for Project-3 The total length of human DNA in each nucleus (~2 meters) multipled by the number of nucleated cells in an adult human (~10 trillion) gives a total length of DNA in each person that would stretch from the Sun to Pluto and back. A lamina of proteins akin to keratins in your fingernails underlies the nuclear envelope and surrounds the chromosomes contained within each nucleus, and while lamin proteins somehow contribute to nuclear shape and DNA stability, roles for lamins in cancer are extremely unclear. This project focuses on nuclear rheology and stability down to the single molecule level, especially in dynamically migrating and invasive cells. Hepatocellular carcinoma (HCC) tumors exhibit atypical nuclei as many cancers do, and initial profiling of HCC suggests significant changes in lamins, which need to be confirmed and understood. We have recently shown that lamin levels can be mechanosensitive in responding to tissue stiffness [Swift Science 2013], which is especially relevant to HCC because the human liver generally stiffens prior to HCC development [Mueller 2010]. We have also recently found in initial studies that at least one lamin isofom can regulate cell migration and survival through constraining pores [Harada J Cell Biol 2014]. Preliminary results further indicate a relation to DNA damage and repair that we seek to clarify mechanistically down to single molecule levels through the expertise of the Greenberg Lab [Shanbhag Cell 2010].
Our Aims to more deeply study lamin effects on nuclear rheology and stability illustrate the potential consequences of liver tumor stiffening studied in Project-1 and the potential downstream mechanosensitive phenotypes for Project-2.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA193417-03
Application #
9263919
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Lee, Calvin K; de Anda, Jaime; Baker, Amy E et al. (2018) Multigenerational memory and adaptive adhesion in early bacterial biofilm communities. Proc Natl Acad Sci U S A 115:4471-4476
Nair, Praful R; Alvey, Cory; Jin, Xiaoling et al. (2018) Filomicelles Deliver a Chemo-Differentiation Combination of Paclitaxel and Retinoic Acid That Durably Represses Carcinomas in Liver to Prolong Survival. Bioconjug Chem 29:914-927
Huang, Mo; Wang, Jingshu; Torre, Eduardo et al. (2018) SAVER: gene expression recovery for single-cell RNA sequencing. Nat Methods 15:539-542
Ban, Ehsan; Franklin, J Matthew; Nam, Sungmin et al. (2018) Mechanisms of Plastic Deformation in Collagen Networks Induced by Cellular Forces. Biophys J 114:450-461
Smith, Lucas R; Cho, Sangkyun; Discher, Dennis E (2018) Stem Cell Differentiation is Regulated by Extracellular Matrix Mechanics. Physiology (Bethesda) 33:16-25
Holle, Andrew W; Young, Jennifer L; Van Vliet, Krystyn J et al. (2018) Cell-Extracellular Matrix Mechanobiology: Forceful Tools and Emerging Needs for Basic and Translational Research. Nano Lett 18:1-8
Pfeifer, Charlotte R; Xia, Yuntao; Zhu, Kuangzheng et al. (2018) Constricted migration increases DNA damage and independently represses cell cycle. Mol Biol Cell 29:1948-1962
Xia, Yuntao; Ivanovska, Irena L; Zhu, Kuangzheng et al. (2018) Nuclear rupture at sites of high curvature compromises retention of DNA repair factors. J Cell Biol 217:3796-3808
Ramakrishnan, N; Bradley, Ryan P; Tourdot, Richard W et al. (2018) Biophysics of membrane curvature remodeling at molecular and mesoscopic lengthscales. J Phys Condens Matter 30:273001
Chen, Gang; Huang, Alexander C; Zhang, Wei et al. (2018) Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560:382-386

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