A subset of diffuse large B-cell lymphomas express the signaling chain gp130 of the IL-6 receptor
In vivo imaging is a useful tool to study orthotopic lymphoma engraftment and growth and to measure treatment success
Flow cytometric analysis of the tumor burden of mice transplanted with MYC-expressing lymphoma B-cells
Western blotting reveals the activity of specific signaling pathways in diffuse large B-cell lymphoma
Our lab has a long-standing interest in understanding the genetic, epigenetic and post-transcriptional mechanisms driving B-cell lymphomagenesis. In particular, we are interested in the contribution of cytokines as growth factors to diffuse large B-cell lymphoma (DLBCL) growth in various models. Specifically, we are interested in IL-6 and IL-10 signaling, both of which are aberrantly active, and TGF-b signaling, which is aberrantly inactivated, in subsets of DLBCL. We further use drug response profiling in conjunction with mutational analysis to identify novel drug sensitivities and their underlying mutations. We specialize in orthotopic xenotransplantation and patient-derived PDX models in conjunction with in vivo imaging, which we apply to the testing and optimization of novel treatment regimens that are rationally derived from our drug screening efforts as well as patient-derived genomic data analyses and mechanistic studies in cell lines using genome editing tools.
The overall objective of this project is to gain a better understanding of this very heterogeneous disease, and to derive novel, personalized treatment strategies from our mechanistic studies using cell culture and mouse models of lymphoma, alongside confirmatory studies conducted on patient cohorts in the framework of key collaborations.
DLBCL cells produce cytokines that act both as autocrine growth factors and as local or systemic modulators of tumor immunity. We deploy both xenotransplantation and genetically modified, immunocompetent lymphoma models to better understand the relative contribution of the autocrine and paracrine signals provided by IL-10, IL-6 and TGF-b, among others; the same models are useful for testing select targeted and immune-therapies, alone and in rationally derived combinations. In collaboration with other Swiss institutions, we study immune evasion by DLBCL cells in cohorts of immunosuppressed vs. immunocompetent DLBCL patients.
Hashwah, H., Bertram, K., Stelling, A. Manz, M.G., Theocharides, A., Tzankov, A. and Anne Müller. Humanized mice and patient data reveal the IL-6 signaling complex as a critical driver, negative prognostic factor and therapeutic target in diffuse large B-cell lymphoma. EMBO Mol Med. 11:e10576, (2019).
Stelling, A. Wu, C., Hashwah, H., Bertram, K., Theocharides, A., Manz, M.G., Tzankov, A. and Müller, A. SMAD1 silencing by promoter hypermethylation promotes DLBCL pathogenesis. Blood Advances 2019 320:3020-3032 (2019).
Stelling A, Hashwah H, Bertram K, Manz MG, Tzankov A, Müller A. The tumor suppressive TGF-β/SMAD1/S1PR2 signaling axis is recurrently inactivated in diffuse large B-cell lymphoma. Blood. 131:2235-2246 (2018).
Hashwah, H., Schmid, C.A., Kasser, S., Bertram, K., Stelling, A., Manz, M.G., and Müller, A. Inactivation of CREBBP expands the germinal center B cell compartment, down-regulates MHCII expression and promotes DLBCL growth. PNAS, 5;114:9701-9706 (2017).
Flori, M., Schmid, C.A., Sumrall, E.T., Tzankov, A., Law, C.W., Robinson, M.D. and Müller, A. The hematopoietic oncoprotein FOXP1 promotes tumor cell survival in diffuse large B-cell lymphoma by repressing S1PR2 signaling. Blood, 127:1438-48 (2016).
Schmid, C.A., Robinson, M.D., Scheifinger, N.A., Müller, S., Cogliatti, S., Tzankov, A. and Müller, A. DUSP4 deficiency caused by promoter hypermethylation drives JNK signaling and tumor cell survival in diffuse large B cell lymphoma. J Exp Med. 212:775-92 (2015).