faculty photo

Richard K. Assoian, Ph.D.

Professor of Pharmacology
Member, Center for Cancer Pharmacology, University of Pennsylvania School of Medicine
Member, Cardiovascular Institute, University of Pennsylvania School of Medicine
Member, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine
Director, Program in Translational Biomechanics, Institute of Translational Medicine and Therapeutics
Department: Pharmacology

Contact information
Department of Systems Pharmacology and Translational Therapeutics
421 Curie Blvd.
Rm 805(office)/833 (lab)
Philadelphia, PA 19104-6160
Office: (215) 898-7157
Fax: (215) 573-5656
Lab: (215) 898-7265
Graduate Group Affiliations
B.A. (Natural Science)
Johns Hopkins University, 1975.
Ph.D. (Biochemistry)
University of Chicago, 1981.
Permanent link
> Perelman School of Medicine   > Faculty   > Details

Description of Research Expertise

Key words

Extracellular matrix, microenvironment, adhesion receptor signaling, mechanotransduction, integrins, cadherins, actin, cytoskeleton, focal adhesions, matrix remodeling, deformable substrata, micropatterning, cell cycle, proliferation, cyclin-dependent kinases, mouse modeling, tissue mechanics, cardiovascular biology, progeria.

Overview of laboratory research:

We are an interactive group of cell/molecular biologists and bioengineers interested in understanding how cells sense changes in the physical properties of their microenvironment and how they convert this information into chemical signals, behavior and function. Within this broad area, we try to understand how physiological and pathological changes in the stiffness of the extracellular matrix (ECM) affects adhesion receptor signaling, the actin cytoskeleton, and fate decisions such as proliferation, migration and differentiation. We perform mechanistic analyses in cell culture, use genome- and proteome-wide approaches, assess mechanical properties of tissues and cells, and ultimately test physiological and pathological relevance in mouse models of vascular aging, injury, and atherosclerosis.

We are currently working in the following areas.

i) Cell Mechanobiology.
The ECM is a dynamic structure that provides both chemical and mechanical cues to cells. Remodeling of the ECM occurs in several diseases and generally tends to increase the stiffness of a cell's microenvironment. The effects of extracellular stiffness on cellular function are difficult to study when cells are cultured on traditional rigid plastic or glass substrata that are irrelevant to in vivo microenvironments. We therefore use deformable substrata (ECM-coated hydrogels) to model the stiffness of tissues that cells inhabit in vivo. With this approach, we can determine how changes in ECM stiffness affect adhesion receptor (integrin and cadherin) expression and signaling as well as downstream gene expression, proliferation, motility and differentiation. High through-put approaches are used to identify transcriptional and post-transcriptional responses to ECM stiffening. We have also used micropatterned substrata to examine the effect of cell-cell adhesion on the spreading and shape requirements for cell proliferation. Recent work with these approaches has led to the identification of stiffness-dependent signaling pathways, specific focal adhesion components controlling cyclin D1 expression, and novel mechanisms of crosstalk between cell-ECM and N-cadherin mediated cell-cell adhesion.

ii) Tissue Mechanobiology.
We are using atomic fore microscopy (AFM) and pressure myography ex vivo to interrogate how changes in ECM composition and mechanosensory proteins--often through genetic manipulation of mice--affects vessel mechanics. AFM allows us to detect microheterogeneity in the stiffness of isolated arteries. Pressure myography allows us to probe stress-strain relationships in the pressurized artery and can help to distinguish effects mediated by elastin vs. collagens. Much of our current interest in this area is related to the effects of age on vessel mechanics and mechanosensing.

iii) In vivo Mechanobiology
We place significant effort on in vivo mouse models to document the relevance of adhesion receptor signaling and stiffness-sensing to mammalian biology. For example, we use mice to study adhesion receptor signaling and vascular smooth muscle cell (SMC) proliferation during the in vivo response to vascular injury, a model of acute arterial stiffening. By comparing the degree of SMC proliferation in wild-type mice and mice with knock-outs/knock-ins of integrin-regulated, mechanosensing, and cell cycle genes, we can test the importance of the adhesion- and stiffness-regulated events we detect in primary SMCs cultured on hydrogels as described above. Similar studies are exploring the proliferative effects of N-cadherin and the role of arterial stiffening in SMC de-differentiation/re-differentiation.

We are also identifying regulators of mechanosensitive signaling, ECM remodeling, and arterial stiffening in vascular disease. One set of studies has focused on apolipoprotein E (apoE). Although best known for its role in reverse cholesterol transport, we found that apoE suppresses the expression of several ECM genes including those for collagen-I, collagen-VIII, fibronectin and lysyl oxidase. These effects protect against arterial stiffening, reduce monocyte adhesion to subendothelial ECM, and provide cholesterol-independent protection against atherosclerosis in mice. Ongoing work focuses on MMP12 as a global inducer of arterial stiffening with age, vascular injury and atherosclerosis. Finally, our newest interest is in mechano-signaling and ECM remodeling in Hutchinson-Guilford Progeria Syndrome, a genetic disease of premature aging and death that is associated with arterial stiffening, atherosclerosis and stroke.

Current Lab Members:
Irene Dang, PhD
Ziba Razinia, PhD
Shefali Talwar, PhD
Sonja Brankovic, graduate student
Ryan von Kleeck, graduate student
Nate Bade, graduate student (with Stebe lab)
Beth Hawthorne, research specialist/lab manager
Tina Xu, research specialist

ITMAT Biomechanics Core:
Paola Castagnino, PhD (Technical Director)
Ian Roberts, MSE (Research Specialist)

Selected Publications

Cosgrove BD, Mui KL, Driscoll TP, Caliari SR, Mehta KD, Assoian RK, Burdick JA, Mauck RL. : N-cadherin adhesive interactions modulate matrix mechanosensing and fate commitment of mesenchymal stem cells. Nature Materials 15: 1297-1306, 2016.

Liu SL, Bae YH, Yu C, Monslow J, Hawthorne EA, Castagnino P, Branchetti E, Ferrari G, Damrauer SM, Puré E, Assoian RK: Matrix metalloproteinase-12 is an essential mediator of acute and chronic arterial stiffening. Scientific Reports 5: 17189, 2015.

Mui, KM., Bae, YH, Gao, L., Liu, S-L. Xu, T., Radice, GL., Chen, CS, and Assoian, RK: N-cadherin induction by ECM stiffness and FAK overrides the spreading requirement for proliferation of vascular smooth muscle cells. Cell Reports 10: 1477-1486, 2015.

Bae YH, Mui KL, Hsu BY, Liu SL, Cretu A, Razinia Z, Xu T, Puré E, Assoian RK. : A FAK-Cas-Rac-Lamellipodin Signaling Module Transduces Extracellular Matrix Stiffness into Mechanosensitive Cell Cycling. Science Signaling 7: ra57, 2014.

Kothapalli, D.*, Liu, S.L.*, Bae, Y.H., Monslow, J., Xu, T., Hawthorne, E.A., Castagnino, P., Byfield, F.J., Rao, S., Rader, D.J., Pure, E., Phillips, M.C., Lund-Katz, S., Janmey, P.A., Assoian, R.K.: Cardiovascular protection by apoE and apoE-HDL linked to suppression of ECM gene expression and arterial stiffening. Cell Reports 2: 1259-1271, 2012.

Klein, E.A., Yin, L., Kothapalli, D., Castagnino, P., Byfield, F.J., Xu, T., Levantal, I., Hawthorne, E., Janmey, P.A., and Assoian, R.K.: Cell cycle control by physiological matrix elasticity and in vivo tissue stiffening. Current Biology 19: 1511-8, 2009.

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Last updated: 10/12/2017
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