0000000000925051
AUTHOR
Marianna Silvano
Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma
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 autocrin…
Abstract 2484: Non-canonical Hedgehog/Gli1 signaling drives lung adenocarcinoma stem cells survival and its targeting inhibits CSC-derived tumors
Abstract Introduction: Lung Adenocarcinoma (AC) is the most frequent lung cancer histological subtype and is a leading cause of cancer-related death worldwide. Hedgehog/Gli (Hh/Gli) signaling pathway regulates lung development and its aberrant activation contributes to tumor pathogenesis and play a role in cancer stem cells (CSC) control. We investigated oncogenic Hh/Gli signaling in AC-CSC. Methods: human AC-CSC were derived from primary tumors. For in vitro studies AC-CSC were maintained in serum-free medium supplemented with EGF/bFGF. For in vivo experiments, immunocompromised mice were injected with AC-CSC. Gli1 inhibitor GANT61 was used both in vitro and in vivo (IP 40 mg/kg twice/we) …