Patched1 haploinsufficiency severely impacts intermediary metabolism in the skin of Ptch1+/-/ODC transgenic mice.

The study of dominantly heritable cancers has provided insights about tumor development. Gorlin syndrome (GS) is an autosomal dominant disorder wherein affected individuals develop multiple basal cell carcinomas (BCCs) of the skin. We developed a murine model of Ptch1 haploinsufficiency on an ornithine decarboxylase (ODC) transgenic background (Ptch1+/-/ODCt/C57BL/6) that is more sensitive to BCCs growth as compared with Ptch1+/+/ODCt/C57BL/6 littermates. Ptch1+/-/ODCt/C57BL/6 mice show an altered metabolic landscape in the phenotypically normal skin, including restricted glucose availability, restricted ribose/deoxyribose flow and NADPH production, an accumulation of α-ketoglutarate, aconitate, and citrate that is associated with reversal of the tricarboxylic acid cycle, coupled with increased ketogenic/lipogenic activity via acetyl-CoA, 3-hydroybutyrate, and cholesterol metabolites. Also apparent was an increased content/acetylation of amino-acids, glutamine and glutamate, in particular. Accordingly, metabolic alterations due to a single copy loss of Ptch1 in Ptch1+/-/ODCt/C57BL/6 heterozygous mice may provide insights about the cancer prone phenotype of BCCs in GS patients, including biomarkers/targets for early intervention.

Citation

Changzhao Li, Bharat Mishra, Mahendra Kashyap, Zhiping Weng, Shaida A Andrabi, Shahid M Mukhtar, Arianna L Kim, David R Bickers, Levy Kopelovich, Mohammad Athar. Patched1 haploinsufficiency severely impacts intermediary metabolism in the skin of Ptch1+/-/ODC transgenic mice. Scientific reports. 2019 Sep 10;9(1):13072

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PMID: 31506465

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