{"id":453,"date":"2021-09-30T00:07:29","date_gmt":"2021-09-30T04:07:29","guid":{"rendered":"http:\/\/glundelab.org\/?page_id=453"},"modified":"2021-09-30T00:11:41","modified_gmt":"2021-09-30T04:11:41","slug":"creatine-metabolism-in-cancer","status":"publish","type":"page","link":"http:\/\/glundelab.org\/?page_id=453","title":{"rendered":"Creatine Metabolism in Cancer"},"content":{"rendered":"<p><span style=\"text-decoration: underline;\">Reprogramming of creatine metabolism in\u00a0breast cancer metastasis<\/span><\/p>\n<p>Metabolic reprogramming is a hallmark of cancer, enabling cancer cells to rapidly proliferate, invade, and\u00a0metastasize. Several key enzymes have been identified that modulate cancer metabolism. These include\u00a0enzymes in glucose, amino acid, nucleic acid, and lipid metabolism, including lactate dehydrogenase A,\u00a0glutaminase 1, thymidylate synthase, and choline kinase alpha, to name just a few. Ubiquitous mitochondrial\u00a0creatine kinase 1 (CKMT1) is emerging as a novel key enzyme in creatine metabolism of cancer. Few studies\u00a0to date have investigated the role of CKMT1 in cancer, and the specific role of CKMT1 in breast cancer\u00a0migration, invasion and metastasis remains largely unknown. To close this knowledge gap, we seek to\u00a0investigate reprogramming of creatine metabolism in breast cancer. Our preliminary data show that CKMT1\u00a0drives cellular creatine (Cr) and phosphocreatine (PCr) concentrations and activates glycolysis in breast\u00a0cancer cells. We consistently show in cell lines, mouse models, and patients that creatine metabolite levels\u00a0along with CKMT1 expression are downregulated in metastatic breast cancer cells and metastatic tumor\u00a0tissues. Overexpression of CKMT1 in metastatic breast cancer cells reduces migration, invasion, and\u00a0metastasis, while increasing proliferation and primary tumor growth. Silencing of CKMT1 in nonmetastatic\u00a0breast cancer cells increases migration and invasion, which occurs through generation of reactive oxygen\u00a0species (ROS) that upregulate adhesion and degradative factors, epithelial-to-mesenchymal transition (EMT),\u00a0and signaling pathways. In Aim 1, we will rigorously investigate the cause-and-effect relationships between\u00a0reprogramming of creatine metabolism, related molecular pathways, and metastasis-driving cancer cell\u00a0properties. In Aim 2, we will assess if genes\/enzymes and related molecular pathways responsible for\u00a0reprogramming creatine metabolism drive primary tumor growths and metastasis in mouse models of breast\u00a0cancer. Our preliminary data show that CKMT1 expression was significantly decreased in clinical breast cancer\u00a0metastases as compared to primary breast tumors. In Aim 3, we will further investigate in unique single-patient\u00a0tissue microarrays (TMAs) from our rapid autopsy program how creatine metabolic enzyme expression levels\u00a0and creatine metabolites, as well as related molecular pathways, are affected when breast cancers\u00a0metastasize in patients. In our three Aims, we will test our overall hypothesis that reprogramming of creatine\u00a0metabolism participates in driving breast cancer metastasis. Our preliminary findings provide evidence that\u00a0creatine metabolism, and in particular CKMT1, holds promise as prognostic indicator and potential therapeutic\u00a0target for metastatic breast cancer. Our proposal will significantly advance our understanding of\u00a0reprogramming of creatine metabolism in tumor progression and metastasis. We will develop integrated\u00a0multiplex matrix-assisted laser desorption\/ionization imaging and immunohistochemistry approaches to detect\u00a0creatine enzymes and metabolites in breast cancer specimens for future use in pathology workflows.<\/p>\n","protected":false},"excerpt":{"rendered":"<p class=\"excerpt\">Reprogramming of creatine metabolism in\u00a0breast cancer metastasis Metabolic reprogramming is a hallmark of cancer, enabling cancer cells to rapidly proliferate, invade, and\u00a0metastasize. Several key enzymes have been identified that modulate cancer metabolism. These include\u00a0enzymes in glucose, amino acid, nucleic acid, and lipid metabolism, including lactate dehydrogenase A,\u00a0glutaminase 1, thymidylate synthase, and choline kinase alpha, to name just a few. Ubiquitous&hellip;<\/p>\n<p class=\"more-link-p\"><a class=\"btn btn-default\" href=\"http:\/\/glundelab.org\/?page_id=453\">Read more<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":""},"_links":{"self":[{"href":"http:\/\/glundelab.org\/index.php?rest_route=\/wp\/v2\/pages\/453"}],"collection":[{"href":"http:\/\/glundelab.org\/index.php?rest_route=\/wp\/v2\/pages"}],"about":[{"href":"http:\/\/glundelab.org\/index.php?rest_route=\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"http:\/\/glundelab.org\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"http:\/\/glundelab.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=453"}],"version-history":[{"count":3,"href":"http:\/\/glundelab.org\/index.php?rest_route=\/wp\/v2\/pages\/453\/revisions"}],"predecessor-version":[{"id":456,"href":"http:\/\/glundelab.org\/index.php?rest_route=\/wp\/v2\/pages\/453\/revisions\/456"}],"wp:attachment":[{"href":"http:\/\/glundelab.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=453"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}