancer, and measurements of androgen receptor (AR) activity in prostate cancer. We have applied next generation single-molecule RNA sequencing to identify non-canonical Wnt signaling as a suppressor of anoikis pathways in circulating pancreatic cancer cells, while in melanoma and in glioblastoma, we developed tools to isolate and molecularly characterize CTCs.
Our most recent studies have focused on breast cancer, where we demonstrated treatment-associated epithelial-to-mesenchymal transition (EMT) within CTCs. Using a combination of mouse models and patient-derived studies, we observed that tumor-derived fragments generate CTC-Clusters, which have greatly enhanced metastatic propensity compared with single CTCs. CTC-Clusters are held together by plakoglobin, whose knockdown dramatically suppresses CTC-Cluster formation and metastatic spread of breast cancer cells. We successfully established long-term in vitro cultures of CTCs from patients with estrogen-receptor positive breast cancer, identifying treatment-associated mutations in the estrogen receptor (ESR1), as well as acquired mutations in drugable therapeutic targets, such as PIK3CA and FGFR. The development of such CTC-derived cultures may enable functional predictive drug testing, combined with detailed genetic analysis of tumor cells sampled noninvasively during the course of cancer treatment.
Current efforts are directed at isolating single CTCs to uncover the heterogeneous nature of these rare metastatic precursors, including remarkable cell plasticity that contributes to drug resistance. Further technological improvements in CTC capture and detection are under study for potential applications in early detection of cancer, monitoring tumor genotypes over the course of treatment, and biological characterization of CTCs themselves.
View a list of publications by researchers at the Haber Laboratory
Nicole Vicent Jordan, Aditya Bardia, Ben S. Wittner, Cyril Benes, Matteo Ligorio, Yu Zheng, Min Uu, Tilak D. Sundaresan, Joseph A. Licausi, Rushil Desai, Ryan M. O'Keefe, Richard Y. Ebright, Myriam Boukhali, Srinjoy Sil, Maristela L. Onozato, Anthony J. Iafrate, Ravi Kapur, Dennis Sgroi, David T. Ting, Mehmet Toner, Sridhar Ramaswamy, Wilhelm Haas, Shyamala Maheswaran, Daniel A. Haber. HER2 expression identifies dynamic functional states within circulating breast cancer cells. Nature, in press, 2016.
Miyamoto DT, Zheng Y, Wittner BS, Lee RJ, Zhu H, Broderick KT, Desai R, Fox DB, Brannigan BW, Trautwein J, Arora KS, Desai N, Dahl DM, Sequist LV, Smith MR, Kapur R, Wu C-L, Shioda T, Ramaswamy S, Ting DT, Toner M, Maheswaran S*, Haber DA*. RNA-Seq of single pros-tate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance Science 349 (6254)L 1351-6, 2015.
Rothenberg SM, Concannon K, Cullen S, Boulay G, Turke AB, Faber AC, Lockerman EL, Rivera MN, Engelman JA, Maheswaran S, Haber DA. Inhibition of mutant EGFR in lung cancer cells trig-gers SOX2-FOXO6-dependent survival pathways. Elife Feb 16: 4 doi: 10.7554/eLife.06132, 2015.
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, Aceto N, Bersani F, Madden M, Donaldson MC, Desai R, Comaills V, Zheng Z, Wittner BS, Stojanov P, Brachtel E, Sgroi D, Kapur R, Shioda T, Ting, DT, Ramaswamy S, Getz G, Iafrate AJ, Benes C, Toner, M, Maheswaran S* and Haber DA*. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science. 346(6193): 216-22, 2014.
Ting DT, Wittner BS, Ligorio M, Vincent Jordan N, Shah AM, Miyamoto DT, Aceto N, Bersani F, Brannigan BW, Xega K, Ciciliano JC, Zhu H, MacKenzie OC, Trautwein J, Arora KS, Shahid M, Ellis HL, Qu N, Bardeesy N, Rivera MN, Deshpande V, Ferrone CR, Kapur R, Ramaswamy S, Shioda T, Toner M, Maheswaran S*, Haber DA*. Single-cell RNA sequencing identiﬁes extracellular matrix gene expression by pancreatic circulating tumor cells. Cell Rep. 8(6): 1905-18, 2014.
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