Distinguished Professor of Biological Sciences and Adjunct Professor of Oncological Sciences
Jon M. Huntsman Presidential Endowed Chair
Chief Executive Officer, Huntsman Cancer Institute
Associate Vice President for Cancer Affairs, University of Utah
Cell Adhesion, Cytoskeleton, Mouse Models, Knockout Mice, Pre-Clinical Mouse Models of Cancer, Ewing Sarcoma
My laboratory utilizes biochemical and genetic approaches to study central problems in cell biology such as signal transduction and cell motility. Below I describe several examples of current interests in the lab:
1. Understanding the molecular mechanism of cell movement
The ability of cells to migrate plays a central role in many normal biological processes including embryonic development, the cell-mediated immune response, and wound healing. The uncontrolled motility of cells is a hallmark of the deadliest cancers. It has been clear for some time that cell migration depends on the ability of cells to adhere to the underlying substratum and to extend the cell surface in the direction of movement. Our lab has identified components of the machinery that regulates cell motility. We are currently employing biochemical and genetic approaches to analyze the physiological roles of the motility machinery in normal and transformed cells.
2. Signaling from the cell surface to the nucleus
Cell adhesion to specific molecules in the extracellular environment can trigger a variety of physiological responses including changes in gene expression and cell proliferation. We are interested in understanding how cell adhesion events at the cell surface can affect processes that depend on the activity of the cell nucleus. We have discovered a protein that can shuttle between the nucleus and sites of cell adhesion, suggesting a possible mechanism for communication between these spatially segregated cellular compartments.
3. Investigating Ewing sarcoma cell biology
Ewing Sarcoma is an aggressive pediatric bone cancer driven by a chromosomal rearrangement that generates an oncogenic fusion protein. This oncogene directs an altered gene regulation program in the Ewing Sarcoma cells, resulting in dramatic changes in protein expression patterns, cell adhesion and cell migration. As a consequence, Ewing sarcoma cells often migrate to distant organs, leading to poor prognosis for the patient. We are investigating the molecular mechanisms of this cell behavior with the goal of translating the experimental findings to the clinic and preventing the progression and metastasis of Ewing sarcoma.
- Mechanical stress triggers nuclear remodeling and the formation of Transmembrane Actin Nuclear lines with associated Nuclear Pore Complexes.Mol Biol Cell. 2020 Jan 22:mbcE19010027
- Pishas KI, Drenberg CD, Taslim C, Theisen ER, Johnson KM, Saund RS, Pop IL, Crompton BD, Lawlor ER, Tirode F, Mora J, Delattre O, Beckerle MC, Callen DF, Sharma S, Lessnick SL. (2018) Therapeutic Targeting of KDM1A/LSD1 in Ewing Sarcoma with SP-2509 Engages the Endoplasmic Reticulum Stress Response. Mol Cancer Ther. 17(9):1902-1916
- Hoffman L, Jensen CC, Yoshigi M, Beckerle MC. (2017) Mechanical signals activate p38 MAPK pathway-dependent reinforcement of actin via mechanosensitive HspB1. Mol Biol Cell. 28(20):2661-2675.
- Rosner SR, Pascoe CD, Blankman E, Jensen CC, Krishnan R, James AL, Elliot JG, Green FH, Liu JC, Seow CY, Park JA, Beckerle MC, Paré PD, Fredberg JJ, Smith MA. (2017) The actin regulator zyxin reinforces airway smooth muscle and accumulates in airways of fatal asthmatics. PLoS One. 12(3):e0171728.
- Piccolo SR, Hoffman LM, Conner T, Shrestha G, Cohen AL, Marks JR, Neumayer LA, Agarwal CA, Beckerle MC, Andrulis IL, Spira AE, Moos PJ, Buys SS, Johnson WE, Bild AH. (2016) Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility. Mol Syst Biol. 12(3):860.
- Stachowiak MR, Smith MA, Blankman E, Chapin LM, Balcioglu HE, Wang S, Beckerle MC, O'Shaughnessy B. (2014) A mechanical-biochemical feedback loop regulates remodeling in the actin cytoskeleton. Proc Natl Acad Sci U S A. 111(49):17528-33.
- Chaturvedi A, Hoffman LM, Jensen CC, Lin YC, Grossmann AH, Randall RL, Lessnick SL, Welm AL, Beckerle MC. (2014) Molecular dissection of the mechanism by which EWS/FLI expression compromises actin cytoskeletal integrity and cell adhesion in Ewing sarcoma. Mol Biol Cell. 25(18):2695-709.
- Sankar S, Theisen ER, Bearss J, Mulvihill T, Hoffman LM, Sorna V, Beckerle MC, Sharma S, Lessnick SL. (2014) Reversible LSD1 inhibition interferes with global EWS/ETS transcriptional activity and impedes Ewing sarcoma tumor growth. Clin Cancer Res. 20(17):4584-97.
- Smith MA, Blankman E, Deakin NO, Hoffman LM, Jensen CC, Turner CE, Beckerle MC. (2013) LIM domains target actin regulators paxillin and zyxin to sites of stress fiber strain. PLoS One. 8(8):e69378.
- Chapin LM, Blankman E, Smith MA, Shiu YT, Beckerle MC. (2012) Lateral communication between stress fiber sarcomeres facilitates a local remodeling response. Biophys J. 103(10):2082-92.
- Elias MC, Pronovost SM, Cahill KJ, Beckerle MC, Kadrmas JL. (2012) A crucial role for Ras suppressor-1 (RSU-1) revealed when PINCH and ILK binding is disrupted. J Cell Sci. 125(Pt 13):3185-94.
- Hoffman LM, Jensen CC, Chaturvedi A, Yoshigi M, Beckerle MC. (2012) Stretch-induced actin remodeling requires targeting of zyxin to stress fibers and recruitment of actin regulators. Mol Biol Cell. 23(10):1846-59.
- Chaturvedi A, Hoffman LM, Welm AL, Lessnick SL, Beckerle MC. (2012) The EWS/FLI Oncogene Drives Changes in Cellular Morphology, Adhesion, and Migration in Ewing Sarcoma. Genes Cancer. 3(2):102-16.
- Beckerle MC. (2010) How cell biologists can contribute to improving cancer outcomes. Mol Biol Cell. 21(22):3788-9.
- Hervy M, Hoffman LM, Jensen CC, Smith MA, Beckerle MC. (2010) The LIM protein Zyxin binds CARP-1 and promotes apoptosis. Genes & Cancer. 1(5):506-515.
- Smith MA, Blankman E, Gardel ML, Luettjohann L, Waterman CM, Beckerle MC. (2010) A zyxin-mediated mechanism for actin stress fiber maintenance and repair. Dev Cell. 19(3):365-76.
- Yoshigi M, Hoffman LM, Jensen CC, Yost HJ, Beckerle MC. (2005) Mechanical force mobilizes zyxin from focal adhesions to actin filaments and regulates cytoskeletal reinforcement. J Cell Biol. 171(2):209-15.
- Kadrmas JL, Beckerle MC. (2004) The LIM domain: from the cytoskeleton to the nucleus. Nat Rev Mol Cell Biol. Review. 5(11):920-31.