AG Gessler

Manfred Gessler: Mechanisms of pediatric kidney tumor formation

Summary

We have identified several genes as drivers of oncogenesis in either Wilms tumors (e.g. WT1, CTNNB1, WTX, IGF2, SIX1/2, DROSHA, DGCR8, MYCN, TP53), or the less frequent clear cell sarcomas (BCOR) and connatal mesoblastic nephromas (NTRK3, BRAF, EGFR). Biochemical and cell biological approaches as well as mouse models are used to understand the molecular function of these mutant genes and to decipher their contribution of oncogenesis. 2D and 3D primary tumor cell cultures recapitulate many aspects of tumor growth. These are complemented by the analysis of tumor-specific mutations in embryonic stem cells and developing kidneys of transgenic mice.

Selcted Publications

Wegert, J, Zauter L, Appenzeller S, Otto C, Bausenwein S, Vokuhl C, Ernestus K, Furtwangler R, Graf N, Gessler M. High-risk blastemal Wilms tumor can be modeled by 3D spheroid cultures in vitro. Oncogene. 2020; 39: 849-861.

Kruber P, Angay O, Winkler A, Bosl MR, Kneitz S, Heinze KG, Gessler M. Loss or oncogenic mutation of DROSHA impairs kidney development and function but is not sufficient for Wilms tumor formation. Int J Cancer, 2019; 144:1391-400.

Gröbner SN, Worst BC, Weischenfeldt J, Buchhalter I, Kleinheinz K, Rudneva VA, Johann PD, Balasubramanian GP, Segura-Wang M, Brabetz S, Bender S, Hutter B, Sturm D, Pfaff E, Hübschmann D, Zipprich G, Heinold M, Eils J, Lawerenz C, Erkek S, Lambo S, Waszak S, Blattmann C, Borkhardt A, Kuhlen M, Eggert A, Fulda S, Gessler M, Wegert J, Kappler R, Baumhoer D, Burdach S, Kirschner-Schwabe R, Kontny U, Kulozik AE, Lohmann D, Hettmer S, Eckert C, Bielack S, Nathrath M, Niemeyer C, Richter GH, Schulte J, Siebert R, Westermann F, Molenaar JJ, Vassal G, Witt H, Burkhardt B, Kratz CP, Witt O, van Tilburg CM, Kramm CM, Fleischhack G, Dirksen U, Rutkowski S, Frühwald M, von Hoff K, Wolf S, Klingebiel T, Koscielniak E, Landgraf P, Koster J, Resnick AC, Zhang J, Liu Y, Zhou X, Waanders AJ, Zwijnenburg DA, Raman P, Brors B, Weber UD, Northcott PA, Pajtler KW, Kool M, Piro RM, Korbel JO, Schlesner M, Eils R, Jones DTW, Lichter P, Chavez L, Zapatka M, Pfister SM. The landscape of genomic alterations across childhood cancers. Nature. 2018; 555: 321-327.

Kenny C, Bausenwein S, Lazaro A, Furtwängler R, Gooskens SL, van den Heuvel Eibrink M, Vokuhl C, Leuschner I, Graf N, Gessler M, O'Sullivan MJ. Mutually exclusive BCOR internal tandem duplications and YWHAE-NUTM2 fusions in clear cell sarcoma of kidney: not the full story. The Journal of pathology. 2016; 238: 617-20.

Williams RD, Chagtai T, Alcaide-German M, Apps J, Wegert J, Popov S, Vujanic G, van Tinteren H, van den Heuvel-Eibrink MM, Kool M, de Kraker J, Gisselsson D, Graf N, Gessler M, Pritchard-Jones K. Multiple mechanisms of MYCN dysregulation in Wilms tumour. Oncotarget. 2015; 6:7232-7243.