IMT

Institute of Molecular Biology and Tumor Research

Research Group Lauth
(Cellular signal transduction group)

-PI: Dr. Matthias Lauth-




Our research focuses mainly on two areas:
1.) Tumor-stroma interactions in pancreatic cancer
2.) Signaling pathways in pediatric cancer


1.) Tumor-stroma interactions in pancreatic cancer

Basically all solid tumors are composed of a mixture of cancer cells and surrounding normal cells, the stromal cells. These stromal cells have profound impact on the behavior of cancer cells and can influence traits such as cell growth and differentiation, invasiveness or chemoresistance. One type of cancer with a prominent stromal hyperplasia is pancreatic cancer.

pancreatic cancer
Tissue section of a normal pancreas (left) and of pancreatic cancer (right). Note the prominent stroma reaction in the cancer tissue



In pancreatic cancer, tumor cells secrete ligands of the ‘Hedgehog’ family which act on surrounding mesenchymal fibroblasts, leading to their proliferation and activation. Pancreatic ductal adenocarcinoma is therefore characterized by a high percentage of non-cancerous stromal cells which surround Hedgehog-ligand producing tumor cells.

growth factors
Schematic diagram depicting the Hedgehog (Hh)-mediated crosstalk between Hh-producing tumor cells (blue) and Hh-receiving ‘normal’ stroma cells (red). In turn, Hh-activated stromal fibroblasts provide crucial signaling molecules to the tumor cells. This crosstalk regulates cancer growth, chemoresistance and metastasis


What are we interested in?
We are looking into the functional role of tumor-cell secreted Hedgehog ligands on the tumor cells themselves and on their surrounding normal stromal cells. We are focusing on aspects such as tumor cell migration, survival, differentiation and formation/maintenance of cancer stem cells. In particular, we wish to target the tumor/stroma compartments with specific small molecule drugs in order to integrate the stromal cells into a pharmacological treatment approach.
Included in this line of research, we are investigating the molecular steps of Hedgehog signaling in the activation of fibroblasts (leading to ‘stromal desmoplasia’). Our aim is to apply the acquired information to set up first steps of a targeted therapy in desmoplastic cancer types and organ fibrosis. To achieve these goals, we are using state-of-the-art molecular biology and cell culture methodologies as well as mouse cancer models.

Our activities on pancreatic cancer are part of a DFG-funded consortium on the interplay between tumor and stroma compartments: Have a look at the members and the research done within the clinical research unit 325: https://www.uni-marburg.de/fb20/zti/kfo325



Short introduction to Hedgehog Signaling
In the mammalian embryo, approximately a handful of signal transduction pathways are involved in orchestrating the key steps of embryogenesis. One of these instructive cues is represented by the Hedgehog (Hh) signaling pathway, which induces such diverse cellular responses as proliferation, differentiation or neuronal guidance, depending on the biological context [Hooper et al. (2005), Nat Rev Mol Cell Biol 6, 306-317]. Pattern formation in tissues such as the skin, brain and the neural tube, or the developing limbs has been shown to be subject to regulation by Hh signaling. Improper Hh signaling is a major cause of holoprosencephaly, the most common child birth defect. In postnatal life, the Hh pathway is spatially restricted and its proposed role is in the induction of proliferation of adult stem cells, which are required for tissue maintenance and repair [Beachy et al. (2004), Nature 432, 324-331]. Persistent or aberrantly reactivated signaling is associated with hyperproliferative disease and tumor development [Pak & Segal (2016), Dev Cell 38, 333-344]. It is currently estimated that approximately one third of all cancer deaths are linked to erroneous Hh pathway activation [Lum et al. (2004), Science 304, 1755-1759].

An unusual cell organelle, the primary cilium, has been identified as being essential for Hh signaling. Most of the cells of our body harbor one primary cilium on their surface. Primary cilia are non-motile protrusions of the cell’s membrane, held in shape by a microtubular axoneme. Primary cilia function as cellular sensors for chemical or mechanical signals emanating from the environment.

Immunofluorescence
(A) Immunofluorescence picture of fibroblast primary cilia (red, stained with acetylated tubulin antibody); nuclei are DAPI stained (blue).
(B) Electron micrograph of a primary cilium (NIH3T3 fibroblast).



2.) Signaling pathways in pediatric cancer
Hedgehog signaling belongs to a group of cellular pathways which are active very early in embryonic development and which are therefore called ‘embryonic signaling pathways (ESPs)’. Because of this early involvement in cell proliferation, migration and differentiation, these ESPs are often found associated with cancers developing early in life, i.e. in children. Examples of solid pediatric cancers in which Hh signaling has been implicated are neuroblastoma, medulloblastoma or various sarcomas

embryonic signaling pathways
Staining for HDAC6 protein (brown) in tissue sections of a normal cerebellum (left) or of a Hedgehog-induced medulloblastoma (right). Taken from Dhanyamraju et al. (2015).

Our group is interested in deciphering the role of Hh signaling in pediatric cancer types and the mechanisms of signal transduction in these tumors. Our final goal is to identify novel drug targets for these cancers and to perform preclinical proof-of-principle studies using small-molecule inhibitors.