title: Selective Ablation of Tumor Suppressors in Parafollicular C Cells Elicits Medullary Thyroid Carcinoma.
abstract: Among the four different types of thyroid cancer, treatment of medullary thyroid carcinoma poses a major challenge because of its propensity of early metastasis. To further investigate the molecular mechanisms of medullary thyroid carcinoma and discover candidates for targeted therapies, we developed a new mouse model of medullary thyroid carcinoma based on ourCGRPCreERmouse line. This system enables gene manipulation in parafollicular C cells in the thyroid, the purported cells of origin of medullary thyroid carcinoma. Selective inactivation of tumor suppressors, such asp53,Rb, andPten, in mature parafollicular C cells via an inducible Cre recombinase fromCGRPCreERled to development of murine medullary thyroid carcinoma. Loss ofPtenacceleratedp53/Rb-induced medullary thyroid carcinoma, indicating interactions between pathways controlled by tumor suppressors. Moreover, labeling differentiated parafollicular C cells byCGRPCreERallows us to follow their fate during malignant transformation to medullary thyroid tumor. Our findings support a model in which mutational events in differentiated parafollicular C cells result in medullary thyroid carcinoma. Through expression analysis including RNA-Seq, we uncovered major signaling pathways and networks that are perturbed following the removal of tumor suppressors. Taken together, these studies not only increase our molecular understanding of medullary thyroid carcinoma but also offer new candidates for designing targeted therapies or other treatment modalities.
authors.affiliation: From the Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China and.|the Cardiovascular Research Institute, University of California, San Francisco, California 94158.
authors.forename: Hai
authors.initials: H
authors.lastname: Song
authors.affiliation: the Cardiovascular Research Institute, University of California, San Francisco, California 94158.
authors.forename: Chuwen
authors.initials: C
authors.lastname: Lin
authors.affiliation: the Cardiovascular Research Institute, University of California, San Francisco, California 94158.
authors.forename: Erica
authors.initials: E
authors.lastname: Yao
authors.affiliation: the Cardiovascular Research Institute, University of California, San Francisco, California 94158.
authors.forename: Kuan
authors.initials: K
authors.lastname: Zhang
authors.affiliation: From the Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China and.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.affiliation: From the Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China and.
authors.forename: Qingzhe
authors.initials: Q
authors.lastname: Wu
authors.affiliation: the Cardiovascular Research Institute, University of California, San Francisco, California 94158 pao-tien.chuang@ucsf.edu.
authors.forename: Pao-Tien
authors.initials: PT
authors.lastname: Chuang
mesh_terms: D000483:Alleles; D000818:Animals; D002116:Calcitonin / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005260:Female; D016147:Genes, Tumor Suppressor; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D055099:Neuroendocrine Cells / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D013961:Thyroid Gland / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D049452:Green Fluorescent Proteins; D002116:Calcitonin; C045073:Cre recombinase; D019426:Integrases; D015740:Calcitonin Gene-Related Peptide
keywords: CGRP; calcitonin; cancer biology; gene knock-out; genomics; medullary thyroid carcinoma; mouse genetics; parafollicular C cells; tumor suppressor gene