Dr. Lester. F. Lau
- PhD, Cornell University
- Postdoctoral Fellow, Johns Hopkins University School of Medicine
Extracellular Matrix Signaling in Inflammation, Wound Healing, and Cancer
The extracellular matrix plays critical roles in regulating diverse biological and pathological processes, including developmental morphogenesis, tissue repair and remodeling, inflammation and host defense, and progression of diseases such as cancer. Our laboratory is interested in the biological functions of CCNs, a family of cysteine-rich, dynamically expressed matricellular proteins that regulates a broad range of cellular activities through direct binding to cell surface integrin receptors and heparan sulfate proteoglycans. Ccn1- and Ccn2-null mice are embryonic and perinatal lethal due to cardiovascular and skeletal defects, respectively. Aberrant expression of Ccn1 is associated with pathological conditions including wound healing, atherosclerosis, restenosis, rheumatoid arthritis, and cancer. We are using biochemical and cell biological approaches to elucidate the functions of CCN1, complemented by in vivo studies using mouse models that genetically alter Ccn1 by targeted and conditional knockouts, allelic replacements, and transgenic expression.
Inflammation and Wound Healing
We have shown that CCN1 can profoundly alter the activities of the tumor necrosis factor (TNF) family of cytokines, and polarize macrophages towards the classically activated M1 pathway that participates in Th1 responses. In addition, CCN1 is dynamically expressed at sites of inflammation and wound healing, suggesting a role in these contexts. Our recent studies showed that CCN1 can directly induce cellular senescence in fibroblasts, thereby triggering the expression of an anti-fibrotic genetic program. Furthermore, we showed that senescent cells accumulate as a healing response in murine cutaneous wounds and function to limit fibrosis, and these processes are dependent on CCN1. We are currently investigating the role and therapeutic potential of CCN1-induced senescence in the control of fibrosis and wound healing in animal models.
Our laboratory has established that CCN proteins (CCN1, CCN2, and CCN3) are potent angiogenic inducers in vivo. The angiogenic activity of CCNs may play a critical role in the observed association of CCN expression in cancers of several tissues, including the breast, glia, and pancreas. We are analyzing the contribution of CCN1-regulated angiogenesis in tumor growth and metastasis.
Aleksandar M. Babic, M.D., Ph.D., The Methodist Hospital Research Institute
Ian J. Davis, M.D. Ph.D., University of North Carolina at Chapel Hill
Carrie Franzen, Ph.D., Northwestern University
Tatiana M. Grzeszkiewicz, M.D., Ph.D.,Palo Alto Medical Foundation
Thomas H. Hazel, Ph.D., Neuralstem, Inc.
Vladislava Juric, Ph.D., University of California at San Francisco
Maria L. Kireeva, Ph.D., National Cancer Institute
Branko V. Latinkic, Ph.D., Cardiff University, UK.
Shr-Jeng Leu, Ph.D., National Yang Ming University, Taiwan
Fan-E Mo, Ph.D., National Cheng Kung University, Taiwan
Ricardo I. Monzon, Ph.D., Saint Xavier University
Timothy P. O’Brien, Ph.D., Cornell University
Dimitri G. Pestov, Ph.D., University of Medicine and Dentistry of New Jersey
Zaklina Strezoska, Ph.D., Altana Pharma
Viktor Todorović, Ph.D., Northwestern University
Gregg T. Williams, Ph.D., Abbott Laboratories
Mayme Wong, Ph.D., Eli Lilly and Company
George P. Yang, M.D., Ph.D., Stanford University
Jeong Kyo Yoon, Ph.D, Maine Medical Center Research Institute
Jennifer Young, Ph.D., University of Rochester
Jun, J.I. and Lau, L.F. (2010) The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat. Cell Biol. 12:676-685.
Jun, J.I. and Lau, L.F. (2011) Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nat. Rev. Drug Discov. 10:945-963.
Juric, V., Chen, C.C., and Lau, L.F. (2012) TNFa-induced apoptosis enabled by CCN1/CYR61: pathways of reactive oxygen species generation and cytochrome c release. PLoS One 7(2):e31303.
Kim, K.H,, Chen, C.C., Monzon, R.I., and Lau, L.F. (2013) The Matricellular Protein CCN1 Promotes Regression of Liver Fibrosis through Induction of Cellular Senescence in Hepatic Myofibroblasts. Mol. Cell. Biol. Mar. 18 [Epub ahead of print].