Reference SummarySong H, J Biol Chem 2017 Mar 3;292(9):3888-3899

Title

 Selective Ablation of Tumor Suppressors in Parafollicular C Cells Elicits Medullary Thyroid Carcinoma.

Authors

 Song H; Lin C; Yao E; Zhang K; Li X; Wu Q; Chuang PT

Journal

 J Biol Chem

Volume

 292

Issue

 9

Year

 2017

Pages

 3888-3899

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 our CGRP(CreER) mouse 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 as p53, Rb, and Pten, in mature parafollicular C cells via an inducible Cre recombinase from CGRP(CreER) led to development of murine medullary thyroid carcinoma. Loss of Pten accelerated p53/Rb-induced medullary thyroid carcinoma, indicating interactions between pathways controlled by tumor suppressors. Moreover, labeling differentiated parafollicular C cells by CGRP(CreER) allows 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.

Links

 J:264655 – MGI References
28119454 – National Library of Medicine/PubMed

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
[not specified]-Calcatm1.1(cre/ERT2)Ptch/+ Rb1tm2Brn Trp53tm1Brn Thyroid gland - Medulla - C cell carcinoma
  • tamoxifen (for inducing expression from mutant alleles)
 Thyroid gland - Medulla - C cell

100
[not specified]-Calcatm1.1(cre/ERT2)Ptch/+ Ptentm1Hwu Rb1tm2Brn Trp53tm1Brn Thyroid gland - Medulla - C cell carcinoma
  • tamoxifen (for inducing expression from mutant alleles)
 Thyroid gland - Medulla - C cell

100
[not specified]-Calcatm1.1(cre/ERT2)Ptch/+ Ptentm1Hwu Trp53tm1Brn Thyroid gland - Medulla - C cell carcinoma
  • tamoxifen (for inducing expression from mutant alleles)
 Thyroid gland - Medulla - C cell

0
[not specified]-Calcatm1.1(cre/ERT2)Ptch/+ Gt(ROSA)26Sortm4(ACTB-tdTomato,-EGFP)Luo/+ Rb1tm2Brn Trp53tm1Brn Thyroid gland - Medulla - C cell carcinoma
  • tamoxifen (for inducing expression from mutant alleles)
 Thyroid gland - Medulla - C cell

100
[not specified]-Calcatm1.1(cre/ERT2)Ptch/+ Gt(ROSA)26Sortm4(ACTB-tdTomato,-EGFP)Luo/+ Ptentm1Hwu Rb1tm2Brn Trp53tm1Brn Thyroid gland - Medulla - C cell carcinoma
  • tamoxifen (for inducing expression from mutant alleles)
 Thyroid gland - Medulla - C cell

100
[not specified]-Calcatm1.1(cre/ERT2)Ptch/+ Rb1tm2Brn Trp53tm1Brn Thyroid gland - Medulla - C cell hyperplasia
  • tamoxifen (for inducing expression from mutant alleles)
 Thyroid gland - Medulla - C cell

100
[not specified]-Calcatm1.1(cre/ERT2)Ptch/+ Gt(ROSA)26Sortm4(ACTB-tdTomato,-EGFP)Luo/+ Rb1tm2Brn Trp53tm1Brn Thyroid gland - Medulla - C cell hyperplasia
  • tamoxifen (for inducing expression from mutant alleles)
 Thyroid gland - Medulla - C cell

observed
[not specified]-Calcatm1.1(cre/ERT2)Ptch/+ Gt(ROSA)26Sortm4(ACTB-tdTomato,-EGFP)Luo/+ Ptentm1Hwu Rb1tm2Brn Trp53tm1Brn Thyroid gland - Medulla - C cell hyperplasia
  • tamoxifen (for inducing expression from mutant alleles)
 Thyroid gland - Medulla - C cell

observed