Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma

A. Po, M. Silvano, E. Miele, C. Capalbo, A. Eramo, V. Salvati, M. Todaro, Z. M. Besharat, G. Catanzaro, D. Cucchi, S. Coni, L. Di Marcotullio, G. Canettieri, A. Vacca, G. Stassi, E. De Smaele, M. Tartaglia, I. Screpanti, R. De Maria, E. Ferretti

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Abstract

Aberrant Hedgehog/GLI signaling has been implicated in a diverse spectrum of human cancers, but its role in lung adenocarcinoma (LAC) is still under debate. We show that the downstream effector of the Hedgehog pathway, GLI1, is expressed in 76% of LACs, but in roughly half of these tumors, the canonical pathway activator, Smoothened, is expressed at low levels, possibly owing to epigenetic silencing. In LAC cells including the cancer stem cell compartment, we show that GLI1 is activated noncanonically by MAPK/ERK signaling. Different mechanisms can trigger the MAPK/ERK/GLI1 cascade including KRAS mutation and stimulation of NRP2 by VEGF produced by the cancer cells themselves in an autocrine loop or by stromal cells as paracrine cross talk. Suppression of GLI1, by silencing or drug-mediated, inhibits LAC cells proliferation, attenuates their stemness and increases their susceptibility to apoptosis in vitro and in vivo. These findings provide insight into the growth of LACs and point to GLI1 as a downstream effector for oncogenic pathways. Thus, strategies involving direct inhibition of GLI1 may be useful in the treatment of LACs.

Original languageEnglish
Pages (from-to)4641-4652
Number of pages12
JournalOncogene
Volume36
Issue number32
DOIs
Publication statusPublished - Aug 10 2017

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Growth
Neoplasms
Neoplastic Stem Cells
Stromal Cells
Epigenomics
Vascular Endothelial Growth Factor A
Cell Proliferation
Apoptosis
Mutation
Pharmaceutical Preparations
Adenocarcinoma of lung
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma. / Po, A.; Silvano, M.; Miele, E.; Capalbo, C.; Eramo, A.; Salvati, V.; Todaro, M.; Besharat, Z. M.; Catanzaro, G.; Cucchi, D.; Coni, S.; Di Marcotullio, L.; Canettieri, G.; Vacca, A.; Stassi, G.; De Smaele, E.; Tartaglia, M.; Screpanti, I.; De Maria, R.; Ferretti, E.

In: Oncogene, Vol. 36, No. 32, 10.08.2017, p. 4641-4652.

Research output: Contribution to journalArticle

Po, A, Silvano, M, Miele, E, Capalbo, C, Eramo, A, Salvati, V, Todaro, M, Besharat, ZM, Catanzaro, G, Cucchi, D, Coni, S, Di Marcotullio, L, Canettieri, G, Vacca, A, Stassi, G, De Smaele, E, Tartaglia, M, Screpanti, I, De Maria, R & Ferretti, E 2017, 'Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma', Oncogene, vol. 36, no. 32, pp. 4641-4652. https://doi.org/10.1038/onc.2017.91
Po, A. ; Silvano, M. ; Miele, E. ; Capalbo, C. ; Eramo, A. ; Salvati, V. ; Todaro, M. ; Besharat, Z. M. ; Catanzaro, G. ; Cucchi, D. ; Coni, S. ; Di Marcotullio, L. ; Canettieri, G. ; Vacca, A. ; Stassi, G. ; De Smaele, E. ; Tartaglia, M. ; Screpanti, I. ; De Maria, R. ; Ferretti, E. / Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma. In: Oncogene. 2017 ; Vol. 36, No. 32. pp. 4641-4652.
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