Heidi Hahn

Universitätsklinikum Freiburg, Freiburg an der Elbe, Lower Saxony, Germany

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Publications (54)354.17 Total impact

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    ABSTRACT: The Patched1 (Ptch)-mediated inhibition of Smoothened (Smo) is still an open question. However, a direct Ptch/Smo interaction has been excluded, Smo modulators were identified, but the endogenous signal transmitting molecule remains undiscovered. Here, we demonstrate that calcitriol, the hormonally active form of vitamin D3, is an excellent candidate for transmission of Ptch/Smo interaction. Our study reveals that Ptch expression is sufficient to release calcitriol from the cell and that calcitriol inhibits Smo action and ciliary translocation by acting on a site distinct from the 7-transmembrane-domain or the cysteine-rich-domain. Moreover calcitriol strongly synergizes with itraconazole (ITZ) in Smo inhibition which not results from elevated calcitriol bio-availability due to ITZ-mediated 24-hydroxylase inhibition but rather from a direct interaction of the compounds at the level of Smo. Together, we suggest that calcitriol represents a possible endogenous transmitter of Ptch/Smo interaction. Moreover calcitriol or calcitriol derivatives combined with ITZ might be a treatment option of Hedgehog-associated cancers. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 06/2015; DOI:10.1074/jbc.M115.646141 · 4.57 Impact Factor
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    ABSTRACT: Recent genomic studies revealed a high rate of recurrent mutations in the RAS pathway in primary rhabdomyosarcoma (RMS) samples. In the present study, we therefore investigated how oncogenic RAS mutants impinge on the regulation of cell death of RMS13 cells. Here, we report that ectopic expression of NRAS12V, KRAS12V, or HRAS12V protects RMS13 cells from oxidative stress-induced cell death. RMS13 cells engineered to express NRAS12V, KRAS12V, or HRAS12V were significantly less susceptible to loss of cell viability upon treatment with several oxidative stress inducers including the thioredoxin reductase inhibitor Auranofin, the glutathione (GSH) peroxidase 4 inhibitor RSL3 or Erastin, an inhibitor of the cysteine/glutamate amino acid transporter system [Formula: see text] that blocks GSH synthesis. Notably, addition of Ferrostatin-1 confers protection against Erastin- or RSL3-induced cytotoxicity, indicating that these compounds trigger ferroptosis, an iron-dependent form of programed cell death. Furthermore, RMS13 cells overexpressing oncogenic RAS mutants are significantly protected against the dual PI3K/mTOR inhibitor PI103, whereas they are similarly sensitive to DNA-damaging drugs such as Doxorubicin or Etoposide. This suggests that oncogenic RAS selectively modulates cell death pathways triggered by cytotoxic stimuli in RMS13 cells. In conclusion, our discovery of an increased resistance to oxidative stress imposed by oncogenic RAS mutants in RMS13 cells has important implications for the development of targeted therapies for RMS.
    Frontiers in Oncology 06/2015; 5:131. DOI:10.3389/fonc.2015.00131
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    ABSTRACT: Rhabdomyosarcoma (RMS) are the most common soft tissue sarcoma in children and are divided into two major histological subgroups, i.e. embryonal (ERMS) and alveolar RMS (ARMS). RMS can show HEDGEHOG/SMOOTHENED (HH/SMO) signaling activity and several clinical trials using HH inhibitors for therapy of RMS have been launched. We here compared the antitumoral effects of the SMO inhibitors GDC-0449, LDE225, HhA and cyclopamine in two ERMS (RD, RUCH-2) and two ARMS (RMS-13, Rh41) cell lines. Our data show that the antitumoral effects of these SMO inhibitors are highly divers and do not necessarily correlate with inhibition of HH signaling. In addition, the responsiveness of the RMS cell lines to the drugs is highly heterogeneous. Whereas some SMO inhibitors (i.e. LDE225 and HhA) induce strong proapoptotic and antiproliferative effects in some RMS cell lines, others paradoxically induce cellular proliferation at certain concentrations (e.g. 10 µM GDC-0449 or 5 µM cyclopamine in RUCH-2 and Rh41 cells) or can increase HH signaling activity as judged by GLI1 expression (i.e. LDE225, HhA and cyclopamine). Similarly, some drugs (e.g. HhA) inhibit PI3K/AKT signaling or induce autophagy (e.g. LDE225) in some cell lines, whereas others cannot (e.g. GDC-0449). In addition, the effects of SMO inhibitors are concentration-dependent (e.g. 1 µM and 10 µM GDC-0449 decrease GLI1 expression in RD cells whereas 30 µM GDC-0449 does not). Together these data show that some SMO inhibitors can induce strong antitumoral effects in some, but not all, RMS cell lines. Due to the highly heterogeneous response we propose to conduct thorough pretesting of SMO inhibitors in patient-derived short term RMS cultures or patient-derived xenograft mouse models before applying these drugs to RMS patients.
    Frontiers in Oncology 06/2015; 5. DOI:10.3389/fonc.2015.00130
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    ABSTRACT: Mice with heterozygous loss of the tumor suppressor Patched1 (Ptch) develop rhabdomyosarcoma (RMS)-like tumors. However, Ptch transcripts are consistently overexpressed in these tumors. We have recently shown that the upregulated transcripts are derived from the mutated Ptch allele thus leading to the hypothesis that the wild-type allele is repressed during RMS development. Here we describe epigenetic changes taking place at the Ptch locus during RMS development. We showed a lower degree of DNA-methylation in methylation-sensitive CpG regions of the Ptch promoter in RMS compared to normal muscle from heterozygous Ptch animals. In agreement with these results, treatment of heterozygous Ptch mice with the DNA demethylating agent 5-aza-2-deoxycytidine (5-aza-dC) between embryonic days E9.5-E11.5 significantly accelerated RMS formation. Since Ptch promoter methylation occurs after/around E13.5, the window for RMS initiation during embryogenesis, these results provide additional evidence that Ptch promoter hypomethylation may contribute to RMS formation. We have also demonstrated increased trimethylation of histone H3 lysine 4 (H3K4me3) and preferential binding of Gli1, a known Ptch activator, to the mutant locus in RMS. Together, these findings support an alternative model for RMS formation in heterozygous Ptch mice including loss of methylation and concomitant occupancy by activating histone marks of mutant Ptch.
    Oncotarget 03/2015; · 6.63 Impact Factor
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    Ulrike Graab · Heidi Hahn · Simone Fulda
    Oncotarget 03/2015; · 6.63 Impact Factor
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    ABSTRACT: Objective. During development of the vertebrate skeleton chondrocytes form a cartilage template that is gradually replaced by bone. Hormones of the Hedgehog (Hh) family have been implicated in the ossification process but their exact role to normal or pathogenic bone formation is unclear. The aims of this study were first, the establishment of a genetic tool that allows the discrete inactivation of genes in spinal chondrocytes, and second, the in vivo investigation of how chondrocyte-specific ablation of the inhibitory Hh receptor Patched1 (Ptch1) affects skeleton integrity. Methods. A Cre-deleter mouse strain for gene recombination in spinal chondrocytes was identified by in situ hybridization and histology (mb1-Cre). Breeding of mb1-Cre(+/-) animals with mice that harbor a loxP-flanked Ptch1 gene (Ptch1(flox/flox) ) abrogated the inhibition of the Hh signaling pathway in chondrocytes. The skeleton integrity of F1-mice was characterized by high-resolution flat panel-based volume-computed tomography (fpVCT) and histological staining procedures. Results. During the first weeks after birth all mb1-Cre(+/-) /Ptch1(flox/flox) mice developed a progressive spinal fusion with malformation of the vertebrae. The aclampsia phenotype was caused by aberrant chondrocyte proliferation in the intervertebral discs that blocked endochondral ossification. Importantly, the disease pattern occurred in an inflammation-independent manner. Conclusion. Chronic activation of the Hh signal pathway in spinal chondrocytes can trigger an ankylosing spine morphology without immune cell contributions. Hence, the destruction of cartilage and loss of axial joint integrity can result from chondrocyte-intrinsic defects of monogenic origin. © 2013 American College of Rheumatology.
    Arthritis & Rheumatology 04/2014; 66(4). DOI:10.1002/art.38325 · 7.87 Impact Factor
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    ABSTRACT: Basal cell carcinoma (BCC) belongs to the group of non-melanoma skin tumors and is the most common tumor in the western world. BCC arises due to mutations in the tumor suppressor gene Patched1 (Ptch). Analysis of the conditional Ptch knockout mouse model for BCC reveals that macrophages and dendritic cells (DC) of the skin play an important role in BCC growth restraining processes. This is based on the observation that a clodronate-liposome mediated depletion of these cells in the tumor-bearing skin results in significant BCC enlargement. The depletion of these cells does not modulate Ki67 or K10 expression, but is accompanied by a decrease in collagen-producing cells in the tumor stroma. Together, the data suggest that cutaneous macrophages and DC in the tumor microenvironment exert an antitumor effect on BCC.
    PLoS ONE 04/2014; 9(4):e93555. DOI:10.1371/journal.pone.0093555 · 3.23 Impact Factor
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    ABSTRACT: The development of basal cell carcinoma (BCC), the most frequently diagnosed tumor among persons with European ancestry, is closely linked to mutations in the Hedgehog (Hh)-receptor and tumor suppressor Patched1 (Ptch). Using Ptch(flox/flox)CD4Cre(+/-) mice, in which Ptch was ablated in CD4Cre-expressing cells, we demonstrate that the targeted cells can give rise to BCC after treatment with 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA), but not after wounding of the skin. In addition, in this model BCC are not caused by malfunctioning of Ptch-deficient T cells since BCC did not develop when bone marrow (BM) of Ptch(flox/flox)CD4Cre(+/-) mice was transplanted into Ptch wildtype mice. Instead lineage tracing experiments and flowcytometric analyses suggest that the tumors are initiated from rare Ptch-deficient stem cell-like cells of the epidermis that express CD4. Since DMBA/TPA is a prerequisite for BCC development in this model, the initiated cells need a second stimulus for expansion and tumor formation. However, in contrast to papilloma this stimulus seems to be unrelated to alterations in the Ras-signaling cascade. Together these data suggest that biallelic loss of Ptch in CD4(+) cells does not suffice for BCC formation and that BCC formation requires a second so far unknown event, at least in the Ptch(flox/flox)CD4Cre(+/-) BCC mouse model.Journal of Investigative Dermatology accepted article preview online, 24 March 2014; doi:10.1038/jid.2014.157.
    Journal of Investigative Dermatology 03/2014; 134(10). DOI:10.1038/jid.2014.157 · 6.37 Impact Factor
  • Benedikt Albert · Heidi Hahn
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    ABSTRACT: Basal Cell Carcinomas (BCCs) are the most commonly diagnosed tumors among people in the western world. Most BCCs are caused by mutational inactivation of the tumor suppressor Patched (PTCH), which results in activation of Smoothened (SMO) and of the Hedgehog (HH) signaling pathway. Recent studies indicate that BCC progression involves a crosstalk between Hh signaling, vitamin D derivatives and the vitamin D receptor (Vdr) signaling pathway. This has been demonstrated in BCC-bearing Ptch mutant mice and BCC cell lines, in which both vitamin D3 and its active metabolite calcitriol (1alpha-25(OH)2D3) exert antitumor effects. Interestingly, the antitumor effects are mainly ascribed to an inhibition of Hh signaling. Furthermore, as evident from studies in Vdr deficient mice, calcitriol may also repress the activity of Hh signaling in a Vdr-dependent fashion thereby establishing an additional inhibitory feedback on Hh signaling activity. In this chapter, we discuss the current understanding and controversial findings of the inhibition of Hh signaling by vitamin D derivatives and the implication of these findings for BCC carcinogenesis.
    Advances in Experimental Medicine and Biology 01/2014; 810:329-41. · 2.01 Impact Factor
  • A Uhmann · H Hahn
    Experimental and Clinical Endocrinology & Diabetes 11/2013; 121(10). DOI:10.1055/s-0033-1359458 · 1.76 Impact Factor
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    ABSTRACT: Liposomes are frequently used in cancer therapy to encapsulate and apply anticancer drugs. Here, we show that a systemic treatment of mice bearing skin tumors with empty phosphatidylcholine liposomes (PCL) resulted in inhibition of tumor growth, which was similar to that observed with the synthetic bacterial lipoprotein and TLR1/2 agonist Pam3CSK4 (BLP). Both compounds led to a substantial decrease of macrophages in spleen and in the tumor-bearing skin. Furthermore, both treatments induced the expression of typical macrophage markers in the tumor-bearing tissue. As expected, BLP induced the expression of the M1 marker genes Cxcl10 and iNOS, whereas PCL, besides inducing iNOS, also increased the M2 marker genes Arg1 and Trem2. In vitro experiments demonstrated that neither PCL nor BLP influenced proliferation or survival of tumor cells, whereas both compounds inhibited proliferation and survival and increased the migratory capacity of bone marrow-derived macrophages (BMDM). However, in contrast to BLP, PCL did not activate cytokine secretion and induced a different BMDM phenotype. Together, the data suggest that similar to BLP, PCL induce an antitumor response by influencing the tumor microenvironment, in particular by functional alterations of macrophages, however, in a distinct manner from those induced by BLP.
    Cancer Immunology and Immunotherapy 08/2013; DOI:10.1007/s00262-013-1444-4 · 3.94 Impact Factor
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    ABSTRACT: Hedgehog (Hh) signaling modulates T cell development and function but its exact role remains a matter of debate. To further address this issue we made use of conditional knock-out mice in which the Hh receptor Patched1 (Ptch) is inactivated in the T cell lineage. Thymocyte development was moderately compromised by the deletion of Ptch as characterized by reduced numbers of CD4 and CD8 single-positive cells. In contrast, peripheral T cells were not affected. Proliferation and IFNγ secretion by Ptch-deficient T cells were indistinguishable from controls irrespectively of whether we used strong or suboptimal conditions for stimulation. Analysis of CTL and Treg cell functions did not reveal any differences between both genotypes, and T cell apoptosis induced by glucocorticoids or γ-irradiation was also similar. Surprisingly, absence of Ptch did not lead to an activation of canonic Hh signaling in peripheral T cells as indicated by unaltered expression levels of Gli1 and Gli2. To test whether we could uncover any role of Ptch in T cells in vivo we subjected the mutant mice to three different disease models, namely allogeneic bone marrow transplantation mimicking graft-versus-host disease, allergic airway inflammation as a model of asthma and growth of adoptively transferred melanoma cells as a means to test tumor surveillance by the immune system. Nonetheless, we were neither able to demonstrate any difference in the disease courses nor in any pathogenic parameter in these three models of adaptive immunity. We therefore conclude that the Hh receptor Ptch is dispensable for T cell function in vitro as well as in vivo.
    PLoS ONE 04/2013; 8(4):e61034. DOI:10.1371/journal.pone.0061034 · 3.23 Impact Factor
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    ABSTRACT: We searched for a drug capable of sensitization of sarcoma cells to doxorubicin (DOX). We report that the dual PI3K/mTOR inhibitor PI103 enhances the efficacy of DOX in several sarcoma cell lines and interacts with DOX in the induction of apoptosis. PI103 decreased the expression of MDR1 and MRP1, which resulted in DOX accumulation. However, the enhancement of DOX-induced apoptosis was unrelated to DOX accumulation. Neither did it involve inhibition of mTOR. Instead, the combination treatment of DOX plus PI103 activated Bax, the mitochondrial apoptosis pathway, and caspase 3. Caspase 3 activation was also observed in xenografts of sarcoma cells in nude mice upon combination of DOX with the specific PI3K inhibitor GDC-0941. Although the increase in apoptosis did not further impact on tumor growth when compared to the efficient growth inhibition by GDC-0941 alone, these findings suggest that inhibition of PI3K may improve DOX-induced proapoptotic effects in sarcoma. Taken together with similar recent studies of neuroblastoma- and glioblastoma-derived cells, PI3K inhibition seems to be a more general option to sensitize tumor cells to anthracyclines.
    PLoS ONE 12/2012; 7(12):e52898. DOI:10.1371/journal.pone.0052898 · 3.23 Impact Factor
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    ABSTRACT: BACKGROUND & AIMS:: A fraction of gastrointestinal stromal tumor (GIST) cells overexpress the platelet-derived growth factor receptor (PDGFR)A, although most overexpress KIT. It is not known if this is because these receptor tyrosine kinases have complementary oncogenic potential, or because of heterogeneity in the cellular origin of GIST. Little is also known about why Hedgehog (HH) signaling is activated in some GIST. HH binds to and inactivates the receptor protein patched homolog (PTCH). METHODS:: Ptch was conditionally inactivated in mice (to achieve constitutive HH signaling) using a Cre recombinase regulated by the lysozyme M (LysM) promoter. Cre-expressing cells were traced using R26R-LacZ reporter mice. Tumors were characterized by in situ hybridization, immunohistochemistry, immunoblot, and quantitative reverse transcriptase PCR analyses. Cell transformation was assessed by soft agar assay. RESULTS:: Loss of Ptch from LysM-expressing cells resulted in development of tumors of GIST-like localization and histology; these were reduced when mice were given imatinib, a drug that targets KIT and PDGFRA. The Hh signaling pathway was activated in the tumor cells, and Pdgfrα, but not Kit, was overexpressed and activated. Lineage tracing revealed that Cre-expressing intestinal cells were Kit-negative. These cells sometimes expressed Pdgfrα and were located near Kit-positive interstitial cells of Cajal (ICC). In contrast to KIT, activation of PDGFRA increased anchorage-independent proliferation and was required for tumor formation in mice by cells with activated HH signaling. CONCLUSIONS:: Inactivation of Ptch in mice leads to formation of GIST-like tumors that express Pdgfrα, but not Kit. Activation of Pdgfrα signaling appears to facilitate tumorigenesis.
    Gastroenterology 10/2012; 144(1). DOI:10.1053/j.gastro.2012.09.061 · 13.93 Impact Factor
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    ABSTRACT: Basal cell carcinoma (BCC) is the most common human tumor. Mutations in the hedgehog (HH) receptor Patched (PTCH) are the main cause of BCC. Due to their high and increasing incidence, BCC are becoming all the more important for the health care system. Adequate animal models are required for the improvement of current treatment strategies. A good model should reflect the situation in humans (i.e., BCC initiation due to Ptch mutations on an immunocompetent background) and should allow for (i) BCC induction at a defined time point, (ii) analysis of defined BCC stages, and (iii) induction of BCC in 100% of animals. In addition, it should be easy to handle. Here, we compare several currently existing conventional and conditional Ptch knockout mouse models for BCC and their potential use in preclinical research. In addition, we provide new data using conditional Ptch(flox/flox) mice and the K5-Cre-ER(T+/-) driver.
    09/2012; 2012(5):907543. DOI:10.1155/2012/907543
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    ABSTRACT: OBJECTIVE: In the intestine Hedgehog (Hh) signalling is directed from epithelium to mesenchyme and negatively regulates epithelial precursor cell fate. The role of Hh signalling in the oesophagus has not been studied in vivo. Here the authors examined the role of Hh signalling in epithelial homeostasis of oesophagus. DESIGN: The authors used transgenic mice in which the Hh receptor Patched1 (Ptch1) could be conditionally inactivated in a body-wide manner and mice in which Gli1 could be induced specifically in the epithelium of the skin and oesophagus. Effects on epithelial homeostasis of the oesophagus were examined using immunohistochemistry, in situ hybridisation, transmission electron microscopy and real-time PCR. Hh signalling was examined in patients with oesophageal squamous cell carcinoma (SCC) by quantitative real-time PCR. RESULTS: Sonic Hh is signalled in an autocrine manner in the basal layer of the oesophagus. Activation of Hh signalling resulted in an expansion of the epithelial precursor cell compartment and failure of epithelial maturation and migration. Levels of Hh targets GLI1, HHIP and PTCH1 were increased in SCC compared with normal tissue from the same patients. CONCLUSION: Here the authors find that Hh signalling positively regulates the precursor cell compartment in the oesophageal epithelium in an autocrine manner. Since Hh signalling targets precursor cells in the oesophageal epithelium and signalling is increased in SCCs, Hh signalling may be involved in oesophageal SCC formation.
    Gut 04/2012; 62(3). DOI:10.1136/gutjnl-2011-301141 · 13.32 Impact Factor
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    ABSTRACT: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Aberrant Hedgehog (Hh) signaling is characteristic of the embryonal subtype (ERMS) and of fusion-negative alveolar RMS. In the mouse, ERMS-like tumors can be induced by mutations in the Hh receptor Patched1 (Ptch). As in humans these tumors show increased Hh pathway activity. Here we demonstrate that the treatment with the active form of vitamin D 3 , calcitriol, inhibits Hh signaling and proliferation of murine ERMS in vivo and in vitro . Concomitantly, calcitriol activates vitamin D receptor (Vdr) signaling and induces tumor differentiation. In addition, calcitriol inhibits ERMS growth in Ptch -mutant mice, which is, however, a rather late response. Taken together, our results suggest that exogenous supply of calcitriol could be beneficial in the treatment of RMS, especially in those which are associated with aberrant Hh signaling activity.
    Sarcoma 02/2012; 2012(16):357040. DOI:10.1155/2012/357040
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    ABSTRACT: Activation of the Hedgehog (Hh)-signaling pathway due to deficiency in the Hh receptor Patched1 (Ptch) is the pivotal defect leading to formation of basal cell carcinoma (BCC). Recent reports provided evidence of Ptch-dependent secretion of vitamin D(3)-related compound, which functions as an endogenous inhibitor of Hh signaling by repressing the activity of the signal transduction partner of Ptch, Smoothened (Smo). This suggests that Ptch-deficient tumor cells are devoid of this substance, which in turn results in activation of Hh-signaling. Here, we show that the application of the physiologically active form of vitamin D(3), calcitriol, inhibits proliferation and growth of BCC of Ptch mutant mice in vitro and in vivo. This is accompanied by the activation of the vitamin D receptor (Vdr) and induction of BCC differentiation. In addition, calcitriol inhibits Hh signaling at the level of Smo in a Vdr-independent manner. The concomitant antiproliferative effects on BCC growth are stronger than those of the Hh-specific inhibitor cyclopamine, even though the latter more efficiently inhibits Hh signaling. Taken together, we show that exogenous supply of calcitriol controls the activity of 2 independent pathways, Hh and Vdr signaling, which are relevant to tumorigenesis and tumor treatment. These data suggest that calcitriol could be a therapeutic option in the treatment of BCC, the most common tumor in humans.
    Molecular Cancer Therapeutics 08/2011; 10(11):2179-88. DOI:10.1158/1535-7163.MCT-11-0422 · 6.11 Impact Factor
  • Cancer Research 07/2011; 71(8 Supplement):5343-5343. DOI:10.1158/1538-7445.AM2011-5343 · 9.28 Impact Factor
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    ABSTRACT: Embryonal rhabdomyosarcoma (ERMS) is a tumor of the skeletal muscle in children and is frequently initiated by heterozygous germline mutations in the Hedgehog (Hh) receptor Patched1 (Ptch), both in humans and mice. Using a conditional knock-out strategy in Ptch(flox/+) mice, we demonstrate that early embryonic stages are more susceptible to ERMS development than later stages and that cells normally not committed to undergo myogenesis at this stage represent the major source of ERMS. We found that deletion of a single copy of the Ptch allele at E9.5 using the ubiquitously active Rosa26CreERT2 resulted in a tumor incidence of 88% but reached only 44% and 12% when the Ptch allele was inactivated at E11.5 and E13.5, respectively. Induction of the Ptch mutation at E9.5 did also significantly shorten ERMS-free survival and increased tumor multiplicity compared with tumor induction at E11.5 and E13.5. Interestingly, we observed a more that 10-fold reduction of ERMS incidence when the Ptch mutation was specifically introduced in Myf5-expressing cells, which is the myogenic factor expressed in all muscle cells at E9.5. We conclude that Myf5-negative cells are more susceptible to ERMS development than Myf5-positive embryonic precursors. As the propensity to undergo tumorigenic transformation declined with age, concomitant with the increase of stably committed muscle cells, it seems likely that the Ptch mutation favors tumor formation in progenitor cells, which have not yet acquired a muscle cell fate.
    Oncogene 05/2011; 30(43):4428-36. DOI:10.1038/onc.2011.157 · 8.56 Impact Factor

Publication Stats

2k Citations
354.17 Total Impact Points

Institutions

  • 2012–2015
    • Universitätsklinikum Freiburg
      • Institute of Human Genetics
      Freiburg an der Elbe, Lower Saxony, Germany
  • 2003–2015
    • Georg-August-Universität Göttingen
      • Institute for Cellular and Molecular Immunology
      Göttingen, Lower Saxony, Germany
  • 2010–2011
    • Universitätsmedizin Göttingen
      • Department of Human Genetics
      Göttingen, Lower Saxony, Germany
  • 2007
    • Institute of Human Genetics
      Amadavad, Gujarāt, India
  • 2002–2003
    • Technische Universität München
      München, Bavaria, Germany
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany
  • 1999
    • National Institutes of Health
      • Laboratory of Genetics (LG)
      베서스다, Maryland, United States
  • 1998
    • National Institute of Mental Health (NIMH)
      Maryland, United States