title: Mitochondrial Metabolism as a Treatment Target in Anaplastic Thyroid Cancer.
abstract: Anaplastic thyroid cancer (ATC) is one of the most aggressive human cancers. Key signal transduction pathways that regulate mitochondrial metabolism are frequently altered in ATC. Our goal was to determine the mitochondrial metabolic phenotype of ATC by studying markers of mitochondrial metabolism, specifically monocarboxylate transporter 1 (MCT1) and translocase of the outer mitochondrial membrane member 20 (TOMM20). Staining patterns of MCT1 and TOMM20 in 35 human thyroid samples (15 ATC, 12 papillary thyroid cancer [PTC], and eight non-cancerous thyroid) and nine ATC mouse orthotopic xenografts were assessed by visual and Aperio digital scoring. Staining patterns of areas involved with cancer versus areas with no evidence of cancer were evaluated independently where available. MCT1 is highly expressed in human anaplastic thyroid cancer when compared to both non-cancerous thyroid tissues and papillary thyroid cancers (P<.001 for both). TOMM20 is also highly expressed in both ATC and PTC compared to non-cancerous thyroid tissue (P<.01 for both). High MCT1 and TOMM20 expression is also found in ATC mouse xenograft tumors compared to non-cancerous thyroid tissue (P<.001). These xenograft tumors have high (13)C- pyruvate uptake. ATC has metabolic features that distinguish it from PTC and non-cancerous thyroid tissue, including high expression of MCT1 and TOMM20. PTC has low expression of MCT1 and non-cancerous thyroid tissue has low expression of both MCT1 and TOMM20. This work suggests that MCT1 blockade may specifically target ATC cells presenting an opportunity for a new drug target.
authors.affiliation: Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Johnson
authors.affiliation: Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX; Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Lai
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cotzia
authors.affiliation: Department of Otolaryngology, Thomas Jefferson University, Philadelphia, PA.
authors.forename: David
authors.initials: D
authors.lastname: Cognetti
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA.
authors.forename: Adam
authors.initials: A
authors.lastname: Luginbuhl
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA.
authors.forename: Edmund A
authors.initials: EA
authors.lastname: Pribitkin
authors.affiliation: Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhan
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA.
authors.forename: Mehri
authors.initials: M
authors.lastname: Mollaee
authors.affiliation: Please provide affiliation text.
authors.forename: Marina
authors.initials: M
authors.lastname: Domingo-Vidal
authors.affiliation: Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Please provide affiliation text.
authors.forename: Barbara
authors.initials: B
authors.lastname: Campling
authors.affiliation: Please provide affiliation text.
authors.forename: Voichita
authors.initials: V
authors.lastname: Bar-Ad
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Birbe
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA.
authors.forename: Madalina
authors.initials: M
authors.lastname: Tuluc
authors.affiliation: Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA. Electronic address: Ubaldo.martinez-outschoorn@jefferson.edu.
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Martinez Outschoorn
authors.affiliation: Department of Otolaryngology, Thomas Jefferson University, Philadelphia, PA. Electronic address: Joseph.Curry@jefferson.edu.
authors.forename: Joseph
authors.initials: J
authors.lastname: Curry
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002277:Carcinoma / Q000378:metabolism; D002291:Carcinoma, Papillary; D005260:Female; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008819:Mice, Nude; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D016019:Survival Analysis; D027981:Symporters / Q000378:metabolism*; D000077273:Thyroid Cancer, Papillary; D065646:Thyroid Carcinoma, Anaplastic / Q000378:metabolism* / Q000401:mortality / Q000601:surgery; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000601:surgery; D023041:Xenograft Model Antitumor Assays; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D027501:Monocarboxylic Acid Transporters; D011956:Receptors, Cell Surface; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C084008:TOMM20 protein, human