title: Identification of Reprogrammed Myeloid Cell Transcriptomes in NSCLC.
abstract: 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.
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America.
authors.forename: Anna
authors.initials: A
authors.lastname: Durrans
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America.
authors.forename: Dingcheng
authors.initials: D
authors.lastname: Gao
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, 3601 Spruce St, Philadelphia, PA 19104, United States of America.
authors.forename: Ravi
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America.
authors.forename: Kari R
authors.initials: KR
authors.lastname: Fischer
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America.
authors.forename: Tina
authors.initials: T
authors.lastname: El Rayes
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America.
authors.forename: Seongho
authors.initials: S
authors.lastname: Ryu
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America.
authors.forename: Abu
authors.initials: A
authors.lastname: Nasar
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America.
authors.forename: Cathy F
authors.initials: CF
authors.lastname: Spinelli
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America.
authors.forename: Weston
authors.initials: W
authors.lastname: Andrews
authors.affiliation: Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: HHMI, Department of Genetic Medicine, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nolan
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America.
authors.forename: Brendon
authors.initials: B
authors.lastname: Stiles
authors.affiliation: HHMI, Department of Genetic Medicine, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America.
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.affiliation: Department of Pathology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America.
authors.forename: Navneet
authors.initials: N
authors.lastname: Narula
authors.affiliation: Molecular and Cellular Oncogenesis Program, The Wistar Institute, 3601 Spruce St, Philadelphia, PA 19104, United States of America.
authors.forename: Ramana
authors.initials: R
authors.lastname: Davuluri
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America.
authors.forename: Nasser K
authors.initials: NK
authors.lastname: Altorki
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America; Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, United States of America.
authors.forename: Vivek
authors.initials: V
authors.lastname: Mittal
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D054410:Chemokine CCL7 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D053495:Osteopontin / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D059467:Transcriptome
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D014408:Biomarkers, Tumor; D054410:Chemokine CCL7; D012333:RNA, Messenger; C481348:SPZ1 protein, human; D053495:Osteopontin