Subtype-specific secretomic characterization of pulmonary neuroendocrine tumor cells

Xu-Dong Wang, Rongkuan Hu, Qing Ding, Trisha K. Savage, Kenneth E. Huffman, Noelle Williams, Melanie H. Cobb, John D. Minna, Jane E. Johnson and Yonghao Yu ()
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Xu-Dong Wang: University of Texas Southwestern Medical Center
Rongkuan Hu: University of Texas Southwestern Medical Center
Qing Ding: University of Texas Southwestern Medical Center
Trisha K. Savage: University of Texas Southwestern Medical Center
Kenneth E. Huffman: University of Texas Southwestern Medical Center
Noelle Williams: University of Texas Southwestern Medical Center
Melanie H. Cobb: University of Texas Southwestern Medical Center
John D. Minna: University of Texas Southwestern Medical Center
Jane E. Johnson: University of Texas Southwestern Medical Center
Yonghao Yu: University of Texas Southwestern Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Pulmonary neuroendocrine (NE) cancer, including small cell lung cancer (SCLC), is a particularly aggressive malignancy. The lineage-specific transcription factors Achaete-scute homolog 1 (ASCL1), NEUROD1 and POU2F3 have been reported to identify the different subtypes of pulmonary NE cancers. Using a large-scale mass spectrometric approach, here we perform quantitative secretome analysis in 13 cell lines that signify the different NE lung cancer subtypes. We quantify 1,626 proteins and identify IGFBP5 as a secreted marker for ASCL1High SCLC. ASCL1 binds to the E-box elements in IGFBP5 and directly regulates its transcription. Knockdown of ASCL1 decreases IGFBP5 expression, which, in turn, leads to hyperactivation of IGF-1R signaling. Pharmacological co-targeting of ASCL1 and IGF-1R results in markedly synergistic effects in ASCL1High SCLC in vitro and in mouse models. We expect that this secretome resource will provide the foundation for future mechanistic and biomarker discovery studies, helping to delineate the molecular underpinnings of pulmonary NE tumors.

Date: 2019
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DOI: 10.1038/s41467-019-11153-5

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