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Daniel Haber, MD, PhD
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
Haber Laboratory*
bioengineering team led by Dr. Mehmet Toner, the molecular biology group
Nicola Aceto, PhD
of Dr. Shyamala Maheswaran, and the Massachusetts General Hospital
Francesca Bersani, PhD
Cancer Center clinical disease centers to develop, characterize and apply a
Katherine Broderick
microfluidic device capable of isolating rare circulating tumor cells (CTCs)
Valentine Comaills, PhD
Rushil Desai
applying novel targeted therapies. We have also collaborated with the
in the blood of patients with cancer. This new technology offers the promise
Maria Donaldson
of 1) noninvasive monitoring of cancers during their treatment for the
Nora Feeney
emergence of drug resistance; 2) early detection of invasive cancers; and
Douglas Fox
ultimately 3) understanding and preventing blood-borne spread of cancer.
Daniel Haber, MD, PhD
Xin Hong, PhD
Sarah Javaid, PhD
Our laboratory is interested in the genetics of
emergence of drug resistance mutations, we
Woo Jae Kim, PhD
human cancer. Current projects include the use
are now collaborating with the Toner and
Laura Libby
of a microfluidic device to capture circulating
Maheswaran laboratories to characterize
Joseph Licausi
tumor cells (CTCs) and its application in
novel microfluidic devices capable of isolating
Robert Maher
molecular-directed therapy and in the study of
CTCs from the blood of cancer patients. Our
David Miyamoto, MD, PhD
human cancer metastasis.
most advanced version of these CTC-Chips
Brian Nahed, MD
Circulating Tumor Cells and Molecular
Genetics Underlying Targeted Cancer
Therapeutics
Ryan O’Keefe
Shiwei Pan
S. Michael Rothenberg, MD, PhD
James Sullivan, PhD
Tilak Sundaresan, MD
Nicole Vincent Jordan, PhD
Marissa Wells
Kristina Xega
Toshifumi Yae, MD, PhD
Yu (Eric) Zheng, PhD
* co-directed with Shyamala
Maheswaran, PhD
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
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MGH Center For Cancer Research ANNUAL REPORT 2014
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
Selected Publications:
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):111022, 2014.
Circulating prostate tumor cell cluster stained for PSA (green) along with Ki67 (orange) and CD45 (red).
pathways in circulating pancreatic cancer
combined with detailed genetic analysis of
cells, while in melanoma and in glioblastoma,
tumor cells sampled noninvasively during the
we developed tools to isolate and molecularly
course of cancer treatment.
characterize CTCs.
Current efforts are directed at isolating single
Our most recent studies have focused on
CTCs to uncover the heterogeneous nature
breast cancer, where we demonstrated
of these rare metatastic precursors. Further
treatment-associated epithelial-to-
technological improvements in CTC capture
mesenchymal transition (EMT) within CTCs.
and detection are under study for potential
Using a combination of mouse models and
applications in early detection of cancer,
patient-derived studies, we observed that
monitoring tumor genotypes over the course
tumor-derived fragments generate CTC-
of treatment, and biological characterization of
Clusters, which have greatly enhanced
CTCs themselves.
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.
Finally, 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,
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.
Luo X, Mitra D, Sullivan RJ, Wittner BS,
Kimuar AM, Pan S, Hoang MP, Brannigan
BW, Lawrence DP, Flaherty KT, Sequist
LV, McMahon M, Bosenberg MW, Stott
SL, Ting DT, Ramaswamy S, Toner, M,
Fisher DE, Maheswaran S* and Haber
DA* Isolation and molecular characcterization of circulating melanoma
cells. Cell Reports. 7: 645-653, 2014.
Haber DA and Velculescu VE. Blood-based
analyses of cancer: Circulating tumor cells
and circulating tumor DNA. Cancer Discovery. 4: 650-661, 2014.
Yu M*, Bardia A*, Wittner BS, Stott SL,
SMas ME, Ting DT, Isakoff SJ, Ciciliano
JC, Wells MN, Shah AM, Concannon KE,
Donaldson MC, Sequist LV, Bracheter
E, Sgroi D, Baselga J, Ramaswamy S,
Toner M, Haber DA* and Maheswaran
S*. Circulating breast tumor cells exhibit
dynamic changes in epithelial and mesenchymal composition. Science 339: 580-4,
2013.
Ozkumur E*, Shah AM*, Cicilano JC, Emmink BL, Miyamoto DT, Brachter E, Yu M,
Chen PI, Morgan B, Trautwein J, Kimura
A, Sengupta S, Stott SL, Karabacak NM,
Barber TA, Walsh JR, Smith K, Spuhler
PS, Sullivan JP, Lee RJ, Ting DT, Luo X,
Shaw AT, Bardia A, Sequist LV, Louis
DN, Maheswaran S, Kapur R, Haber DA,
Toner M. Inertial focusing for tumor
antigen-dependent and –independent
sorting of rare circulating tumor cells.
Science Transl. Med 3: 179, 2013.
*Co-corresponding authors
Principal Investigators
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