The replication and segregation of the genome (the cell cycle) and the increase in bio-mass of individual cells (cell growth) must be coordinated in all cells. But the mechanism(s) underlying this coordination are very poorly understood, particularly in mammalian cells. The goal of Project 1 is to deconvolve cell growth and the cell division cycle, determine the molecular basis for the coordination of these two processes, and determine how these two processes and their coordination are altered in cancer. The proposed measurement platform will be developed by the Manalis lab in close collaboration with the Amon and Kirschner labs and will consist of separate modules for: obtaining synchronous populations of new-born daughter cells, measuring single cell growth rate, fixing cells, sequential storage of cells with known identity, staining these cell in parallel with probes against mRNAs, proteins, and protein phosphorylation sites, and high-resolution fluorescent Imaging of the stained cells. Our investigations will be focused on white blood cells that proliferate without adhesion in culture, as these cells can be easily manipulated within our measurement platform and are inherently tolerant of fluid flow and shear stress. Similarly, we will begin our investigations using common lines of cultured cells, but we are cognizant of the danger of being seriously misled by transformed cells. Once our technologies are established, we will progress to studying primary lymphocytes derived from mice as well as untransformed epithelial cells. Finally, we will begin to directly apply our technologies to cancer by characterizing the cell growth and the cell cycles of rare cells isolated from a human lymphoma in collaboration with the Nolan lab at Stanford.
The relationship between the cell cycle and cell growth is fundamental to cell proliferation and needs to be understood if we are to understand how cell proliferation is altered in cancers. The rational design of cancer therapies would greatly benefit from understanding how oncogenes and tumor suppressors actually drive and/or permit proliferation.
|Almendro, Vanessa; Cheng, Yu-Kang; Randles, Amanda et al. (2014) Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity. Cell Rep 6:514-27|
|Semrau, Stefan; Crosetto, Nicola; Bienko, Magda et al. (2014) FuseFISH: robust detection of transcribed gene fusions in single cells. Cell Rep 6:18-23|
|Knouse, Kristin A; Wu, Jie; Whittaker, Charles A et al. (2014) Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. Proc Natl Acad Sci U S A 111:13409-14|
|Mizuguchi, Takeshi; Fudenberg, Geoffrey; Mehta, Sameet et al. (2014) Cohesin-dependent globules and heterochromatin shape 3D genome architecture in S. pombe. Nature 516:432-5|
|Barreca, A; Martinengo, C; Annaratone, L et al. (2014) Inter- and intratumoral heterogeneity of BCL2 correlates with IgH expression and prognosis in follicular lymphoma. Blood Cancer J 4:e249|
|McFarland, Christopher D; Mirny, Leonid A; Korolev, Kirill S (2014) Tug-of-war between driver and passenger mutations in cancer and other adaptive processes. Proc Natl Acad Sci U S A 111:15138-43|
|Mentink, Remco A; Middelkoop, Teije C; Rella, Lorenzo et al. (2014) Cell intrinsic modulation of Wnt signaling controls neuroblast migration in C. elegans. Dev Cell 31:188-201|
|Polak, Paz; Lawrence, Michael S; Haugen, Eric et al. (2014) Reduced local mutation density in regulatory DNA of cancer genomes is linked to DNA repair. Nat Biotechnol 32:71-5|
|Almendro, Vanessa; Kim, Hee Jung; Cheng, Yu-Kang et al. (2014) Genetic and phenotypic diversity in breast tumor metastases. Cancer Res 74:1338-48|
|Slavov, Nikolai; Budnik, Bogdan A; Schwab, David et al. (2014) Constant growth rate can be supported by decreasing energy flux and increasing aerobic glycolysis. Cell Rep 7:705-14|
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