title: Medulloblastomas derived from Cxcr6 mutant mice respond to treatment with a smoothened inhibitor.
abstract: The sonic hedgehog (Shh) pathway is activated in approximately 30% of human medulloblastoma resulting in increased expression of downstream target genes. In about half of these cases, this has been shown to be a consequence of mutations in regulatory genes within the pathway, including Ptc1, Smo, and Sufu. However, for some tumors, no mutations have been detected in known pathway genes. This suggests that either mutations in other genes promote tumorigenesis or that epigenetic alterations increase pathway activity in these tumors. Here, we report that 3% to 4% of mice lacking either one or both functional copies of Cxcr6 develop medulloblastoma. Although CXCR6 is not known to be involved in Shh signaling, tumors derived from Cxcr6 mutant mice expressed Shh pathway target genes including Gli1, Gli2, Ptc2, and Sfrp1, indicating elevated pathway activity. Interestingly, the level of Ptc1 expression was decreased in tumor cells although two normal copies of Ptc1 were retained. This implies that reduced CXCR6 function leads to suppression of Ptc1 thereby increasing Smoothened function and promoting tumorigenesis. We used a direct transplant model to test the sensitivity of medulloblastoma arising in Cxcr6 mutant mice to a small-molecule inhibitor of Smoothened (HhAntag). We found that transplanted tumors were dramatically inhibited in mice treated for only 4 days with HhAntag. These findings suggest that HhAntag may be effective against tumors lacking mutations in known Shh pathway genes.
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Sasai
authors.forename: Justyna T
authors.initials: JT
authors.lastname: Romer
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Kimura
authors.forename: Derek E
authors.initials: DE
authors.lastname: Eberhart
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Rice
authors.forename: Tom
authors.initials: T
authors.lastname: Curran
mesh_terms: D000818:Animals; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D053823:Hedgehog Proteins / Q000378:metabolism; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D054387:Receptors, CXCR; D000075744:Receptors, CXCR6; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D019707:Receptors, Chemokine / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072086:Smoothened Receptor
chemical_list: C482906:Cxcr6 protein, mouse; D053823:Hedgehog Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D054387:Receptors, CXCR; D000075744:Receptors, CXCR6; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; C465570:Shh protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor