Rainer Heuchel

Rainer Heuchel

Principal Researcher | Docent
Visiting address: Hälsovägen, Enheten för kirurgi C1:77, 14186 Stockholm
Postal address: H9 Klinisk vetenskap, intervention och teknik, H9 CLINTEC Kirurgi och onkologi, 141 52 Huddinge
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About me

  • 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. In December 2021, he became associate professor in cell and molecular
    biology.
    *Teaching interest*
    Cancer biology, molecular biology, animal models of human diseases.

Research

  • *Research interests*
    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.

Articles

All other publications

Grants

  • Desmoplastic stroma (fibrotic connective tissue) is the common denominator of pancreatic ductal adenocarcinoma and chronic pancreatitis.
    Swedish Cancer Society
    1 January 2018
    Pancreatic ductal adenocarcinoma (BDAK) is the fourth most common cancer-related death cause characterized by an unusually high content of fibrotic scar-like connective tissue (desmoplasia) similar to histological chronic pancreatitis (KP), which is also, ultimately, a fatal disease. The fibrotic stroma / desmoplasia in BDAK is responsible for the chemo and radiation resistance. In most cases of BDAK, chronic pancreatitis occurs in the surrounding pancreatic tissue, which has led to the pre-genomic honor that PDAC was misdiagnosed as KP. In our research, we investigate the reactive, fibrotic stromal in PDAC and CP, by modulating the signaling of a growth factor (TGF-beta) responsible for the fibrotic scar-like connective tissue of BDAK and KP. We use genetically modified mice, where we can alter the TGF-beta signaling in the various cell types in the pancreas, namely epithelial cells, macrophages and stellate cells / fibroblasts, and look at their role in the onset of desmoplasia. In addition, we investigate the TGF-beta's tumor-inhibiting role during the onset of BDAK and its later, driving role in the emergence of daughter tumors. The purpose of this project is to gain a better understanding of the reactive torch in KP and BDAK, with particular emphasis on TGF-beta signaling. Finally, we hope that our results will give us new ideas on how we can use the modulation of TGF-beta signaling to defeat the stroma-based chemoresistence in PDAC and to change the lethal fate BDAK develops.
  • Desmoplastic stroma (fibrotic connective tissue) is the common denominator of pancreatic ductal adenocarcinoma and chronic pancreatitis.
    Swedish Cancer Society
    1 January 2017
    Pancreatic ductal adenocarcinoma (BDAK) is the fourth most common cancer-related death cause characterized by an unusually high content of fibrotic scar-like connective tissue (desmoplasia) similar to histological chronic pancreatitis (KP), which is also, ultimately, a fatal disease. The fibrotic stroma / desmoplasia in BDAK is responsible for the chemo and radiation resistance. In most cases of BDAK, chronic pancreatitis occurs in the surrounding pancreatic tissue, which has led to the pre-genomic honor that PDAC was misdiagnosed as KP. In our research, we investigate the reactive, fibrotic stromal in PDAC and CP, by modulating the signaling of a growth factor (TGF-beta) responsible for the fibrotic scar-like connective tissue of BDAK and KP. We use genetically modified mice, where we can alter the TGF-beta signaling in the various cell types in the pancreas, namely epithelial cells, macrophages and stellate cells / fibroblasts, and look at their role in the onset of desmoplasia. In addition, we investigate the TGF-beta's tumor-inhibiting role during the onset of BDAK and its later, driving role in the emergence of daughter tumors. The purpose of this project is to gain a better understanding of the reactive torch in KP and BDAK, with particular emphasis on TGF-beta signaling. Finally, we hope that our results will give us new ideas on how we can use the modulation of TGF-beta signaling to defeat the stroma-based chemoresistence in PDAC and to change the lethal fate BDAK develops.
  • Swedish Research Council
    1 January 2013 - 31 December 2015

Employments

  • Principal Researcher, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 2022-

Degrees and Education

  • Docent, Karolinska Institutet, 2021

Supervision

  • Supervision to doctoral degree

    • Jessica Norberg, 2019
    • Xiahui Jia, 2014

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