The goal of the Mouse Imaging Core is to develop and apply methods for intravital imaging of apoptosis and mitosis at the single cell level to tumors created by human xenografts, oncogene expression and serial passage of transplanted syngeneic cancer cells. The ability to monitor the molecular and pathophysiological features of tumors is critical for translating discoveries made in cell lines, which constitute the majority of the work in this program project, to actual cancers growing in situ. The mouse imaging core will develop cell lines and transgenic mice expressing tagged fluorescent proteins that serve as morphological and activity based reporters of mitotic and apoptotic state. Because only a limited number of fluorescence channels (2-4) can be monitored simultaneously in live-cell experiments, no single cell line or mouse will be suitable for all of the proposed studies. Thus, several sets of compatible probes will be developed to monitor different aspects of mitosis and apoptosis in situ;experiments involving complementary reporter combinations will then be combined. Typically these will involve intravital imaging through windows implanted in the skin or mammary glands. Animals carrying labeled tumors will then be exposed to various combinations of drugs and tumor responses then monitored over time at single-cell resolution. The core will undertake the development of quantitative methods for immune-fluorescence analysis of fixed whole-mount and sectioned tumors. This work will build on extensive experience in the participating laboratories with automated image analysis in cultured cells. Finally, the Core will provide access to a range of whole-body imaging methods developed for non-invasive determination of tumor morphology and size. Raw images and the results of image analysis will be distributed to all investigators in the Program using a web portal. Core activities will be divided between Massachusettes General Hospital (MGH) where the imaging equipment and Core Director Ralph Weissleder are based, and Harvard Medical School (MGH) where the experimental projects and Core co-Director Sorger are based. Imaging will be performed at MGH whereas mouse colonies will be generated and maintained at HMS. Preliminary studies have demonstrated this arrangement to be highly effective.
Translating results obtained in culture, in which imaging and cell-manipulation are much easier, to actual tumors is critical to understanding how cell-to-cell and tumor-to-tumor variation arises responses to cytotoxic and targeted therapies arise. The core will develop an apply fundamentally new methods for imaging tumors and, through existing core capabilities, program investigators will have ready access to instrumentation, expertise and software required for quantitative analysis of tumor biology in mice.
|Shi, Jue; Mitchison, Timothy J (2017) Cell death response to anti-mitotic drug treatment in cell culture, mouse tumor model and the clinic. Endocr Relat Cancer 24:T83-T96|
|Miller, Miles A; Askevold, Bjorn; Mikula, Hannes et al. (2017) Nano-palladium is a cellular catalyst for in vivo chemistry. Nat Commun 8:15906|
|Foijer, Floris; Albacker, Lee A; Bakker, Bjorn et al. (2017) Deletion of the MAD2L1 spindle assembly checkpoint gene is tolerated in mouse models of acute T-cell lymphoma and hepatocellular carcinoma. Elife 6:|
|Fallahi-Sichani, Mohammad; Becker, Verena; Izar, Benjamin et al. (2017) Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de-differentiated state. Mol Syst Biol 13:905|
|Giedt, Randy J; Fumene Feruglio, Paolo; Pathania, Divya et al. (2016) Computational imaging reveals mitochondrial morphology as a biomarker of cancer phenotype and drug response. Sci Rep 6:32985|
|Lee, Robin E C; Qasaimeh, Mohammad A; Xia, Xianfang et al. (2016) NF-?B signalling and cell fate decisions in response to a short pulse of tumour necrosis factor. Sci Rep 6:39519|
|Sarosiek, Kristopher A; Letai, Anthony (2016) Directly targeting the mitochondrial pathway of apoptosis for cancer therapy using BH3 mimetics - recent successes, current challenges and future promise. FEBS J 283:3523-3533|
|Bhola, Patrick D; Mar, Brenton G; Lindsley, R Coleman et al. (2016) Functionally identifiable apoptosis-insensitive subpopulations determine chemoresistance in acute myeloid leukemia. J Clin Invest 126:3827-3836|
|Chittajallu, Deepak R; Florian, Stefan; Kohler, Rainer H et al. (2015) In vivo cell-cycle profiling in xenograft tumors by quantitative intravital microscopy. Nat Methods 12:577-85|
|Krukenberg, Kristin A; Kim, Sujeong; Tan, Edwin S et al. (2015) Extracellular poly(ADP-ribose) is a pro-inflammatory signal for macrophages. Chem Biol 22:446-452|
Showing the most recent 10 out of 61 publications