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Journal Article

PHD3 controls lung cancer metastasis and resistance to EGFR inhibitors through TGFalpha

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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 TGFalpha. Cancer Research, 78(7), 1805-1819. doi:10.1158/0008-5472.CAN-17-1346.

Cite as: http://hdl.handle.net/21.11116/0000-0002-743F-6
Lung cancer is the leading cause of cancer-related death worldwide, in large part due to its high propensity to metastasize and to develp theray 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. Herel, we show that the oxygen sensor PHD3 links hypoxic signaling and EMT regulation in the lung tumor microenvironment. PHD3 was repressed by signals that indec 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 TGFbeta or by promotor methylation, enhanced EMT and spontaneous metastasis via HIF-dependent upreguation of the EGFR ligand TGFalpha. In turn, TGFalpha 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 inhibitorssuch 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.