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Richard L. Eckert

Richard L. Eckert Ph.D.

Academic Title: Professor
Primary Appointment: Biochemistry and Molecular Biology
Secondary Appointments: Dermatology, Obstetrics, Gynecology and Reproductive Sciences
Administrative Title: Chair, Department Of Biochemistry & Molecular Biology
Additional Title(s): John F.B. Weaver Professor, Associate Director - Basic Sciences Greenebaum Cancer Center
Location: 108NG 110

Personal History:

Dr. Eckert received his Bachelor degree from the University of Wisconsin and PhD from the University of Illinois - Urbana. He then completed post-doctoral work at the Massachusetts Institute of Technology in the Department of Cell Biology, and at Harvard Medical School in the Department of Physiology and Biophysics with Dr. Howard Green, a member of the National Academy of Medicine. In 1986 he joined the faculty of Case Reserve University (CRWU) School of Medicine as an assistant professor of physiology and biophysics, dermatology, reproductive biology, oncology and biochemistry. He was subsequently promoted to associate professor with tenure in 1992 and professor in 1996. He elucidated the structure of several human keratin genes and initiated studies using the involucrin gene as a model to understand gene regulation in epidermis. It is also while at CWRU that he initiated studies on retinoid regulation of skin cancer, the ability of diet-derived agents to reduce cancer cell proliferation and survival, the TIG3 tumor suppressor protein that regulates suprabasal keratinocyte survival, and S100 proteins as controllers of inflammation. The Eckert laboratory was among the first to perform extensive studies in several of these areas. In 2006 he accepted the position as the John F.B. Weaver Distinguished Professor and Chair of the Department of Biochemistry and Molecular Biology at the University of Maryland School of Medicine. In 2013 was named Associate Director for Basic Science in the Greenebaum Cancer Center, and in 2015 assumed the role as Basic Science Director of the Mesothelioma Cancer Center. He is also Chair of the University of Maryland School of Medicine Research Affairs Advisory Committee (RAAC). Dr. Eckert is a member of the Molecular and Structural Biology Program within the University of Maryland Marlene and Stewart Greenebaum Cancer Center Program in Oncology. While at UMSOM, Dr. Eckert’s laboratory initiated new studies on epigenetic regulation including studies of the polycomb group genes, PRMT5 methyltransferase and transglutaminase II as a cancer stem cell survival factors. Dr. Eckert has extensive service on national grant review panels, science advocacy panels and extensive service to national scientific societies. He has published over 200 peer reviewed manuscripts, presented many national and international lectures and received awards for this research and service. He holds patents from the United States Patent Office, and has been continuously funded as a principal NIH investigator since 1989. He is presently principal investigator on multiple grants from the National Institutes of Health and has also been supported by the Department of the Navy, the American Cancer Society, the Dermatology Foundation, American Institute for Cancer Research and the Congressionally Directed Medical Research Program Breast Cancer Research Program.

Research Interests:

References are not necessarily current depending upon when each section was updated - please check PubMed for current citations.

Dr. Eckert's research focuses on understanding how normal surface epithelial cells function to protect people from illnesses and how those cells are altered during disease states. The laboratory has a strong focus on characterization and treatment of epidermal squamous cell carcinoma and melanoma. The laboratory also works on head & neck cancer and mesothelioma. A particular emphasis is the characterization of natural dietary agents as treatments that target cancer stem cells to reduce tumor formation.

The skin, the largest organ of the human body, provides structural integrity to the body surface, and provides the interface with the environment. The epidermis, the outermost epithelial surface, is a first line of defense. This tissue houses the capacity to mount an immune response, position sensory cells, and repel insults. Understanding the mechanisms that regulate development and maintenance of this organ is of utmost importance (Eckert et al., Physiol Rev 77:397-424, 1997).

The epidermis is a multi-layered tissue, containing a reservoir of stem cells (in the hair follicle shaft and basal layer). The stem cells proliferate to give rise to daughter cells which then differentiate to produce mature keratinocytes, thereby populating the epidermal surface.  Ultimately these cells undergo terminal cell death. This process results in the production of the multi-layered structure (Fig. 1)

Key Words:

epidermis, differentiation, melanoma, squamous cell carcinoma, mesothelioma, tumor suppressors, cancer stem cells, epigenetic regulation, diet-derived agents in cancer prevention and therapy, transgenic models, cell culture, patient-derived cell culture, molecular biology

Lab Techniques and Equipment:

Laboratory Approaches

The Eckert laboratory uses biochemistry, cell culture, cell biology, molecular biology, chip array, proteomics, transgenic and knockout mouse models to study epithelial cell differentiation. This includes molecular cloning and expression of regulatory proteins, cellular transfection with cDNAs and infection with adenovirus, immunological studies of regulatory proteins and protein complexes, cell and tissue culture of epidermal keratinocytes, cryo-sectioning of biopsies from humans and rodents; confocal laser scanning and electron microscopy and gene array and genomics approaches.

Research Projects:

Surface Epithelial Cell Differentiation:

The skin, the largest organ of the human body, provides structural integrity to the body surface, and provides the interface with the environment. The epidermis, the outermost epithelial surface, is a first line of defense. This tissue houses the capacity to mount an immune response, position sensory cells, and repel insults. Understanding the mechanisms that regulate development and maintenance of this organ is of utmost importance (Eckert et al., Physiol Rev 77:397-424, 1997).

The epidermis is a multi-layered tissue, containing a reservoir of stem cells (in the hair follicle shaft and basal layer) (Fig. 1). The stem cells proliferate to give rise to daughter cells which then differentiate to produce mature keratinocytes, thereby populating the epidermal surface. Ultimately these cells undergo terminal cell death. This process results in the production of the multi-layered structure. The human epidermis consists of multiple layers. The main cell type is the keratinocyte. The small yellow arrows indicate the basal keratinocyte which are derived from stem cells and have the ability to divide to give rise to the other epidermal layers. As these cells migrate upwards (black arrows) they differentiate to form the spinous, granular and cornified layers (Eckert et al., Physiol Rev 77:397-424, 1997) (Fig. 1)

Under normal conditions, epidermal stem cells have unlimited ability to divide, but as part of the differentiation process they lose this ability. Identifying the mechanisms that regulate the transition from stem cell to daughter cell to terminally differentiated cell is an important area of investigation, and requires that we understand the mechanisms that control keratinocyte proliferation, apoptosis, differentiation, and senescence. A major goal of our laboratory is to understand these processes and identify the control factors.

  1. MAPK signaling and transcriptional control of gene expression

    As a strategy to understand the control of keratinocyte differentiation, we study the mechanisms that drive expression of the involucrin gene. Involucrin is a key structural protein that is expressed in differentiated keratinocytes. We’ve shown that a transcriptional complex which includes jun/fos transcription factor family members (junB, junD, Fra-1) and Sp1, and C/EBP transcription factors binds to unique transcriptional elements (DRR and PRR) in the involucrin promoter to activate gene expression (Fig. 2). We have further shown that the activity and level of this complex is controlled by a multi-protein mitogen-activated protein kinase (MAPK) signalsome-like complex which includes protein kinase c, Ras, MEKK1, MEK3 and p38delta-ERK1/2. These studies define a pathway of information flow from the cell surface to the nucleus which controls gene expression during differentiation (Efimova and Eckert, J Biol Chem 275:1601-1607, 2000; Efimova et al., Mol Cell Biol 24:8167-8183, 2004; Eckert et al., J Invest Derm 123:13-22, 2004).

    We are addressing several key questions regarding this regulation, including defining the protein components of the signalsome and transcriptional complexes, understanding how these complexes change when cells are stimulated to differentiate, and how scaffolding proteins influence the flow of information through this signaling cascade. We are using cell and molecular biological, biochemical, protein purification, proteomic and transgenic approaches in this study. Our ultimate goal is to understand how these complexes activate involucrin expression in differentiated cells. We have recently shown suppression of involucrin is controlled by protein arginine methyltransferase 5 (PRMT5) and its cofactor MEP50 silence involucrin expression via methylation of chromatin (Saha et al., J Invest Dermatol 2015; Saha and Eckert J Biol Chem 290:13521, 2015).

  2. The TIG3 tumor suppressor protein - keratinocyte survival control

    We have identified a novel regulatory protein, TIG3, that is expressed in the upper epidermal layers. TIG3 expression is markedly reduced in diseases of enhanced cell proliferation such as cancer. We believe that this protein regulates cell survival during keratinocyte differentiation. We have recently demonstrated that TIG3 expression in keratinocytes reduces cell survival by interacting with and activating type 1 transglutaminase (TG1). TG1 is a membrane-localized protein that acts to covalently crosslink intracellular proteins, ultimately causing cell death. Fig. 3 is a confocal image showing co-localization of full-length TIG3 (TIG31-164) with activated TG1 (Sturniolo et al., J Biol Chem 278:48066-48073, 2003; Sturniolo et al., Oncogene 24:2963-2972, 2005; Scharadin et al., PLoS One 6:23230, 2011). Also shown, a TIG3 mutant (TIG31-134) which lacks the c-terminal membrane-anchoring domain does not localize with or activate TG1.

    We have shown that TIG3 and TG1 are components of a multiprotein complex that forms in cells. We are presently addressing several important issues including characterizing the molecular interaction between TIG3 and TG1, identifying other proteins that may be involved in this interaction, monitoring TIG3 and TG1 movement within cells, and elucidating the structure of the TIG3 protein..

  3. Epidermal stem cells for cell-based therapy

    The keratinocytes that populate the epidermal surface are derived from stem cells located in specific niche areas in the tissue. These niches harbor a reservoir of cells that could be tapped for therapy applications. Using the epidermis as a source of cells is an attractive idea because the cells are abundant (the skin is the largest organ of the body) and the epidermis is readily accessible (on the skin surface). The strategy is to convert the epidermal cells into multipotent stem cells and then to "reprogram" them to make other cell types. As part of an ongoing collaboration with Dr. Jackie Bickenbach, PhD (University of Iowa), we are studying how stem cells that are committed to produce keratinocytes can be reprogrammed to produce other cell types (e.g., neuronal cells). If the ability to convert these cells to the multipotent state can be perfected, epidermal cells could provide an abundant and accessible source of cells for therapy. We have recently shown that these cells can be converted to multipotent status by vector-mediated expression of the embryonic stem cell transcription factor, Oct 4, and that these cells can then be reprogrammed to produce neuronal cells (Grinnell et al., J. Invest. Dermatol 127:372-380, 2007). Oct-4 is required for maintenance of embryonic stem cells. The ability to manipulate cells in this manner has tremendous medical importance for the large scale generation of therapeutically useful cells. Given the number of cells in the skin and the relative ease with which these cells can be harvested, they could provide a potentially huge reservoir of reprogrammable cells for use in cell-based disease therapy. A key question is how genes that control stem cell status (such as Oct 4), are regulated in keratinocytes. We are presently working to identify mechanisms that control expression of several genes involved in this process.

  4. Animal models of disease - keratoderma

    A major focus of our laboratory is production of genetically engineered transgenic animal (mouse) models that mimic human disease. The idea is to use these models to understand the disease process and develop therapies. Keratoderma is one example (Fig. 4). Keratodermas comprise a heterogeneous group of highly debilitating and painful disorders characterized by thickening of the skin with marked hyperkeratosis. Some of these diseases are caused by genetic mutation, whereas other forms are acquired in response to environmental factors. Our understanding of signaling changes that underlie these diseases is limited. We have generated a keratoderma phenotype in mice in response to suprabasal epidermis-specific inhibition of activator protein 1 transcription factor signaling. These mice develop a severe phenotype characterized by hyperplasia, hyperkeratosis, parakeratosis, and impaired epidermal barrier function. The skin is scaled, constricting bands encircle the tail and digits, the footpads are thickened and scaled, and loricrin staining is markedly reduced in the cornified layers and increased in the nucleus. Features of this phenotype, including nuclear loricrin localization and pseudoainhum, are observed (autoamputation). We also show that the phenotype regresses when suprabasal AP1 factor signaling is restored. Our findings suggest that suppression of AP1 factor signaling in the suprabasal epidermis is a key event in the pathogenesis of keratoderma. Our recent studies, using a newly developed transgenic animal model, suggest a new way of thinking about this disease. We propose that the outer layer of the skin, the epidermis, may play a key role in triggering keratoderma. We show that disrupting epidermal function produces major and rapid keratoderma-like changes (Rorke et al., J Invest Dermatol 135:170-180, 2014; Rorke et al., Cell Death Dis 6: e1647, 2015). An interesting finding is that these mice are resistant to induction of cancer (Rorke et al., Oncogene 29:5873-5882, 2010). Fig. 4 displays a description of the phenotype of these mice (see Rorke et al., J Invest Dermatol 135:170-180, 2014).

  5. Dietary agents in cancer prevention

    Cancer begins with a normal cell that, due to persistent environmental insult, is transformed, via a series of progressively more insidious steps, into a cancer cell. A major goal of chemopreventive therapy is to alter the normal cell response to the environmental stress agent in order to inhibit disease progression. These agents act via a variety of different mechanisms. Some chemopreventive agents enhance cell differentiation. (-)-Epigallocatechin-3-gallate (EGCG) is an important bioactive antioxidant, derived from tea, which possesses remarkable cancer preventive properties. Our studies clearly indicate that EGCG markedly increases keratinocyte differentiation. Based on these results, we argue that EGCG acts to prevent cancer development by forcing neoplastic cells to undergo differentiation. This is an important hypothesis, as it indicates that green tea may act to prevent disease before it develops (Balasubramanian et al., J Biol Chem 277:1828-1836, 2002). In addition, our studies show that all chemopreventive agents are not created equal, and that these agents can influence each others action (Balasubramanian et al., J Biol Chem 281:36162-36172, 2006; Balasubramanian et al., J Biol Chem 282:6707-6715, 2007). This implies that the use of these compounds for cancer prevention must be carefully considered. An immediate goal is to examine how these agents influence epigenetic regulation.

  6. Polycomb genes and epigenetic regulation of normal and cancer cell survival

    The Polycomb Group (PcG) genes are epigenetic suppressors of gene expression that play an important role in development through modification of chromatin. They act to methylate and ubiquitinate histones to produce closed chromatin to silence tumor suppressor gene expression. We are interested in these proteins because they are highly overexpressed in cancer stem cells and enhance their survival. Fig. 6 shows that inhibition of Ezh2 function, with GSK126, a specific inhibitor, reduces epidermal cancer stem cell survival in culture and also reduces the growth of cancer stem cell-derived tumors (see Adhikary et al., Carcinogenesis 36:800-810, 2015).

  7. Cancer stem cells

    Epidermal squamous cell carcinoma is among the most common cancers in humans. These tumors are comprised of phenotypically diverse populations of cells that display varying potential for proliferation and differentiation. An important goal is identifying cells from this population that drive tumor formation. To enrich for tumor-forming cells, cancer cells were grown as spheroids in non-attached conditions. We show that spheroid-selected cells form faster growing and larger tumors in immune-compromised mice as compared to non-selected cells. Moreover, spheroid-selected cells gave rise to tumors following injection of as few as one hundred cells, suggesting these cells have enhanced tumor-forming potential. Cells isolated from spheroid-selected tumors retain an enhanced ability to grow as spheroids when grown in non-attached culture conditions. Thus, these tumor-forming cells retain their phenotype following in vivo passage as tumors. Detailed analysis reveals that spheroid-selected cultures are highly enriched for expression of epidermal stem cell and embryonic stem cell markers, including aldehyde dehydrogenase 1, keratin 15, CD200, keratin 19, Oct4, Bmi-1, Ezh2 and trimethylated histone H3. These studies indicate that a subpopulation of cells that possess stem cell-like properties and express stem cell markers can be derived from human epidermal cancer cells and that these cells display enhanced ability to drive tumor formation. Fig. 7 shows an example of how epidermal cancer stem cells are able to make aggressive and highly vascularized (red, spheroid cells) tumors that are much larger than tumors formed by non-stem cancer cells (monolayer cells) (from Adhikary et al., PLoS One 8:e84324, 2013). These are an extremely dangerous subpopulation of cells in tumors. We are interested in identifying agents that target and kill these cells.


The Eckert laboratory has published more than 200 journal articles and over 150 meeting abstracts.  This work has been completed due to the dedicated effort of numerous graduate students and post-doctoral associates. Dr. Eckert also serves as an editorial board member or reviewer for scientific journals including the Journal of Biological Chemistry, Endocrinology, Cancer Research, and the Journal of Investigative Dermatology.