The overarching goal of this project is to forward and backward track cancer cell fates and histories using new imaging approaches to redefine cancer evolution and therapeutic escape on the cellular and molecular level. The project will focus on clonal selection, in order to develop a single unifying hypothesis, which can explain a variety of clinical observations including that of primary tumor cell heterogeneity, the propensity for metastases to develop at specific sites, and the differences in therapeutic responses. Current methodologies for studying in vivo clonal expansion and tumor growth have been hampered by the overwhelming challenge of being able to follow the development of distinct cellular lineages from a single common progenitor. By adopting vanguard technologies such as combinatorial expression of multiple fluorescent proteins (Livet et al., 2007, Nature, 450, 56-62), we will be able to perform fluorescent-based lineage tracing of cancer cells in vivo. The overarching goal for this project is to better understand the clonal fates of both tumor cells and their associated stromal cells.
The specific aims are thus: 1) to develop, test and validate multicolor tools and reagents to track multiple clonally derived cellular lineages;2) to determine whether tumor formation, progression and resistance to therapy are characterized by dominant subclones;and 3) to examine whether tumor cells recruit unique subpopulations of host stromal cells to the growing tumor.

Public Health Relevance

The project will address a number of fundamental questions regarding tumor biology such as: 1) Is primary tumor growth stochastic or deterministic ? 2) Is secondary seeding and engraftment of metastatic tumors driven/sustained by unique subsets of cells? 3) Do incomplete treatment responses result from unique tumor subclones that harbor differential sensitivities to the chemotherapeutic agent (i.e. a BRAFV600E mutant specific drug)? 4) Do tumor-associated stromal cells expand clonally or in a stochastic manner?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-SRLB-9)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Keliher, Edmund J; Klubnick, Jenna A; Reiner, Thomas et al. (2014) Efficient acid-catalyzed (18) F/(19) F fluoride exchange of BODIPY dyes. ChemMedChem 9:1368-73
Dubach, J Matthew; Vinegoni, Claudio; Weissleder, Ralph (2014) Steady state anisotropy two-photon microscopy resolves multiple, spectrally similar fluorophores, enabling in vivo multilabel imaging. Opt Lett 39:4482-5
Pittet, Mikael J; Nahrendorf, Matthias; Swirski, Filip K (2014) The journey from stem cell to macrophage. Ann N Y Acad Sci 1319:1-18
Thurber, Greg M; Reiner, Thomas; Yang, Katherine S et al. (2014) Effect of small-molecule modification on single-cell pharmacokinetics of PARP inhibitors. Mol Cancer Ther 13:986-95
Courtis, Alexandra M; Santos, Sofia A; Guan, Yinghua et al. (2014) Monoalkoxy BODIPYs--a fluorophore class for bioimaging. Bioconjug Chem 25:1043-51
Hideshima, T; Mazitschek, R; Santo, L et al. (2014) Induction of differential apoptotic pathways in multiple myeloma cells by class-selective histone deacetylase inhibitors. Leukemia 28:457-60
Kim, Eunha; Yang, Katherine S; Giedt, Randy J et al. (2014) Red Si-rhodamine drug conjugates enable imaging in GFP cells. Chem Commun (Camb) 50:4504-7
Dubach, J M; Vinegoni, C; Mazitschek, R et al. (2014) In vivo imaging of specific drug-target binding at subcellular resolution. Nat Commun 5:3946
Turetsky, Anna; Kim, Eunha; Kohler, Rainer H et al. (2014) Single cell imaging of Bruton's tyrosine kinase using an irreversible inhibitor. Sci Rep 4:4782
Aceto, Nicola; Bardia, Aditya; Miyamoto, David T et al. (2014) Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158:1110-22

Showing the most recent 10 out of 266 publications