1. Research Background:
We investigate functions of mammalian polarity proteins in skin homeostasis, epithelial regeneration, stress responses, and cancer. We study how deregulated polarity signaling impacts on cyto-architecture, mechanosensation, survival and cell death using genetically modified mice in developmental and disease models as well as cell culture systems. Our aim is to better understand how cell polarity signaling contributes to fundamental epithelial functions and to age-associated pathologies to reveal novel directions for targeted therapies.
Keywords: Cell polarity, cell-cell adhesion, cellular crosstalk, mouse models, skin homeostasis & skin cancer, epithelial cell biology, melanocyte & melanoma biology, oncogenic signaling, mechanochemical signaling, skin immunology, DNA damage
2. Research questions addresses by the group:
- How do polarity networks cooperate with other signalling pathways underlying skin cancer?
- How is crosstalk between different resident skin cell types coordinated to ensure tissue homeostasis and prevent skin pathologies?
- Which mechanisms dictate skin stem cell aging and degeneration?
- How is tissue architecture and cellular plasticity regulated to ensure proper wound-induced epidermal regeneration? Understand which processes are defective in human wound pathologies (i.e. chronic wounds in diabetes patients, venous ulcers)
- How does cell polarity signalling in the skin control UV-B-induced stress responses to maintain tissue integrity?
- Understanding molecular mechanisms that couple control of cyto-architecture with mechanosensation and cellular responses upon mechanical stress
- Which polarity networks drive or prevent melanoma plasticity? How can we target these for clinical application?
- Establishment of new mouse tumor models to uncover underlying disease mechanisms
3. Possible projects:
- CRISPR/Cas9-based screen for polarity regulators that drive melanoma initiation and metastasis (lentiviral transduction, functional studies using cell (co)cultures and mouse melanoma models, gene expression studies, analysis of human cancer specimen)
- Identifying disease mechanisms underlying formation of keratoacanthoma (skin cancer) upon Par3 loss (RNASeq, mouse model for keratoacanthoma, human tumor specimen, cell culture, imaging)
- Understanding molecular mechanisms through which polarity proteins maintain genome stability (primary cell culture & mouse models, UV-B treatment, structure-function analyses)
- Cooperation of different polarity networks in control of cyto-architecture (CRISPR/Cas9, proteomics, protein-protein interaction studies, cell biological assays)
- Other projects to be discussed based on above group's research topics, recent data and interest of candidates
4. Applied Methods and model organisms:
Primary model organism: mouse; complemented by cell culture approaches and human tissue analyses
Mouse disease models for:
- skin cancer (epithelial cancers, cutaneous melanoma, conjunctival melanoma; autochthonous & transplantation models)
- skin wound healing & regeneration
- UV-B induced stress
- skin aging and degeneration
- cell culture (primary keratinocytes & melanocytes, skin tumor cells, stable lines)
- cell biological assays (cell-cell adhesion, cell migration & invasion, epithelial barrier, colony formation, cell division, protein localization studies, proliferation/apoptosis etc.)
- signal transduction studies related to cell adhesion, oncogenes, regeneration, mechanotransduction
- fluoresc. microscopy, live cell imaging, automated morphometric analyses (ie.g. Cell Profiler, QuimP)
- protein biochemistry (protein expression, protein-protein interaction, posttranslational modifications e.g. phosphorylation, methylation, enzymatic cleavage)
- CRISPR/Cas9, RNAi, Cre/loxP-med. gene inactivation, protein expression, lentiviral transduction
- chromatin conformation & accessibility, transcriptional activity, iFISH
- mechanical strain & cellular responses
5. Desirable skills and qualifications:
- Creative thinking & open for active scientific discussion
- Interest in cell biology & tissue homeostasis mechanisms
- Experience in cell culture or protein biochemistry or modelling or imaging of advantage
- Team player (we are an international team of ~7-10 enthusiastic scientists)
- Dias Gomes M, Letzian S, Saynisch M, Iden S (2018, preprint). Polarity signaling ensures epidermal homeostasis by coupling cellular mechanics and genomic integrity. bioRxiv, doi: doi.org/10.1101/401562
- Vorhagen S*, Kleefisch D*, et al., Niessen CM#, Iden S#. Shared and independent functions of aPKClambda and Par3 in skin tumorigenesis. Oncogene, 2018 Sep;37(37):5136-5146. doi:10.1038/s41388-018-0313-1 (*,#: equal contributions)
- Mescher M, Jeong P, et al., Iden S. The epidermal polarity protein Par3 is a non-cell autonomous suppressor of malignant melanoma. J Exp Med, Feb 2017, 214 (2) 339-358
- Ali NJA, et al., Iden S. Essential role of polarity protein Par3 for epidermal homeostasis through regulation of barrier function, keratinocyte differentiation and stem cell maintenance. JID 2016 Dec;136
- Mescher M & Iden S. Par Proteins in Tumor Formation and Progression. Cell Polarity 2. Role in Development and Disease. Springer 2015, VIII. ISBN 978-3-319-144466-5. Book Chapter
- Iden S*, et al., Collard JG. Tumor Type-Dependent Function of the Par3 Polarity Protein in Skin Tumorigenesis. Cancer Cell 2012 Sep;22(3):389-403.
- Iden S & Collard JG. Crosstalk between small GTPases and polarity proteins in cell polarization. Nature Reviews Molecular Cell Biology 2008 Nov;9(11):846-59