Abstract 1597: Transcriptomic architecture of the field of cancerization in the adjacent normal-appearing airway: Early mechanisms in lung carcinogenesis
Authors: Maki Yuho , Fujimoto Junya , Yoo Suk-Young , Garcia Melinda , Gower Adam , Shen Li , Chow Chi-Wan , Behrens Carmen , Kalhor Neda , Moran Cesar , Wang Jing , Spira Avrum , Coombes Kevin R. , Wistuba Ignacio I. , Kadara Humam 
Published: May 2015

Abstract
Increasing our understanding of early events in the pathogenesis of lung cancer is crucial for identification of new targets for prevention and treatment of this malignancy. Earlier work has shown that seemingly normal cells adjacent to the tumor carry specific molecular alterations that are characteristic of the tumor itself suggestive of a field of cancerization. By sampling and studying normal-appearing tissue, the molecular field of cancerization provides biological insights into early phases in cancer development. In this study, we sought to characterize molecular field effects in the normal-appearing airway that are most representative of the nearby lung tumor, and thus, are most likely to denote early events in lung carcinogenesis. To achieve this, we performed genome-wide expression profiling of resected field cancerization specimens (n=20 patients) comprised of matched early-stage non-small cell lung cancers (NSCLCs), cytologically normal airways with varying spatial distance from the tumors and distant (relative to location of tumors) normal lung tissues (n=194 samples). Using ordinal logistic regression, we identified 422 genes that were progressively modulated in expression in normal-appearing airways by spatial distance from tumors. Notably, when examined in paired NSCLC and normal lung tissues, these genes were found to recapitulate tumor expression profiles. We then sought to examine the role of lysosomal protein transmembrane 4 beta (LAPTM4B), a putative oncogene that was found to be up-regulated in airways by shorter spatial distance from tumors, in lung oncogenesis. LAPTM4B was significantly elevated in NSCLC tissues compared to paired distant normal lung and was predictive of poor survival in lung adenocarcinoma. Moreover, LAPTM4B promoted anchorage-dependent and -independent lung cancer cell growth and was crucial for cellular survival and the autophagy response under nutrient- and serum-deprived conditions. In addition, pathways analysis of a LAPTM4B-dependent gene expression profile revealed decreased activation of the canonical nuclear factor erythroid 2-like 2 (NRF2)-mediated pathway following LAPTM4B knockdown. Further, we found that LAPTM4B augmented the expression and nuclear translocation of the NRF2 transcription factor following serum deprivation pointing to the probable role of the novel LAPTM4B/NRF2 signaling axis in promoting lung cancer cell survival. All in all, our study points to molecular field of cancerization profiles in the normal-appearing airway that highly signify the nearby lung tumor and comprise early mechanisms (e.g. LAPTM4B) in lung carcinogenesis.
Citation Format: Yuho Maki, Junya Fujimoto, Suk-Young Yoo, Melinda Garcia, Adam Gower, Li Shen, Chi-Wan Chow, Carmen Behrens, Neda Kalhor, Cesar Moran, Jing Wang, Avrum Spira, Kevin R. Coombes, Ignacio I. Wistuba, Humam Kadara. Transcriptomic architecture of the field of cancerization in the adjacent normal-appearing airway: Early mechanisms in lung carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1597. doi:10.1158/1538-7445.AM2014-1597