A dual mechanism of activation of the sonic hedgehog pathway in anaplastic thyroid cancer: Crosstalk with RAS-BRAF-MEK pathway and ligand secretion by tumor stroma

Alessia Parascandolo, Mikko O. Laukkanen, Nancy de Rosa, Clara Ugolini, Maria Carmela Cantisani, Anna Maria Cirafici, Fulvio Basolo, Massimo Santoro, Maria Domenica Castellone

Research output: Contribution to journalArticle

Abstract

Sonic Hedgehog (Shh) pathway regulates embryonic development of different organs including the thyroid gland. The aberrant activation of Shh signaling has been found in several types of cancer and according to recent evidences it represents an important regulator of tumor-stroma interaction. In this study, we have analyzed expression, activation and molecular mechanisms regulating the Shh pathway and its involvement in the modulation of tumor stroma interaction in anaplastic thyroid cancer (ATC) cells. Our results suggest that Shh signaling undergoes a dual mechanism of induction in ATC cells: 1) a basal non-canonical Smo-dependent activation of Gli transcription factor that is partly caused by interaction with the RAS/BRAF/MEK oncogenic pathway and is characterized by the absence of Shh ligand expression in thyroid cancer cells and 2) a paracrine response of cancer cells to Shh ligand secreted by tumor stroma (fibroblasts and mesenchymal stromal cells, MSCs) inducing cancer cell migration and in vitro tumorigenesis. Our data therefore suggest Shh as a potential novel therapeutic target in aggressive thyroid cancers.

Original languageEnglish
Pages (from-to)4496-4510
Number of pages15
JournalOncotarget
Volume9
Issue number4
DOIs
Publication statusE-pub ahead of print - Dec 17 2017

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Keywords

  • Co-culture
  • Hedgehog signaling
  • MSC
  • Thyroid cancer
  • Tumor stroma

ASJC Scopus subject areas

  • Oncology

Cite this

Parascandolo, A., Laukkanen, M. O., de Rosa, N., Ugolini, C., Cantisani, M. C., Cirafici, A. M., Basolo, F., Santoro, M., & Castellone, M. D. (2017). A dual mechanism of activation of the sonic hedgehog pathway in anaplastic thyroid cancer: Crosstalk with RAS-BRAF-MEK pathway and ligand secretion by tumor stroma. Oncotarget, 9(4), 4496-4510. https://doi.org/10.18632/oncotarget.23388