Journal article

Publication year: 2018

Pages: 1805-1819

Journal: Cancer Research

Volume number: 78

Issue number: 7

ISSN: 0008-5472

eISSN: 1538-7445

Open access status: Green

DOI Link: https://doi.org/10.1158/0008-5472.CAN-17-1346

Publisher: American Association for Cancer Research

Abstract: 

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 TGF beta or by promoter methylation, enhanced EMT and spontaneous metastasis via HIF-dependent upregulation of the EGFR ligand TGF alpha. In turn, TGF alpha 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. (C) 2018 AACR.

Harvard Citation style: Dopeso, H., Jiao, H., Cuesta, A., Henze, A., Jurida, L., Kracht, M., et al. (2018) PHD3 Controls Lung Cancer Metastasis and Resistance to EGFR Inhibitors through TGFα, Cancer Research, 78(7), pp. 1805-1819. https://doi.org/10.1158/0008-5472.CAN-17-1346

APA Citation style: Dopeso, H., Jiao, H., Cuesta, A., Henze, A., Jurida, L., Kracht, M., Acker-Palmer, A., Garvalov, B., & Acker, T. (2018). PHD3 Controls Lung Cancer Metastasis and Resistance to EGFR Inhibitors through TGFα. Cancer Research. 78(7), 1805-1819. https://doi.org/10.1158/0008-5472.CAN-17-1346