Cytoskeletal rearrangements, altered cell polarity and cell adhesion defects are observed in a wide range of human diseases ranging from degenerative diseases to inflammatory disorders and cancer. We propose that alterations in key regulators of cell- and tissue architecture underlie a broad range of these diseases. We recently demonstrated in mouse skin epidermis that E-cadherin-dependent control of suprabasal EGFR activity orchestrates the polarized, tissue-level organization of junctions, tension, and the cytoskeleton, which is crucial for vivo skin barrier function. These studies also indicate a mechanistic role for EGFR at tight junctions (TJs), potentially explaining why EGFR inhibitors compromise skin barrier function in human cancer patients. Furthermore, we showed that the polarity kinase atypical kinase C (aPKC) integrates regulation of cell fate with control of the structural and immunological skin barrier. The goal of the current proposal is to address how cadherins and aPKCs cooperate to spatiotemporally coordinate the formation and maintenance of a functional multi-layered epithelial barrier with the explicit aim to identify novel therapy targets for a range of (inflammatory) skin barrier related diseases.
Inflammatory and degenerative skin diseases, such as psoriasis, atopic dermatitis and non- healing wounds, are highly prevalent. However, specific treatments are still mostly lacking due to a poor understanding of the underlying molecular causes. A dysfunctional skin barrier is considered to be one major contributor to disease. The two main components that build up the skin barrier are the outermost dead stratum corneum and the tight junctions in the uppermost viable stratum granulosum. This project addresses the molecular mechanisms that coordinate the formation and maintenance of these two epidermal barriers and explores their therapeutic potential in dysfunctional skin barrier related diseases.
Persa, O.D., and Niessen, C.M. (2019). Epithelial polarity limits EMT. Nat Cell Biol 21, 299-300.
Clayton, R.W., Gobel, K., Niessen, C.M., Paus, R., van Steensel, M.A.M., and Lim, X. (2019). Homeostasis of the sebaceous gland and mechanisms of acne pathogenesis. Br J Dermatol 10.1111/bjd.17981.
Miroshnikova YA, Le HQ, Schneider D, Thalheim T, Rubsam M, Bremicker N, Polleux J, Kamprad N, Tarantola M, Wang I, Balland M, Niessen CM, Galle J, and Wickstrom SA (2018). Adhesion forces and cortical tension couple cell proliferation and differentiation to drive epidermal stratification. Nat Cell Biol 20, 69-80.
Noethel B, Ramms L, Dreissen G, Hoffmann M, Springer R, Rubsam M, Ziegler WH, Niessen CM, Merkel R, and Hoffmann B (2018). Transition of responsive mechanosensitive elements from focal adhesions to adherens junctions on epithelial differentiation. Mol Biol Cell 29, 2317-2325.
Rubsam M, Broussard JA, Wickstrom SA, Nekrasova O, Green KJ, and Niessen CM (2018). Adherens Junctions and Desmosomes Coordinate Mechanics and Signaling to Orchestrate Tissue Morphogenesis and Function: An Evolutionary Perspective. Cold Spring Harb Perspect Biol 10.
Shafraz O, Rubsam M, Stahley SN, Caldara AL, Kowalczyk AP, Niessen CM, and Sivasankar S (2018). E-cadherin binds to desmoglein to facilitate desmosome assembly. Elife 7.
von Olshausen G, Quasdorff M, Bester R, Arzberger S, Ko C, van de Klundert M, Zhang K, Odenthal M, Ringelhan M, Niessen CM, and Protzer U (2018). Hepatitis B virus promotes beta-catenin-signalling and disassembly of adherens junctions in a Src kinase dependent fashion. Oncotarget 9, 33947-33960.
Vorhagen S, Kleefisch D, Persa OD, Graband A, Schwickert A, Saynisch M, Leitges M, Niessen CM, and Iden S (2018). Shared and independent functions of aPKClambda and Par3 in skin tumorigenesis. Oncogene10.1038/s41388-018-0313-1.
Weiland D, Brachvogel B, Hornig-Do HT, Neuhaus JFG, Holzer T, Tobin DJ, Niessen CM, Wiesner RJ, and Baris OR (2018). Imbalance of Mitochondrial Respiratory Chain Complexes in the Epidermis Induces Severe Skin Inflammation. J Invest Dermatol 138, 132-140.
Welcker D, Jain M, Khurshid S, Jokic M, Hohne M, Schmitt A, Frommolt P, Niessen CM, Spiro J, Persigehl T, Wittersheim M, Buttner R, Fanciulli M, Schermer B, Reinhardt HC, Benzing T, and Hopker K (2018). AATF suppresses apoptosis, promotes proliferation and is critical for Kras-driven lung cancer. Oncogene 37, 1503-1518.
Wickstrom SA, and Niessen CM (2018). Cell adhesion and mechanics as drivers of tissue organization and differentiation: local cues for large scale organization. Curr Opin Cell Biol 54, 89-97.
Mescher M, Jeong P, Knapp SK, Rubsam M, Saynisch M, Kranen M, Landsberg J, Schlaak M, Mauch C, Tuting T, Niessen CM, and Iden S (2017). The epidermal polarity protein Par3 is a non-cell autonomous suppressor of malignant melanoma. J Exp Med 214, 339-58.
Miroshnikova YA, Le HQ, Schneider D, Thalheim T, Rubsam M, Bremicker N, Polleux J, Kamprad N, Tarantola M, Wang I, Balland M, Niessen CM, Galle J, and Wickstrom SA (2017). Adhesion forces and cortical tension couple cell proliferation and differentiation to drive epidermal stratification. Nat Cell Biol10.1038/s41556-017-0005-z.
Persa O, Vorhagen S, Miyanji J, and Niessen C (2017). Loss of aPKC1/lambda requires p53 mediated Carcinogenesis. Journal Der Deutschen Dermatologischen Gesellschaft 15, 5-.
Rahn E, Thier K, Petermann P, Rubsam M, Staeheli P, Iden S, Niessen CM, and Knebel-Morsdorf D (2017). Epithelial Barriers in Murine Skin during Herpes Simplex Virus 1 Infection: The Role of Tight Junction Formation. J Invest Dermatol 137, 884-93.
Rubsam M, Broussard JA, Wickstrom SA, Nekrasova O, Green KJ, and Niessen CM (2017a). Adherens Junctions and Desmosomes Coordinate Mechanics and Signaling to Orchestrate Tissue Morphogenesis and Function: An Evolutionary Perspective. Cold Spring Harb Perspect Biol10.1101/cshperspect.a029207.
Rubsam M, Mertz AF, Kubo A, Marg S, Jungst C, Goranci-Buzhala G, Schauss AC, Horsley V, Dufresne ER, Moser M, Ziegler W, Amagai M, Wickstrom SA, and Niessen CM (2017b). E-cadherin integrates mechanotransduction and EGFR signaling to control junctional tissue polarization and tight junction positioning. Nat Commun 8, 1250.
Weiland D, Brachvogel B, Hornig-Do HT, Neuhaus JFG, Holzer T, Tobin DJ, Niessen CM, Wiesner RJ, and Baris OR (2017). Imbalance of Mitochondrial Respiratory Chain Complexes in the Epidermis Induces Severe Skin Inflammation. J Invest Dermatol10.1016/j.jid.2017.08.019.
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Department Cell Biology of the Skin / CECAD
CMMC - PI - A 08
Executive Board Membershow more…
Dr. Oana Persa (MD)
Dr. Susanne Vorhagen (Postdoc)
Jabiz Nafisi (PhD Student)
Frederik Tellkamp (PhD Student)
Julia Stinn (Technician)