Abstract 1822: Proteome signatures distinguish lung cancer subtypes, define metabolism states, and have prognostic impact
Authors: Zhang Wen , Taylor Paul , Li Lei , Wei Yuhong , Tong Jiefei , Ignatchenko Vladimir , Pham Nhu-An , Kislinger Thomas , Tsao Ming-sound , Moran Michael 
Published: August 2015

Lung cancer is one of the most common cancers worldwide, and is the number one cause of cancer death in both men and women. Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers and is subdivided into two major histological subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC). There is an unmet need to better understand and stratify NSCLC according to distinctive molecular features that may help develop diagnostic and therapeutic strategies to improve patient outcomes. The proteome is expected to have a pronounced and direct effect on cancer phenotypes. Therefore, proteomic approaches hold promise as superior methods to characterize cancers, with the ultimate goal to translate research results into clinical utilities. Mass spectrometry (MS)-based quantitative comprehensive proteome analysis resolved the proteomes of human lung ADC and SCC primary tumor-derived xenografts. A multi-protein signature able to distinguish between ADC and SCC was identified and validated in an independent cohort of samples. The signature is comprised of various components of the epithelial barrier and metabolism enzymes. Signatures composed of metabolism proteins were found to be highly recapitulated between primary and matched xenograft tumors, and when extrapolated to DNA alterations in the encoding genes, to have prognostic impact for overall patient survival. The ability of NSCLC primary tumors to engraft in severely immune deficient mice is an independent predictor of shorter disease-free survival in early-stage NSCLC patients. Therefore, we sought to identify proteome signatures of engraftment, which would then be tested for prognostic impact. The proteomes of a series of &gt;50 NSCLC primary tumors that engrafted or not were quantitatively compared by using the so-called super-SILAC method, in which a mixture of metabolically-labeled, stable-isotope-encoded NSCLC-derived cell lines were used as an internal standard. ADC and SCC tumors were analyzed, and a signature of proteins including enzymes involved in central carbon metabolism were identified as differentially expressed between engrafting and non-engrafting tumors. These results highlight the significance of metabolic remodeling as a feature that might be a determinant of more aggressive cancer phenotypes. These results support the further development of proteome signatures to diagnose, stratify, and precisely treat NSCLC.

Citation Format: Wen Zhang, Paul Taylor, Lei Li, Yuhong Wei, Jiefei Tong, Vladimir Ignatchenko, Nhu-An Pham, Thomas Kislinger, Ming-sound Tsao, Michael Moran. Proteome signatures distinguish lung cancer subtypes, define metabolism states, and have prognostic impact. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1822. doi:10.1158/1538-7445.AM2015-1822