Hoepken_Lab_Header

Höpken Lab

Microenvironmental Regulation in Autoimmunity and Cancer

Profile

Our group dissects cellular requirements and molecular pathways which contribute to the transformation of secondary lymphoid organs (SLOs) toward lymphoma/leukemia-permissive niches in preclinical mouse models.

We aim to identify stromal elements in SLOs that collaborate with lymphoma/leukemia B cells and study lymphoma-induced cellular and molecular remodeling. Secondly, we study chronic autoimmune or pathogen-induced immune reactions that lead to lymphoid neogenesis and development of associated lymphomas. Based on the identification of pivotal stromal cell types and signaling pathways, we will probe pharmacological interventions targeted at the crosstalk between lymphoma cells and the microenvironment.

Team

Research

Cellular interactions and molecular com- munication pathways in the lymphoma survival niche
(F. Scholz, A. Graband (collaboration with A. Rehm, A. Leutz, MDC)

Survival and progression of lymphoma cells is dependent on nodal access and micro- anatomical localization We showed that the chemokine receptor CCR7 is crucial for E
μ- Myc B cell lymphoma nodal dissemination. Malignant cells lodged adjacent to fibroblas- tic reticular cells and dendritic cells (DCs) within the T cell zone. According to their dif- ferentiation status, DCs trigger immunity or tolerance in T lymphocytes. DC-mediated B cell lymphomagenesis remained enigmatic. In DC-depleted mice we observed that progression of B cell lymphomas was delayed. Lymphoma-exposed DCs upregulated im- munomodulatory cytokines, growth factors and the CCAAT/enhancer binding protein β (C/EBPβ). C/EBPβ-deleted DCs were un- responsive to lymphoma imposed cytokine changes and unable to promote lymphoma cell survival. We conclude that DCs have lymphoma-promoting functions and act directly by the provision of growth factors, provided that they express the transcription factor C/EBPβ.


Cellular stromal elements in B cell fol- licles that collaborate with leukemia B cells in an indolent B-CLL mouse model
(V. Stache, F. Brand, T. Börding (collaboration with A. Rehm, MDC)

We characterized non-hematopoetic stro- mal cells in the B cell zone of SLOs that col- laborate with leukemia B cells in an indo- lent Eµ-Tcl1 leukemia mouse model. This relationship involved chemokine-mediated guidance of leukemic cells into promoting niches, followed by a nurse-like function of the stromal follicular dendritic cell (FDC)- network (Figure 1). Crosstalk inhibition of lymphotoxin(LT)/LTRβ signaling or inhibition of the CXCL13/CXCR5 signaling axis retarded lymphoma progression. In addition, we identified gene expression signa tures indicative of a skewed polarization of monocytes and neutrophils. Depletion of macrophages or neutrophils resulted in tumor retardation. Leukemia cells secreted IL-10 and by that rendered splenic neutrophils and macrophages into a tumor supportive phenotype. Also, neutrophils revealed increased expression of B-cell activating factors which supports leukemia cell survival. Hence, immune cells can also be primed towards a lymphoma-supporting milieu.

Cellular stromal elements in B cell fol- licles that collaborate with leukemia B cells in an indolent B-CLL mouse model
(V. Stache, F. Brand, T. Börding (collaboration with A. Rehm, MDC)

We characterized non-hematopoetic stro- mal cells in the B cell zone of SLOs that col- laborate with leukemia B cells in an indo- lent Eµ-Tcl1 leukemia mouse model. This relationship involved chemokine-mediated guidance of leukemic cells into promoting niches, followed by a nurse-like function of the stromal follicular dendritic cell (FDC)- network (Figure 1). Crosstalk inhibition of lymphotoxin(LT)/LTRβ signaling or inhibition of the CXCL13/CXCR5 signaling axis retarded lymphoma progression. In addition, we identified gene expression signa tures indicative of a skewed polarization of monocytes and neutrophils. Depletion of macrophages or neutrophils resulted in tumor retardation. Leukemia cells secreted IL-10 and by that rendered splenic neutrophils and macrophages into a tumor supportive phenotype. Also, neutrophils revealed increased expression of B-cell activating factors which supports leukemia cell survival. Hence, immune cells can also be primed towards a lymphoma-supporting milieu.

Publications

Hoepken, Uta_1652
PD Dr. Uta E. Höpken
Permanent Fellow
Contact
Phone: 030 9406-3330
Max-Delbrück-Centrum für Molekulare Medizin (MDC)
Robert-Rössle-Str. 10
13125 Berlin
Building 31.1, Room 3018