Center for Molecular Medicine Cologne

Carien M Niessen - A 08

Epithelial-stromal crosstalk and cell fate regulation in field cancerization

Introduction

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.

Squamous cell carcinoma (SCC) is the second most frequent skin cancer and 5% of these SCCs metastasize. Despite recent developments in systemic oncology therapies, the current therapy for metastatic SCC is still limited and disease relapse frequently occurs. Classically, SCCs arise in areas of field cancerization and often associated with inflammation.

The mechanistic drivers of field cancerization are only poorly understood.Mutations in p53 are among the most common ones observed in SCC. One key function of p53 is to induce either cell cycle arrest or cell death but combined inactivation of these pathways was not sufficient to drive tumor formation suggesting the involvement of other mechanisms. More recent data indicate that p53 controls lineage commitment of stem cells and regulates cancer stem cells to promote tumorigenesis.

To develop new therapeutic approaches, we thus need to better understand how p53 suppresses tumor initiation, and how loss of these checkpoints drive the clonal expansion of pre-neoplastic cells to give rise to SCC.

Our Aims

We aim to understand how combined epidermal loss of p53 and a key regulator of epidermal architecture and  (stem) cell fate, the polarity protein atypical kinase C (aPKC) in mice

  1. disturbs epidermal-dermal homeostasis
  2. drive the formation of multifocal invasive SCCs. 
  3. can be used as a preclinical model for therapeutics and
  4. assess relevance for human SCCs and other field cancerization driven cancers.

Previous Work

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 tumor initiation and progression through sustaining growth, survival and inflammatory signaling.

This work also identified a Par3 independent role for aPKCl in controlling skin immune homeostasis.  

As the most common mutations in human SCC are in p53, we then asked whether loss of aPKCλ would also inhibit p53 driven non-melanoma skin cancer driven.  Surprisingly, loss of aPKCλ strongly enhanced and accelerated p53-mediated skin carcinogenesis. These aPKCl/p53 DKO mice also displayed features of field cancerization that precedes the development of multiple locally invasive SCCs, a phenotype that resembles human SCC.

Project Related Publications

  1. 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
  2. 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
  3. 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.
  4. 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
  5. Persa OD, Niessen CM. (2019) Epithelial polarity limits EMT.  Nat Cell Biol. Mar;21(3):299-300. doi: 10.1038/s41556-019-0284-7.
  6. 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
  7. 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

Nava MM, Miroshnikova YA, Biggs LC, Whitefield DB, Metge F, Boucas J, Vihinen H, Jokitalo E, Li X, García Arcos JM, Hoffmann B, Merkel R, Niessen CM, Dahl KN, Wickström SA.: Heterochromatin-Driven Nuclear Softening Protects the Genome against Mechanical Stress-Induced Damage. Cell. 2020 May 14;181(4):800-817.e22. doi: 10.1016/j.cell.2020.03.052. Epub 2020 Apr 16. PMID: 32302590 Free PMC article.2

Polányi L, Niessen CM, Vohlen C, Stinn J, Kretschmer T, Jentgen V, Hirani D, Koningsbruggen-Rietschel SV, Dötsch J, Alejandre Alcazar MA.: Intrauterine growth restriction induces skin inflammation, increases TSLP and impairs epidermal barrier function. J Mol Med (Berl). 2020 Feb;98(2):279-289. doi: 10.1007/s00109-019-01867-w. Epub 2020 Jan 7. PMID: 31912169

Bayliss R, Wheeldon J, Caucheteux SM, Niessen CM, Piguet V.: Identification of Host Trafficking Genes Required for HIV-1 Virological Synapse Formation in Dendritic Cells. J Virol. 2020 Apr 16;94(9):e01597-19. doi: 10.1128/JVI.01597-19. Print 2020 Apr 16. PMID: 32075937 Free PMC article.

Green KJ, Roth-Carter Q, Niessen CM, Nichols SA.: Tracing the Evolutionary Origin of Desmosomes. Curr Biol. 2020 May 18;30(10):R535-R543. doi: 10.1016/j.cub.2020.03.047. PMID: 32428495

Peters F, Tellkamp F, Brodesser S, Wachsmuth E, Tosetti B, Karow U, Bloch W, Utermöhlen O, Krönke M, Niessen CM.: Murine Epidermal Ceramide Synthase 4 Is a Key Regulator of Skin Barrier Homeostasis. J Invest Dermatol. 2020 Oct;140(10):1927-1937.e5. doi: 10.1016/j.jid.2020.02.006. Epub 2020 Feb 22. PMID: 32092351

Sahu P, Sussman DM, Rübsam M, Mertz AF, Horsley V, Dufresne ER, Niessen CM, Marchetti MC, Manning ML, Schwarz JM. Soft Matter.: Small-scale demixing in confluent biological tissues. 2020 Apr 1;16(13):3325-3337. doi: 10.1039/c9sm01084j. PMID: 32196025

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.

Persa, O.D., and Niessen, C.M. (2019). Epithelial polarity limits EMT. Nat Cell Biol 21, 299-300.

Ostermann AL, Wunderlich CM, Schneiders L, Vogt MC, Woeste MA, Belgardt BF, Niessen CM, Martiny B, Schauss AC, Frommolt P, Nikolaev A, Hövelmeyer N, Sears RC, Koch PJ, Günzel D, Brüning JC, Wunderlich FT.: Intestinal insulin/IGF1 signalling through FoxO1 regulates epithelial integrity and susceptibility to colon cancer. Nat Metab. 2019 Mar;1(3):371-389. doi: 10.1038/s42255-019-0037-8. Epub 2019 Mar 4. PMID: 32694718

 

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.

 

Prof. Dr. Carien M Niessen CMMC Cologne
Prof. Dr. Carien M Niessen

Department Cell Biology of the Skin / RG location - CECAD Building

Principal Investigator - A 08

Executive Board Member

+49 221 478 89512

+49 221 478 6360

Department Cell Biology of the Skin / RG location - CECAD Building

Joseph-Stelzmann-Str. 26

50931 Cologne

http://www.niessenlab.uni-koeln.de

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Curriculum Vitae (CV)

Publications on PubMed

Publications - Carien M Niessen

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