Park, Kwon-Sik, Martelotto, Luciano G., Peifer, Martin ORCID: 0000-0002-5243-5503, Sos, Martin L., Karnezis, Anthony N., Mahjoub, Moe R., Bernard, Katie, Conklin, Jamie F., Szczepny, Anette, Yuan, Jing, Guo, Ribo, Ospina, Beatrice, Falzon, Jeanette, Bennett, Samara, Brown, Tracey J., Markovic, Ana, Devereux, Wendy L., Ocasio, Cory A., Chen, James K., Stearns, Tim ORCID: 0000-0002-0671-6582, Thomas, Roman K., Dorsch, Marion, Buonamici, Silvia, Watkins, D. Neil, Peacock, Craig D. and Sage, Julien (2011). A crucial requirement for Hedgehog signaling in small cell lung cancer. Nat. Med., 17 (11). S. 1504 - 1510. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1546-170X

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Abstract

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer for which there is no effective treatment(1,2). Using a mouse model in which deletion of Rb1 and Trp53 in the lung epithelium of adult mice induces SCLC3,4, we found that the Hedgehog signaling pathway is activated in SCLC cells independently of the lung microenvironment. Constitutive activation of the Hedgehog signaling molecule Smoothened (Smo) promoted the clonogenicity of human SCLC in vitro and the initiation and progression of mouse SCLC in vivo. Reciprocally, deletion of Smo in Rb1 and Trp53-mutant lung epithelial cells strongly suppressed SCLC initiation and progression in mice. Furthermore, pharmacological blockade of Hedgehog signaling inhibited the growth of mouse and human SCLC, most notably following chemotherapy. These findings show a crucial cell-intrinsic role for Hedgehog signaling in the development and maintenance of SCLC and identify Hedgehog pathway inhibition as a therapeutic strategy to slow the progression of disease and delay cancer recurrence in individuals with SCLC.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Park, Kwon-SikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martelotto, Luciano G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDorcid.org/0000-0002-5243-5503UNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karnezis, Anthony N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mahjoub, Moe R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bernard, KatieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Conklin, Jamie F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szczepny, AnetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yuan, JingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guo, RiboUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ospina, BeatriceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Falzon, JeanetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bennett, SamaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brown, Tracey J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Markovic, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Devereux, Wendy L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ocasio, Cory A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, James K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stearns, TimUNSPECIFIEDorcid.org/0000-0002-0671-6582UNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dorsch, MarionUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buonamici, SilviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Watkins, D. NeilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peacock, Craig D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sage, JulienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-486757
DOI: 10.1038/nm.2473
Journal or Publication Title: Nat. Med.
Volume: 17
Number: 11
Page Range: S. 1504 - 1510
Date: 2011
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1546-170X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
STEM-CELL; MOUSE MODEL; PATHWAY; INHIBITION; GROWTH; MEDULLOBLASTOMA; ACTIVATION; INACTIVATION; EXPRESSION; REVEALSMultiple languages
Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/48675

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