We are studying normal and abnormal hematopoiesis. We and others have described an essential role for STAT5 activation (for overview see Moriggl & Ferbeyre, BBA, 2011) in the regulation of survival genes in myeloid leukemias with a link to PI3K-AKT-mTOR activation. We were the first to link serine phosphorylation and oligomerization of STAT5 to myeloid transformation. We have related the findings to human MPN and our current work is dissecting how pYSTAT5 synergizes with loss of PTEN.
The group of Richard Moriggl is focused on the JAK-STAT core cancer pathway. The group studies hematopoietic cancer with a focus on myeloproliverative neoplasm, melanoma, sarcoma, colon and liver cancer. Molecular mechanisms of transcription factors and kinases are analyzed to gain insights into mechanisms of action to control cellular proliferation/survival, PI3K-Akt activation or metabolism in context of cancer establishment and progression. Moreover, the group is involved in new targeted therapy developments and establishes test systems for translational cancer research.
The research team of Richard Moriggl in 2017
With our research we hope to bridge the gap between laboratory animal models and human patients. We are focussing on transgenic cancer mouse models, to investigate core cancer pathways for their roles in driving the establishment or progression of cancer. We will continue to define key molecules of core cancer pathways as oncogenes or tumour suppressors, often specific to particular cell types or diseases. Moreover, oncogenes or tumour suppressors are dependent on the mutational gene driver context, prominent themes in the RM lab. Our understanding of the context is currently limited and improvements will be essential to enable molecular insights into disease processes. We work closely with genetic/transgenetic clinical research (both human and animal) and with histo-pathology labs, both within Austria and international. Group members focus mainly on aberrant signal transduction and molecular mechanisms of cancer causing disease often involving transgenic animal models and patient sample analysis. We are a research team of approximately 10 people, consisting mainly of PhD and Master students, all focused on translational cancer research. The group of RM formed in 2006 and RM supervises several national and international research projects. Further grant money was attracted through international collaboration.
About Richard Moriggl
RM is director and founding member of the LBI-CR. He runs his own research group since 2006, which is focused on the JAK-STAT core cancer pathway. The group studies hematopoietic cancer, melanoma, sarcoma, colon and liver cancer. Molecular mechanisms of transcription factors and kinases are studied to gain insights into mechanisms of action to control metabolism, cellular proliferation/survival, PI3K-Akt activation in context of cancer establishment and progression.
Dr. Moriggl studied biotechnology in Germany and did his PhD in 1997 working on cytokine signaling with Prof. Groner, Friedrich Miescher Institute, Basel, Switzerland and Institute of Experimental Cancer Research, Freiburg, Germany. After a postdoctoral fellowship at St. Jude Children’s Research Hospital in Memphis, USA, in the area of immunology with Prof. Ihle he moved 2000 to the group of Prof. Beug, Institute for Molecular Pathology, in Vienna. There he studied hematopoiesis and hematopoietic cancer development through oligomeric STAT5. Moreover, he made important contributions to the essential interaction of the hepatic glucocorticoid receptor with STAT5 for body growth, sexual differentiation and metabolism. He heads the Ludwig Boltzmann Institute for Cancer Research (LBI-CR) since 2005. RM obtained the Howard Hughes Medical Institute Postdoctoral Fellowship from 1997 to 2000 and a Marie Curie Industrial Host Fellowship from 2000 to 2002.
RM participates in two special research programmes (SFB) of the Austrian Science Fund:
SFB F28 ran from 2006 to 2016 and is now successfully completed. It was headed by Prof. Mathias Müller from the Vetmeduni Vienna with deputy speaker Prof. Thomas Decker from the Max Perutz Laboratories. The final report is publicly available on the project website.
The particular strength of the research was to apply the fundamental knowledge about Jak-Stat mechanisms in cellular processes to the next level of complexity. The strength of SFB-JakStat was and the contributing research teams remains the pathway-centric view on molecular mechanistics, disease causalities and therapeutic interventions. The national and international renowned collaborative network that developed over the past decade will be further fostered by the long-term members of the consortium. The regular meetings with external speakers and progress reports of the JAK-STAT centric groups will be perpetuated. Most importantly, the core members of the consortium have sumitted a follow-up SFB concept termed Monarchie and Hierarchies in Shaping Chromatin Landscapes, which was invited to submit a full length proposal.
The general aim of the SFB F47 is to identify and characterize novel clinically relevant markers and targets in patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) and other myeloproliferative neoplasms (MPN), thereby providing novel tools and strategies for the development of improved diagnostic and therapeutic approaches.
The well-established biology of Ph+ CML will be employed as a paradigmatic model to study the evolution of leukemic stem cells (LSC) and the mechanisms underlying progression and drug-resistance in the SFB research program. The ultimate aim of the SFB is to improve targeted therapies in CML and other MPN by developing novel LSC-eradicating treatment concepts.
The researchers of the SFB-F47 at its kick-off meeting in 2013.
Ewing sarcoma (ES) is a cancer of bone and soft tissue that is mainly found in pediatric patients. Effective therapy has not been developed due to the lack of relevant test models that faithfully recapitulates ES tumor development. ES is driven by the EWS/FLI1 (EF) translocation product, an aberrant ETS transcription factor. However, it has been challenging to generate a suitable model that harbors the EF translocation. This could suggest that EF is toxic in many cell types and having solely EF translocation expression is insufficient to promote tumor formation.
We have established and molecularly mapped the close interaction of a nuclear hormone receptor, namely the glucocorticoid receptor (GR), with hepatic STAT5 that is largely but not exclusively triggered by hepatic activation of JAK2 kinase. Disruption of the GR-JAK2-STAT5 signaling axis causes metabolic syndrome with aggressive liver cancer development in the case of GR/STAT5 deletion but surprisingly not in the case of JAK2 deletion.
We have established four different genetic mouse models to address the role of STAT transcription factors in metastasizing melanoma driven by oncogenic RAS and loss of Ink4a tumor suppressors. We deleted STAT1, STAT3, STAT5a/b or STAT3/5a/5b conditionally as these transcription factors are regarded as key molecules for melanoma progression. The work is still unpublished and was added to the work of the RM group recently, funded by a melanoma donation.
We are also studying normal and abnormal GI tract function and colorectal carcinomas. Current work in collaboration with international research groups is addressing regulation of the tight junction through cytokine signaling in epithelial cells and intestinal stem cells. In addition, the RM lab is involved in therapeutic intervention studies for chronic inflammatory processes and colorectal cancer prevention. We are preparing three manuscripts for publication.