Investigating the role of CD44 in tumour development and progression
1 PhD project offered in the IPP summer call 2019
Merlin is a tumour suppressor protein that plays a major role in mediating contact inhibition of cell growth. Inactivation of the gene encoding Merlin (NF2) leads to an autosomal dominant familiar cancer syndrome called neurofibromatosis type 2 (NF2). NF2 patients are predisposed to develop multiple central and peripheral nervous system tumours, including schwannomas, meningiomas and ependymomas. In addition to tumours that are associated with familiar neurofibromatosis type 2, loss of NF2 function was also identified in wide range of other solid tumours, including breast, liver and colorectal carcinomas. A number of mutations, both in the germ line of NF2 patients and in sporadically occurring human tumours, have been found in the region of exons 2 and 3, within the so-called FERM (4.1 protein, ezrin, radixin, moesin) domain of Merlin which mediates interaction with membrane bound proteins. This indicates that the membrane localisation of Merlin mediated by the FERM domain might be critical for Merlin´s tumour suppressor function. In the past, we identified cluster of differentiation 44 (CD44) as an important linker protein that anchors Merlin to the plasma membrane. CD44 is a multifunctional cell adhesion molecule that has been identified as a marker of putative cancer stem cells in a variety of human solid tumours. Consistently, increased levels of CD44 are associated with invasive properties of tumour cells and predict a poor prognosis in diverse cancer subtypes including liver cancer.
In order to evaluate the relevance of Merlin-CD44 interaction in vivo, the PhD student will use conditional Nf2-knockout mice (Nf2; Alb-Cre) in which the genetic deficiency of Nf2 was restricted to hepatocytes leading to liver tumour formation; and test the effect of depletion of Cd44 gene on spontaneous liver tumour growth and progression in those mice. In order to allow detailed and reproducible functional studies, tumour cells will be isolated from Nf2-depleted livers and Cd44 expression will be manipulated by using previously generated constructs that allow distinguishing between different molecular modes of CD44 function. Liver tumour cells with modified Cd44 expression will be subjected to in vitro functional assays as well as to xenotransplantation assays in order to study tumorigenic and metastatic potential in vivo. The results obtained will further be applied to authentic human patient’s samples and functionally validated in isolated patient-derived HCC cells to confirm the translational significance of the study.
Publications relevant to the project
Castven D, Becker D, Czauderna C, Wilhelm D, Andersen JB, Strand S, Hartmann M, Heilmann-Heimbach S, Roth W, Hartmann N, Straub BK, Mahn FL, Franck S, Pereira S, Haupts A, Vogel A, Wörns MA, Weinmann A, Heinrich S, Lang H, Thorgeirsson SS, Galle PR, Marquardt JU (2018) Application of patient-derived liver cancer cells for phenotypic characterization and therapeutic target identification. Int J Cancer. [Epub ahead of print]
Parra LM*, Hartmann M*, Schubach S, Ma J, Herrlich P, Herrlich A (2016) Growth factor and co-receptor release by structural regulation of substrate metalloprotease accessibility. Sci Rep. 6:37464 * Both authors contributed equally to this work.
Parra L*, Hartmann M*, Schubach S, Li Y, Herrlich P, Herrlich A (2015) Distinct ICD substrate modifications selectively regulate ectodomain cleavage of NRG1 or CD44. Mol Cell Biol. 35:3381-95 * Both authors contributed equally to this work.
Hartmann, M., Parra, L.M., Ruschel, A., Lindner, C., Morrison, H., Herrlich, A., and Herrlich, P. (2015). Inside-out Regulation of Ectodomain Cleavage of Cluster-of-Differentiation-44 [CD44] and of Neuregulin-1 requires Substrate Dimerization. J Biol Chem. 290: 17041-54
Hartmann, M., Parra, L.M., Ruschel, A., Bohme, S., Li, Y., Morrison, H., Herrlich, A., and Herrlich, P. (2015). Tumor Suppressor NF2 Blocks Cellular Migration by Inhibiting Ectodomain Cleavage of CD44. Mol Cancer Res. 13:879-890.
Lindner C, Urbánek P, Pavelka B, Hartmann M, Herrlich P (2013) A link between two tumorigenic proteins, CD44 and p21WAF1: CD44 increases phorbol ester-induced expression of p21WAF1 by stabilizing its mRNA and extending protein half-life. FEBS Lett. 587:2698-704.
Dang M, Armbruster N, Miller MA, Cermeno E, Hartmann M, Bell GW, Root DE, Lauffenburger DA, Lodish HF, Herrlich A (2013) Regulated ADAM17-dependent EGF family ligand release by substrate-selecting signaling pathways. Proc Natl Acad Sci U S A 110:9776-81
Hartmann M, Herrlich A, Herrlich P (2012) Who decides when to cleave an ectodomain? Trends Biochem Sci. 38: 111-20
Dang M, Dubbin K, D'Aiello A, Hartmann M, Lodish H, Herrlich A (2011) Epidermal growth factor (EGF) ligand release by substrate-specific a disintegrin and metalloproteases (ADAMs) involves different protein kinase C (PKC) isoenzymes depending on the stimulus. J Biol Chem. 286: 17704-13.
Dr Jens Marquardt (Head of research group)
Dr Monika Hartmann (Supervisor of project)
University Medical Center
I. Medizinische Klinik und Poliklinik
Molecular Hepatocarcinogenesis research group