Epithelial-stromal crosstalk and cell fate regulation in field cancerization
Field cancerization, the existence of multifocal and recurrent tumours that arise after widespread albeit morphologically not always visible changes in the surrounding tissue, is considered a major driver of very common epithelial cancers. Many of these cancers have high tumour recurrence and mortality rates with often no long-term effective treatment.
Epithelial tissues are able to maintain functionality and structural integrity in the presence of cancer-causing mutations through mechanisms that are poorly understood. Mutations in key oncogenes and tumor suppressors such as p53 are e.g. common in sun-exposed but physiologically healthy skin. Only a small percentage will proceed to benign lesions such as actinic keratosis defined by field cancerization and inflammation that precedes invasive squamous cell carcinoma (SCC). SCC is the second most frequent skin cancer Despite recent developments in systemic oncology therapies, the current therapy for metastatic SCC is still limited and disease relapse frequently occurs.What prevents evolution to field cancerization and subsequent SCC in skin carrying mutations such as p53 is largely unknown. In the current CMMC project we have identified polarity signaling as barrier for p53 mutant cells to progress to field cancerization and to evolve into SCC.
We aim to explore which settings determine whether polarity signalling, an essential determinant of tissue architecture and stem cell fate, serves a tumour promoting or a tumor inhibitory function. We also ask whether the maintenance of cell and tissue architecture serve as barriers to preserve homeostatic tissue function in the presence of tumor-related mutations such as p53, and how we can exploit this knowledge for novel cancer markers and therapeutic options.
The polarity protein atypical protein kinase C (aPKC)λ is overexpressed in many human tumors and its overexpression associates with poor survival. My laboratory has identified aPKCλ as an important regulator of epidermal homeostasis and stem cell fate (Niessen et al., 2013).Loss of aPKCλ resulted in gradual loss of bulge stem cells and increased differentiation, resulting in premature skin aging. Furthermore, in collaboration with Sandra Iden, we showed that aPKC and Par3 cooperate in promoting Ras-driven two-stage non-melanoma skin carcinogenesis (Vorhagen, Kleefisch et al., 2018).
Mechanistically, we found that aPKCl/Par3 complex promote skin papilloma formation and progression through sustaining growth, survival and inflammatory signalling. This work also identified a Par3 independent role for aPKCl in controlling skin immune homeostasis. Screening a large panel of SCC of the skin revealed not only overexpression of aPKC correlates with increased metastatic risk but also reduced aPKC. In agreement, combined loss of aPKCλ strongly enhanced and accelerated p53-mediated skin carcinogenesis. Unlike p53ep-/- mice, the aPKCl/p53epiDKO mice displayed features of field cancerization that precedes the development of multiple locally invasive SCCs, a phenotype that resembles human SCC. Our data show that combined loss of aPKC/p53 induces epidermal inflammatory signals that recruit macrophages essential for field cancerization and SCC formation. Thus, aPKC polarity signaling provides a critical boundary to skin field cancerization and SCC formation to guarantee physiological tissue function (Persa et al., submitted). We are now using these mice as a model for field cancerization to repurpose new drugs for SCC.
Niessen MT, Scott J, Zielinski JG et al (2013). aPKCλ controls epidermal homeostasis and stem cell fate through regulation of division orientation. J Cell Biol. 202(6):887-900
Rübsam M, Mertz AF, Kubo A et al (2017). E-cadherin integrates mechanotransduction and EGFR signaling to control junctional tissue polarization and tight junction positioning. Nat Commun. 2017; 8: 1250
Vorhagen S, Kleefisch D, Persa OD et al (2018). Shared and independent functions of aPKCλ and Par3 in skin tumorigenesis. Oncogene. 2018; 37(37): 5136–5146.
Von Olshausen G, QuasdorfM, Bester R, Arzberger S, Ko C, van de Klundert M, Zhang K, Odenthal M, Ringelhan M, #Niessen CM, #Protzer U. (2018) Hepatitis B virus promotes β-catenin-signalling and disassembly of adherens junctions in a Src kinase dependent fashion. Oncotarget, 9:2317-2325 #shared corresponding authors
OstermannAL, WunderlichCM, Schneiders L, Vogt MC, Woeste M, Belgardt, BF Niessen CM, MartinyB, SchaussAC, Frommolt P, Nikolaev N, Hövelmeyer RC, Sears RC KochPJ, Gunzel D., BrüningJC, Wunderlich FT.(2019) Intestinal insulin/IGF1 signalling through FoxO1 regulates epithelial integrity and susceptibility to colon cancer. Nature Metabolism, 1: 371-389
Nava MM, Miroshnikova YA, Biggs LC, Whitefield DB, MetgeF, Boucas J, Vihinen H, Jokitalo E, García Arcos JM, HoffmannB, Merkel R, Niessen CM, Dahl KN, and WickströmSA. (2020) Heterochromatin-driven nuclear softening protects the genome against mechanical stress-induced damage. Cell https://doi.org/10.1016/j.cell.2020.03.052
Persa OD, Koester J, Niessen CM. (2021) Regulation of Cell Polarity and Tissue Architecture in Epidermal Aging and Cancer. J Invest Dermatol. 2021;141(4S):1017-1023.
Koehler S, Odenthal J, Ludwig, V, Unnersjö Jess D, Höhne M, Jüngst C, Grawe F, Lemstädter M, Janku JL, Bergmann C, Hozer PF, Henning Hagmann HH, Waly G, Bloch W, Niessen C, Schermer B, Wodary A, Denholm B, Benzing T, Iden S, Brinkkoetter P (2021) Scaffold polarity proteins Par3A and Par3B share redundant functions while Par3B acts independent of atypical kinase C/Par6 in podocytes to maintain the kidney filtration barrier. Kidney International Dec 17:S0085-2538(21)01150-9. doi: 10.1016/j.kint.2021.11.030
Peskoller M, ; Bhosale A, Göbel K, Löhr J, Miceli S, Perot S, Persa OD, Rübsam M, Shah J, Zhang H, Niessen, CM. (2022) ESDR 50th Anniversary Lecture summary: How to build and regenerate a functional skin barrier: the adhesive and cell shaping travels of a keratinocyte. J. Invest. Dermatol. 42(4):1020-1025. doi: 10.1016/j.jid.2021.12.034
Koehler S, Odenthal J, Ludwig V, Unnersjo Jess D, Hohne M, Jungst C, Grawe F, Helmstadter M, Janku JL, Bergmann C, Hoyer PF, Hagmann HH, Walz G, Bloch W, Niessen C, Schermer B, Wodarz A, Denholm B, Benzing T, Iden S, and Brinkkoetter PT (2022). Scaffold polarity proteins Par3A and Par3B share redundant functions while Par3B acts independent of atypical protein kinase C/Par6 in podocytes to maintain the kidney filtration barrier. Kidney Int101, 733-751. doi:10.1016/j.kint.2021.11.030.
Rietscher K, Jahnke HG, Rubsam M, Lin EW, Has C, Omary MB, Niessen CM, and Magin TM (2022). Kinase inhibition by PKC412 prevents epithelial sheet damage in autosomal dominant epidermolysis bullosa simplex via keratin and cell contact stabilization. J Invest Dermatol. doi:10.1016/j.jid.2022.05.1088
Green KJ, Niessen CM, Rubsam M, Perez White BE, and Broussard JA (2022). The Desmosome-Keratin Scaffold Integrates ErbB Family and Mechanical Signaling to Polarize Epidermal Structure and Function. Front Cell Dev Biol10, 903696. doi:10.3389/fcell.2022.903696.
Peskoller M, Bhosale A, Gobel K, Lohr J, Miceli S, Perot S, Persa O, Rubsam M, Shah J, Zhang H, and Niessen CM (2022). How to Build and Regenerate a Functional Skin Barrier: The Adhesive and Cell Shaping Travels of a Keratinocyte. J Invest Dermatol142, 1020-1025. doi:10.1016/j.jid.2021.12.034.
Jiang C, Javed A, Kaiser L, Nava MM, Xu R, Brandt DT, Zhao D, Mayer B, Fernandez-Baldovinos J, Zhou L, Hoss C, Sawmynaden K, Oleksy A, Matthews D, Weinstein LS, Hahn H, Grone HJ, Graumann PL, Niessen CM, Offermanns S, Wickstrom SA, and Worzfeld T (2021). Mechanochemical control of epidermal stem cell divisions by B-plexins. Nat Commun12, 1308. doi:10.1038/s41467-021-21513-9.
Koehler S, Odenthal J, Ludwig V, Jess DU, Hohne M, Jungst C, Grawe F, Helmstadter M, Janku JL, Bergmann C, Hoyer PF, Hagmann HHH, Walz G, Bloch W, Niessen C, Schermer B, Wodarz A, Denholm B, Benzing T, Iden S, and Brinkkoetter PT (2021). Scaffold polarity proteins Par3A and Par3B share redundant functions while Par3B acts independent of atypical protein kinase C/Par6 in podocytes to maintain the kidney filtration barrier. Kidney Int. doi:10.1016/j.kint.2021.11.030.
Koester J, Miroshnikova YA, Ghatak S, Chacon-Martinez CA, Morgner J, Li X, Atanassov I, Altmuller J, Birk DE, Koch M, Bloch W, Bartusel M, Niessen CM, Rada-Iglesias A, and Wickstrom SA (2021). Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility. Nat Cell Biol23, 771-781. doi:10.1038/s41556-021-00705-x.
Tayem R, Niemann C, Pesch M, Morgner J, Niessen CM, Wickstrom SA, and Aumailley M (2021). Laminin 332 Is Indispensable for Homeostatic Epidermal Differentiation Programs. J Invest Dermatol141, 2602-2610 e2603. doi:10.1016/j.jid.2021.04.008.
Persa OD, Koester J, and Niessen CM (2021). Regulation of Cell Polarity and Tissue Architecture in Epidermal Aging and Cancer. J Invest Dermatol141, 1017-1023. doi:10.1016/j.jid.2020.12.012.
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. Elife7.
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. Oncogene37, 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 Med214, 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 Dermatol137, 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 Commun8, 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.
Prof. Dr. Carien M Niessen
Department Cell Biology of the Skin - CECAD Research Center