TY - JOUR
T1 - Stromal Hedgehog pathway activation by IHH suppresses lung adenocarcinoma growth and metastasis by limiting reactive oxygen species
AU - Kasiri, Sahba
AU - Chen, Baozhi
AU - Wilson, Alexandra N.
AU - Reczek, Annika
AU - Mazambani, Simbarashe
AU - Gadhvi, Jashkaran
AU - Noel, Evan
AU - Marriam, Ummay
AU - Mino, Barbara
AU - Lu, Wei
AU - Girard, Luc
AU - Solis, Luisa M.
AU - Luby-Phelps, Katherine
AU - Bishop, Justin
AU - Kim, Jung Whan
AU - Kim, James
N1 - Funding Information:
Acknowledgements We thank Dr John D. Minna for valuable discussions, Drs Rolf Brekken and David Wang for their helpful comments on the manuscript, Nicolas Loof, Kim Nguyen, and Terry Shih of the Moody Foundation Flow Cytometry Core Facility for assistance with FACS, and Denise Ramirez of the Whole Brain Microscopy Facility. We also thank John Shelton at UTSW HistoPathology Core and Dr Cheryl Lewis at UTSW Tissue Management Core for assistance with tissue processing and embedding. This work was supported in part by the National Cancer Institute (P50CA70907: JK; R01CA196851: JK; R21 CA208746: J-WK), National Heart, Lung, and Blood Institute (5T32HL098040 to SK), American Cancer Society (RSG-16-090-01-TBG: JK), American Lung Association (LCD-400239: J-WK), Sidney Kimmel Foundation for Cancer Research (SKF-14-057: JK), Lung Cancer Research Foundation (JK) and Bonnie J. Addario Lung Cancer Foundation (J.K.).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/4/16
Y1 - 2020/4/16
N2 - Activation of the Hedgehog (Hh) signaling pathway by mutations within its components drives the growth of several cancers. However, the role of Hh pathway activation in lung cancers has been controversial. Here, we demonstrate that the canonical Hh signaling pathway is activated in lung stroma by Hh ligands secreted from transformed lung epithelia. Genetic deletion of Shh, the primary Hh ligand expressed in the lung, in KrasG12D/+;Trp53fl/fl autochthonous murine lung adenocarcinoma had no effect on survival. Early abrogation of the pathway by an anti-SHH/IHH antibody 5E1 led to significantly worse survival with increased tumor and metastatic burden. Loss of IHH, another Hh ligand, by in vivo CRISPR led to more aggressive tumor growth suggesting that IHH, rather than SHH, activates the pathway in stroma to drive its tumor suppressive effects—a novel role for IHH in the lung. Tumors from mice treated with 5E1 had decreased blood vessel density and increased DNA damage suggestive of reactive oxygen species (ROS) activity. Treatment of KrasG12D/+;Trp53fl/fl mice with 5E1 and N-acetylcysteine, as a ROS scavenger, decreased tumor DNA damage, inhibited tumor growth and prolonged mouse survival. Thus, IHH induces stromal activation of the canonical Hh signaling pathway to suppress tumor growth and metastases, in part, by limiting ROS activity.
AB - Activation of the Hedgehog (Hh) signaling pathway by mutations within its components drives the growth of several cancers. However, the role of Hh pathway activation in lung cancers has been controversial. Here, we demonstrate that the canonical Hh signaling pathway is activated in lung stroma by Hh ligands secreted from transformed lung epithelia. Genetic deletion of Shh, the primary Hh ligand expressed in the lung, in KrasG12D/+;Trp53fl/fl autochthonous murine lung adenocarcinoma had no effect on survival. Early abrogation of the pathway by an anti-SHH/IHH antibody 5E1 led to significantly worse survival with increased tumor and metastatic burden. Loss of IHH, another Hh ligand, by in vivo CRISPR led to more aggressive tumor growth suggesting that IHH, rather than SHH, activates the pathway in stroma to drive its tumor suppressive effects—a novel role for IHH in the lung. Tumors from mice treated with 5E1 had decreased blood vessel density and increased DNA damage suggestive of reactive oxygen species (ROS) activity. Treatment of KrasG12D/+;Trp53fl/fl mice with 5E1 and N-acetylcysteine, as a ROS scavenger, decreased tumor DNA damage, inhibited tumor growth and prolonged mouse survival. Thus, IHH induces stromal activation of the canonical Hh signaling pathway to suppress tumor growth and metastases, in part, by limiting ROS activity.
UR - http://www.scopus.com/inward/record.url?scp=85080861407&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85080861407&partnerID=8YFLogxK
U2 - 10.1038/s41388-020-1224-5
DO - 10.1038/s41388-020-1224-5
M3 - Article
C2 - 32108165
AN - SCOPUS:85080861407
SN - 0950-9232
VL - 39
SP - 3258
EP - 3275
JO - Oncogene
JF - Oncogene
IS - 16
ER -