Chairperson, Dermatology; Feinberg School of Medicine
TRIST-Skin Cancers,Tumor Invasion, Metastasis & Angiogenesis
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Role of membrane glycosphingolipids in signaling: The Paller laboratory is investigating the role of gangliosides in normal and neoplastic keratinocyte function. Gangliosides are cell-specific sialylated glycosphingolipids of eukaryotic membranes that affect cell-cell recognition, cell-substratum interactions, cell growth regulation, differentiation, and oncogenic transformation. The laboratory has shown that modulation of ganglioside content by a variety of biochemical and molecular biological means profoundly affects skin cell function through interaction with receptors and interruption of downstream signaling. For example gangliosides can: (i) down-regulate EGF receptor phosphorylation; (ii) interact with integrins to prevent keratinocyte adhesion, migration and spreading on a fibronectin matrix; (iii) promote apoptosis of keratinocytes and squamous carcinoma cells plated on fibronectin; and (iv) render cells resistant to apoptosis upon depletion. These effects involve the disruption or formation by gangliosides of membrane-based complexes of signaling proteins. For example, ganglioside GM3 (the predominant ganglioside of epithelial cells) directs the formation of a complex that includes the EGFR, caveolin-1, tetraspanin CD82 and PKC-alpha, thereby enabling PKC-alpha to downregulate EGFR signaling. The laboratory has also found that genetic modulation of ganglioside expression in mouse tumor models and human skin leads to the altered characteristics of squamous cell carcinomas. Specific ganglioside acetylation (9-O-GD3) is found in skin cancers, but not in normal epidermis, and the laboratory is investigating the genetic changes that are required for this acetylation with the plan for biochemical or genetic targeting of the acetylation process as a means to induce cell apoptosis/ differentiation and prevent carcinoma cell survival. The laboratory is also exploring the role of gangliosides on diabetic wound healing and using nanotechnology approaches to reverse the wound healing impairment in this population.
In collaborative research with the Mirkin laboratory in the International Institute of Nanotechnology at Northwestern, the Paller lab is also investigating the ability of topically applied siRNA – conjugated gold nanoparticles as a single agent in gene suppression. The laboratory has demonstrated ~100% uptake of the oligonucleotide- conjugated nanoparticles in cultured keratinocyte and excellent uptake through the epidermal barrier of mouse and human skin when topically applied, leading to gene knockdown in skin. Current studies are addressing knockdown through topical application of Ras-mediated epidermal hyperplasia/ squamous carcinoma and metastatic melanoma, in addition to nonneoplastic disease (diabetes, dominant negative genetic skin disorders).