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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 early detection of invasive cancer, 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 circumvent mutations that alter drug binding affinity. Following these efforts to monitor the emergence of drug resistance mutations, we established collaborations 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 depletion of antibody-tagged leukocytes, thereby enriching for intact CTCs without selection bias. 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 in lung cancer and measurements of androgen receptor (AR) activity in prostate cancer. We have applied next generation single-molecule RNA sequencing and RNA-in-situ hybridization to characterize the heterogeneous expression profiles of individual CTCs in breast, prostate and pancreatic cancers, as well as melanoma and glioblastoma. To facilitate CTC quantitation and provide the sensitivity and specificity required for early cancer detection, we have established a droplet digital PCR readout for CTC-derived RNA, with promising applications in the early detection of liver cancer.
In addition to noninvasive detecting and monitoring of cancer, CTCs provide a window to study the process of blood-borne metastasis. We demonstrated treatment-associated epithelial-to-mesenchymal transitions (EMT) within CTCs from women with breast cancer. 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 (ER)-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. In cultured CTCs from women with advanced ER+ breast cancer, we documented dramatic plasticity, with a proliferative HER2-expressing subpopulation interconverting spontaneously with a drug-resistant Notch1-expressing subset. Using mouse reconstitution models, we demonstrated the consequences of this phenotype switch for both tumorigenesis and drug response. Ongoing studies are directed atusing patient-derived CTCs and mouse models to understand key steps in cancer metastasis, including the shift from cell quiescence to proliferation, viability during blood-borne transit, and resistance to targeted and immune therapies.
View a list of publications by researchers at the Haber Laboratory
Kalinich M, Bhan I, Kwan TT, Miyamoto DT, Javaid S, LiCausi JA, Milner JD, Hong X, Goyal L, Sil S, Choz M, Ho U, Kapur R, Muzikansky A, Zhang H, Weitz DA, Sequist LV, Ryan DP, Chung RT, Zhu AX, Isselbacher KJ, Ting DT, Maheswaran S*, Haber DA*. An RNA-based signature enables high specificity detection of circulating tumor cells in hepatocellular carcinoma. Proc. Natl. Acad. Sci. USA. 114: 1123-1128, 2017.
Jordan NV, Bardia A, Wittner BS, Benes C, Ligorio M, Zheng Y, Yu M, Sundaresan TK, Licausi JA, Desai R, O'Keefe RM, Ebright RY, Boukhali M, Sil S, Onozato ML, Iafrate AJ, Kapur R, Sgroi D, Ting DT, Toner M, Ramaswamy S, Haas W, Maheswaran S*, Haber DA*. HER2 expression identifies dynamic functional states within circulating breast cancer cells. Nature. 537(7618):102-106, 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 prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science 349 (6254): 1351-6, 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.
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 LV, Brachter E, Sgroi D, Baselga J, Ramaswamy S, Toner, M, Maheswaran S*, Haber DA*. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 339: 580-4, 2013.
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