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.
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?
|Dubach, J Matthew; Kim, Eunha; Yang, Katherine et al. (2017) Quantitating drug-target engagement in single cells in vitro and in vivo. Nat Chem Biol 13:168-173|
|Vinegoni, Claudio; Fumene Feruglio, Paolo; Brand, Christian et al. (2017) Measurement of drug-target engagement in live cells by two-photon fluorescence anisotropy imaging. Nat Protoc 12:1472-1497|
|Iaconelli, Jonathan; Lalonde, Jasmin; Watmuff, Bradley et al. (2017) Lysine Deacetylation by HDAC6 Regulates the Kinase Activity of AKT in Human Neural Progenitor Cells. ACS Chem Biol 12:2139-2148|
|Arlauckas, Sean P; Garris, Christopher S; Kohler, Rainer H et al. (2017) In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med 9:|
|Miller, Miles A; Weissleder, Ralph (2017) Imaging the pharmacology of nanomaterials by intravital microscopy: Toward understanding their biological behavior. Adv Drug Deliv Rev 113:61-86|
|Engblom, Camilla; Pfirschke, Christina; Zilionis, Rapolas et al. (2017) Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils. Science 358:|
|Miller, Miles A; Askevold, Bjorn; Mikula, Hannes et al. (2017) Nano-palladium is a cellular catalyst for in vivo chemistry. Nat Commun 8:15906|
|Pucci, Ferdinando; Garris, Christopher; Lai, Charles P et al. (2016) SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions. Science 352:242-6|
|Roy, Jeremy; Kim, Bongki; Hill, Eric et al. (2016) Tyrosine kinase-mediated axial motility of basal cells revealed by intravital imaging. Nat Commun 7:10666|
|Pfirschke, Christina; Engblom, Camilla; Rickelt, Steffen et al. (2016) Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. Immunity 44:343-54|
Showing the most recent 10 out of 316 publications