RT Journal Article
T1 PHD3 Controls Lung Cancer Metastasis and Resistance to EGFR Inhibitors through TGFα
A1 Dopeso, Higinio
A1 Jiao, Hui-Ke
A1 Cuesta Martínez, Ángel
A1 Henze, Anne-Theres
A1 Jurida, Liane
A1 Kracht, Michael
A1 Acker-Palmer, Amparo
A1 Boyan K. Garvalov, 
A1 Acker, Till
AB Lung cancer is the leading cause of cancer-related death worldwide, in large part due to its high propensity to metastasize and to develop therapy resistance. Adaptive responses to hypoxia and epithelial–mesenchymal transition (EMT) are linked to tumor metastasis and drug resistance, but little is known about how oxygen sensing and EMT intersect to control these hallmarks of cancer. Here, we show that the oxygen sensor PHD3 links hypoxic signaling and EMT regulation in the lung tumor microenvironment. PHD3 was repressed by signals that induce EMT and acted as a negative regulator of EMT, metastasis, and therapeutic resistance. PHD3 depletion in tumors, which can be caused by the EMT inducer TGFβ or by promoter methylation, enhanced EMT and spontaneous metastasis via HIF-dependent upregulation of the EGFR ligand TGFα. In turn, TGFα stimulated EGFR, which potentiated SMAD signaling, reinforcing EMT and metastasis. In clinical specimens of lung cancer, reduced PHD3 expression was linked to poor prognosis and to therapeutic resistance against EGFR inhibitors such as erlotinib. Reexpression of PHD3 in lung cancer cells suppressed EMT and metastasis and restored sensitivity to erlotinib. Taken together, our results establish a key function for PHD3 in metastasis and drug resistance and suggest opportunities to improve patient treatment by interfering with the feedforward signaling mechanisms activated by PHD3 silencing.Significance: This study links the oxygen sensor PHD3 to metastasis and drug resistance in cancer, with implications for therapeutic improvement by targeting this system.
PB AACR
SN 0008-5472
YR 2018
FD 2018-04-01
LK https://hdl.handle.net/20.500.14352/100347
UL https://hdl.handle.net/20.500.14352/100347
LA eng
NO Dopeso H, Jiao HK, Cuesta AM, et al. PHD3 Controls Lung Cancer Metastasis and Resistance to EGFR Inhibitors through TGFα. Cancer Res. 2018;78(7):1805-1819. doi:10.1158/0008-5472.CAN-17-1346
NO Deutsche Krebshilfe     (ECCPS; EXC 147) at the  (to T. Acker and A. Acker-Palmer) and Macromolecular Complexes (CEF; EXC 115) at the (to A. Acker-Palmer), and an EMBO Long-Term Fellowship EMBO ALTF 1181-2011 (to H. Dopeso)
NO Behring-Rontgen Foundation
NO Gutenberg Research College
NO Johannes Gutenberg University Mainz
NO Clusters of Excellence Cardio-Pulmonary System
NO Universities of Giessen and Frankfurt
NO University Frankfurt
NO Organización Europea de Biología Molecular
DS Docta Complutense
RD 9 abr 2025