Identification of Reprogrammed Myeloid Cell Transcriptomes in NSCLC.

TitleIdentification of Reprogrammed Myeloid Cell Transcriptomes in NSCLC.
Publication TypeJournal Article
Year of Publication2015
AuthorsDurrans A, Gao D, Gupta R, Fischer KR, Choi H, Rayes TEl, Ryu S, Nasar A, Spinelli CF, Andrews W, Elemento O, Nolan D, Stiles B, Rafii S, Narula N, Davuluri R, Altorki NK, Mittal V
JournalPLoS One
Date Published2015
KeywordsAnimals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Biomarkers, Tumor, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Chemokine CCL7, Gene Expression Regulation, Neoplastic, Hematopoietic Stem Cells, Humans, Lung, Lung Neoplasms, Mice, Inbred C57BL, Myeloid Cells, Osteopontin, RNA, Messenger, Transcriptome

Lung cancer is the leading cause of cancer related mortality worldwide, with non-small cell lung cancer (NSCLC) as the most prevalent form. Despite advances in treatment options including minimally invasive surgery, CT-guided radiation, novel chemotherapeutic regimens, and targeted therapeutics, prognosis remains dismal. Therefore, further molecular analysis of NSCLC is necessary to identify novel molecular targets that impact prognosis and the design of new-targeted therapies. In recent years, tumor "activated/reprogrammed" stromal cells that promote carcinogenesis have emerged as potential therapeutic targets. However, the contribution of stromal cells to NSCLC is poorly understood. Here, we show increased numbers of bone marrow (BM)-derived hematopoietic cells in the tumor parenchyma of NSCLC patients compared with matched adjacent non-neoplastic lung tissue. By sorting specific cellular fractions from lung cancer patients, we compared the transcriptomes of intratumoral myeloid compartments within the tumor bed with their counterparts within adjacent non-neoplastic tissue from NSCLC patients. The RNA sequencing of specific myeloid compartments (immature monocytic myeloid cells and polymorphonuclear neutrophils) identified differentially regulated genes and mRNA isoforms, which were inconspicuous in whole tumor analysis. Genes encoding secreted factors, including osteopontin (OPN), chemokine (C-C motif) ligand 7 (CCL7) and thrombospondin 1 (TSP1) were identified, which enhanced tumorigenic properties of lung cancer cells indicative of their potential as targets for therapy. This study demonstrates that analysis of homogeneous stromal populations isolated directly from fresh clinical specimens can detect important stromal genes of therapeutic value.

Alternate JournalPLoS ONE
PubMed ID26046767
PubMed Central IDPMC4457876
Grant ListP30 CA010815 / CA / NCI NIH HHS / United States
U01 CA188388 / CA / NCI NIH HHS / United States