Rainer Heuchel has done his PhD on transcriptional enhancers at the University of Zuerich/Switzterland under the supervision of Prof. Walter Schaffner. He then joined the Ludwig Institute for Cancer Reseach headed by Carl-Henrik Heldin where his research focussed on PDGF and TGF-beta signaling using genetically engineered mouse models. In 2008 he joined Prof. Matthias Löhr at Karolinska Institutet where he heads the pancreas research lab.
Molecular biology, cell biology, animal models of human diseases.
Inflammatory and cancerous diseases of the pancreas
Acute and chronic pancreatitis are very difficult to treat diseases. Chronic pancreatitis has also been identified as a risk factor for the development of pancreatic cancer. We use different mouse models recapitulating these two forms of human pancreatitis in order to better understand the basic biology of these diseases and to identify new targets for drug and treatment development.
According to the Cancerfonds Rapporten 2012, pancreatic ductal adenocarcinoma (PDAC) has raised from the fifth to the fourth most frequent cause of death by cancer in Sweden, although it is not even among the 10 most common forms of cancer. The fact that PDAC has changed place with breast cancer is, however, not due to an increase in PDAC incidence, but is based on the improvements made in the treatment of breast cancer. This indicates the dilemma of PDAC, in that there is no diagnostic biomarker, the diagnosis is late and the tumor, once identified is almost completely resistant towards conventional chemo- and radiation therapy. The increased therapy resistance is mainly due to the enormous fibrotic response (desmoplasia), seen as excessive collagen disposition (comparable to scar tissue), induced by the stromal cells. Therefore the stroma of an "average" PDAC is consisting to at least 50% of tumor stroma (mainly activated stellate cells, macrophages etc.), which is hindering the access of potential anti-cancer drugs to the actual cancer cells.
Many drugs have been developed, which fight cancer cells successfully in 2-dimensional cell culture and xenograft experiments (subcutaneous injection of cancer cells) in nude mice. These approaches have the critical disadvantages that they do not take into account the collagen-rich stroma (2-D culture and xenograft), the lack of a functioning immune system (nude mice) and the wrong placing of the tumor (subcutaneous vs. into the pancreas). In order to circumvent these systematic problems we have developed 3-dimensional stroma-containing cancer cell cultures (avascular minitumors), which are able to identify those drugs, which only work in 2-D culture and thus have very little chance to ever work in a patient. Drugs with proven anti-cancer potential in our 3-D setup are then tested in genetically defined mouse tumor models, which not only mimic the preneoplastic development of human PDAC, but are characterized by the same collagen-rich stroma. These astonishing similarities between mouse and man are most probably based on the fact that the mouse PDAC is induced by the same genes (KRAS, TP53) that have been found mutated in the majority of patients. Besides drug/therapy testing, we use the pre-clinical mouse models also to 1) identify new biomarkers and drug targets, 2) identify and chararcterize cancer stem cells and to 3) characterize the impact of additional mutations in tumor development and metastasis formation.
In conclusion, we have set up a progressive filter strategy for anti-PDAC drugs (2D to 3D in vitro systems followed floowoed by genetically engineered mouse models) which will significantly reduce the number of mice required in drug testing and hopefully increase the efficacy of drugs entering human phase-I clinical trials for PDAC.