title: Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma.
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.
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Po
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Silvano
authors.affiliation: Center for Life NanoScience@Sapienza, IIT, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Miele
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Capalbo
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Eramo
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Salvati
authors.affiliation: Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.|Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, Palermo, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Todaro
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Z M
authors.initials: ZM
authors.lastname: Besharat
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Catanzaro
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Cucchi
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Coni
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Di Marcotullio
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Canettieri
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Vacca
authors.affiliation: Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Stassi
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: De Smaele
authors.affiliation: Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Tartaglia
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.|Center for Life NanoScience@Sapienza, IIT, Rome, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Screpanti
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.|Institute of General Pathology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: De Maria
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy.|IRCCS Neuromed, Pozzilli, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Ferretti
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D039943:Neuropilin-2 / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C551027:GANT 61; C117307:KRAS protein, human; D039943:Neuropilin-2; D011725:Pyridines; D011743:Pyrimidines; D034741:RNA, Small Interfering; D000071676:Zinc Finger Protein GLI1; D020929:Mitogen-Activated Protein Kinase Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)