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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.

Education

Teaching interest
Molecular biology, cell biology, animal models of human diseases.

Research description

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.

Publications

Fibroblast drug scavenging increases intratumoural gemcitabine accumulation in murine pancreas cancer
Hessmann E, Patzak Ms, Klein L, Chen N, Kari V, Ramu I, et al
Gut 2018;67(3):497-507

A Preliminary Report: Radical Surgery and Stem Cell Transplantation for the Treatment of Patients With Pancreatic Cancer
Omazic B, Ayoglu B, Löhr M, Segersvärd R, Verbeke C, Magalhaes I, et al
Journal of immunotherapy (Hagerstown, Md. : 1997) 2017;():-

Bioinformatory-assisted analysis of next-generation sequencing data for precision medicine in pancreatic cancer
Malgerud L, Lindberg J, Wirta V, Gustafsson-liljefors M, Karimi M, Moro Cf, et al
Molecular oncology 2017;11(10):1413-1429

Discrimination of pancreatic cancer and pancreatitis by LC-MS metabolomics
Lindahl A, Heuchel R, Forshed J, Lehtiö J, Löhr M, Nordström A
Metabolomics : Official journal of the Metabolomic Society 2017;13(5):61-

Pdx1-Cre-driven conditional gene depletion suggests PAK4 as dispensable for mouse pancreas development
Zhao M, Rabieifar P, Costa Tdf, Zhuang T, Minden A, Löhr M, et al
Scientific reports 2017;7(1):7031-

Peptide microarray-based characterization of antibody responses to host proteins after bacille Calmette-Guérin vaccination
Valentini D, Rao M, Rane L, Rahman S, Axelsson-robertson R, Heuchel R, et al
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 2017;56():140-154

Stroma-regulated HMGA2 is an independent prognostic marker in PDAC and AAC
Strell C, Norberg Kj, Mezheyeuski A, Schnittert J, Kuninty Pr, Moro Cf, et al
British journal of cancer 2017;117(1):65-77

Cerulein-induced pancreatic fibrosis is modulated by Smad7, the major negative regulator of transforming growth factor-β signaling
Li X, Nania S, Fejzibegovic N, Moro Cf, Klopp-schulze L, Verbeke C, et al
Biochimica et biophysica acta 2016;1862(9):1839-46

Immunohistochemical Typing of Adenocarcinomas of the Pancreatobiliary System Improves Diagnosis and Prognostic Stratification
Fernández Moro C, Fernandez-woodbridge A, Alistair D'souza M, Zhang Q, Bozoky B, Kandaswamy Sv, et al
PloS one 2016;11(11):e0166067-

Endoscopic papillectomy and KRAS expression in the treatment of adenoma in the major duodenal papilla
Haraldsson E, Swahn F, Verbeke C, Mattsson Js, Enochsson L, Ung Ka, et al
Scandinavian journal of gastroenterology 2015;50(11):1419-27

Fluorescence labeled microbubbles for multimodal imaging
Barrefelt Å, Zhao Y, Larsson Mk, Egri G, Kuiper Rv, Hamm J, et al
Biochemical and biophysical research communications 2015;464(3):737-42

Variant Profiling of Candidate Genes in Pancreatic Ductal Adenocarcinoma
Huang J, Löhr Jm, Nilsson M, Segersvärd R, Matsson H, Verbeke C, et al
Clinical chemistry 2015;61(11):1408-16

Age-dependent and differential effects of Smad7ΔEx1 on neural progenitor cell proliferation and on neurogenesis
Marschallinger J, Krampert M, Couillard-despres S, Heuchel R, Bogdahn U, Aigner L
Experimental gerontology 2014;57():149-54

Desmoplasia and chemoresistance in pancreatic cancer
Schober M, Jesenofsky R, Faissner R, Weidenauer C, Hagmann W, Michl P, et al
Cancers 2014;6(4):2137-54

Real-time assessment of tissue hypoxia in vivo with combined photoacoustics and high-frequency ultrasound
Gerling M, Zhao Y, Nania S, Norberg Kj, Verbeke Cs, Englert B, et al
Theranostics 2014;4(6):604-13

3D pancreatic carcinoma spheroids induce a matrix-rich, chemoresistant phenotype offering a better model for drug testing
Longati P, Jia X, Eimer J, Wagman A, Witt Mr, Rehnmark S, et al
BMC cancer 2013;13():95-

Deficiency of Smad7 enhances cardiac remodeling induced by angiotensin II infusion in a mouse model of hypertension
Wei Lh, Huang Xr, Zhang Y, Li Yq, Chen Hy, Heuchel R, et al
PloS one 2013;8(7):e70195-

Disruption of Smad7 promotes ANG II-mediated renal inflammation and fibrosis via Sp1-TGF-β/Smad3-NF.κB-dependent mechanisms in mice
Liu Gx, Li Yq, Huang Xr, Wei L, Chen Hy, Shi Yj, et al
PloS one 2013;8(1):e53573-

Inhibitory role of Smad7 in hepatocarcinogenesis in mice and in vitro
Wang J, Zhao J, Chu Es, Mok Mt, Go My, Man K, et al
The Journal of pathology 2013;230(4):441-52

Smad7 regulates terminal maturation of chondrocytes in the growth plate
Estrada Kd, Wang W, Retting Kn, Chien Ct, Elkhoury Ff, Heuchel R, et al
Developmental biology 2013;382(2):375-84

Hypoxic pulmonary hypertension in mice with constitutively active platelet-derived growth factor receptor-β
Dahal Bk, Heuchel R, Pullamsetti Ss, Wilhelm J, Ghofrani Ha, Weissmann N, et al
Pulmonary circulation 2011;1(2):259-68

Multiple Phenotypes in Adult Mice following Inactivation of the Coxsackievirus and Adenovirus Receptor (Car) Gene
Pazirandeh A, Sultana T, Mirza M, Rozell B, Hultenby K, Wallis K, et al
PLOS ONE 2011;6(6):e20203-

Nodal/Activin Signaling Drives Self-Renewal and Tumorigenicity of Pancreatic Cancer Stem Cells and Provides a Target for Combined Drug Therapy
Lonardo E, Hermann Pc, Mueller Mt, Huber S, Balic A, Miranda-lorenzo I, et al
CELL STEM CELL 2011;9(5):433-46

The Protective Role of Smad7 in Diabetic Kidney Disease: Mechanism and Therapeutic Potential
Chen Hy, Huang Xr, Wang Ws, Li Jh, Heuchel Rl, Chung Ack, et al
DIABETES 2011;60(2):590-601

CIN85 regulates dopamine receptor endocytosis and governs behaviour in mice
Shimokawa N, Haglund K, Holter Sm, Grabbe C, Kirkin V, Koibuchi N, et al
EMBO JOURNAL 2010;29(14):2421-32

Smad7 Regulates the Adult Neural Stem/Progenitor Cell Pool in a Transforming Growth Factor beta- and Bone Morphogenetic Protein-Independent Manner
Krampert M, Chirasani Sr, Wachs Fp, Aigner R, Bogdahn U, Yingling Jm, et al
MOLECULAR AND CELLULAR BIOLOGY 2010;30(14):3685-94

The human alpha 11 integrin promoter drives fibroblast-restricted expression in vivo and is regulated by TGF-beta 1 in a Smad- and Sp1-dependent manner
Lu N, Carracedo S, Ranta J, Heuchel R, Soininen R, Gullberg D
MATRIX BIOLOGY 2010;29(3):166-76

Disruption of the Smad7 gene promotes renal fibrosis and inflammation in unilateral ureteral obstruction (UUO) in mice
Chung Ack, Huang Xr, Zhou L, Heuchel R, Lai Kn, Lan Hy
NEPHROLOGY DIALYSIS TRANSPLANTATION 2009;24(5):1443-54

Therapy with Cell Encapsulation for Substitution of Organ Function and Tumor Treatment
Lohr Jm, Heuchel R, Jesnowski R, Wallrapp C
ADVANCED ENGINEERING MATERIALS 2009;11(8):B129-B135

A gain-of-function mutation in the PDGFR-beta alters the kinetics of injury response in liver and skin
Krampert M, Heldin Ch, Heuchel Rl
LABORATORY INVESTIGATION 2008;88(11):1204-14

Disruption of the Smad7 gene enhances CCI4-dependent liver damage and fibrogenesis in mice
Hamzavi J, Ehnert S, Godoy P, Ciuclan L, Weng H, Mertens Pr, et al
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE 2008;12(5B):2130-44

An activating mutation in the PDGF receptor-beta causes abnormal morphology in the mouse placenta
Looman C, Sun T, Yu Y, Zieba A, Ahgren A, Feinstein R, et al
INTERNATIONAL JOURNAL OF DEVELOPMENTAL BIOLOGY 2007;51(5):361-70

Expression and function of the gene encoding the voltage-dependent calcium channel beta 3-subunit in the mouse placenta
Singh U, Sun T, Looman C, Heuchel R, Elliott R, Freichel A, et al
PLACENTA 2007;28(5-6):412-20

Platelet-derived growth factor receptor-beta, carrying the activating mutation D849N, accelerates the establishment of B16 melanoma
Suzuki S, Heldin Ch, Heuchel Rl
BMC CANCER 2007;:224-

Platelet-derived growth factor receptor-beta constitutive activity promotes angiogenesis in vivo and in vitro
Magnusson Pu, Looman C, Ahgren A, Wu Y, Claesson-welsh L, Heuchel Rl
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 2007;27(10):2142-9

Profibrogenic transforming growth Factor-beta/Activin receptor-like kinase 5 signaling via connective tissue growth factor expression in hepatocytes
Weng Hl, Ciuclan L, Liu Y, Hamzavi J, Godoy P, Gaitantzi H, et al
HEPATOLOGY 2007;46(4):1257-70

Deletion of exon I of SMAD7 in mice results in altered B cell responses
Li Rg, Rosendahl A, Brodin G, Cheng Am, Ahgren A, Sundquist C, et al
JOURNAL OF IMMUNOLOGY 2006;176(11):6777-84

Platelet-derived growth factor receptor-beta promotes early endothelial cell differentiation
Rolny C, Nilsson I, Magnusson P, Armulik A, Jakobsson L, Wentzel P, et al
BLOOD 2006;108(6):1877-86

Tandem Sp1/Sp3 sites together with an Ets-1 site cooperate to mediate alpha 11 integrin chain expression in mesenchymal cells
Lu N, Heuchel R, Barczyk M, Zhang Wm, Gullberg D
MATRIX BIOLOGY 2006;25(2):118-29

A gain of function mutation in the activation loop of platelet-derived growth factor beta-receptor deregulates its kinase activity
Chiara F, Goumans Mj, Forsberg H, Ahgren A, Rasola A, Aspenstrom P, et al
JOURNAL OF BIOLOGICAL CHEMISTRY 2004;279(41):42516-27

Platelet-derived growth factor production by B16 melanoma cells leads to increased pericyte abundance in tumors and an associated increase in tumor growth rate
Furuhashi M, Sjoblom T, Abramsson A, Ellingsen J, Micke P, Li H, et al
CANCER RESEARCH 2004;64(8):2725-33

The nucleotides responsible for the direct physical contact between the chromatin insulator protein CTCF and the H19 imprinting control region manifest parent of origin-specific long-distance insulation and methylation-free domains
Pant V, Mariano P, Kanduri C, Mattsson A, Lobanenkov V, Heuchel R, et al
GENES & DEVELOPMENT 2003;17(5):586-90

Transforming growth factor-beta 1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 3
Edlund S, Bu Sh, Schuster N, Aspenstrom P, Heuchel R, Heldin Ne, et al
MOLECULAR BIOLOGY OF THE CELL 2003;14(2):529-44

Transient activation of NF-kappa B through a TAK1/IKK kinase pathway by TGF-beta 1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation
Arsura M, Panta Gr, Bilyeu Jd, Cavin Lg, Sovak Ma, Oliver Aa, et al
ONCOGENE 2003;22(3):412-25

Efficient TGF-beta induction of the Smad7 gene requires cooperation between AP-1, Sp1, and Smad proteins on the mouse Smad7 promoter
Brodin G, Ahgren A, Ten Dijke P, Heldin Ch, Heuchel R
JOURNAL OF BIOLOGICAL CHEMISTRY 2000;275(37):29023-30

Retention of PDGFR-beta function in mice in the absence of phosphatidylinositol 3 '-kinase and phospholipase C gamma signaling pathways
Tallquist Md, Klinghoffer Ra, Heuchel R, Mueting-nelsen Pf, Corrin Pd, Heldin Ch, et al
GENES & DEVELOPMENT 2000;14(24):3179-90

Platelet-derived growth factor beta receptor regulates interstitial fluid homeostasis through phosphatidylinositol-3 ' kinase signaling
Heuchel R, Berg A, Tallquist M, Ahlen K, Reed Rk, Rubin K, et al
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999;96(20):11410-5

Embryonic lethality and liver degeneration in mice lacking the metal-responsive transcriptional activator MTF-1
Gunes C, Heuchel R, Georgiev O, Muller Kh, Lichtlen P, Bluthmann H, et al
EMBO JOURNAL 1998;17(10):2846-54

Identification of Smad7, a TGF beta-inducible antagonist of TGF-beta signalling
Nakao A, Afrakhte M, Moren A, Nakayama T, Christian Jl, Heuchel R, et al
NATURE 1997;389(6651):631-5

REGULATION OF METALLOTHIONEIN GENE-EXPRESSION IN CD-ADAPTED OR ZN-ADAPTED RK-13 CELLS
Wan M, Heuchel R, Radtke F, Hunziker Pe, Kagi Jhr
EXPERIENTIA 1995;51(6):606-11

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