PMID- 28652369 OWN - NLM STAT- MEDLINE DCOM- 20180613 LR - 20240326 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 114 IP - 28 DP - 2017 Jul 11 TI - Quantitative proteomics identify Tenascin-C as a promoter of lung cancer progression and contributor to a signature prognostic of patient survival. PG - E5625-E5634 LID - 10.1073/pnas.1707054114 [doi] AB - The extracellular microenvironment is an integral component of normal and diseased tissues that is poorly understood owing to its complexity. To investigate the contribution of the microenvironment to lung fibrosis and adenocarcinoma progression, two pathologies characterized by excessive stromal expansion, we used mouse models to characterize the extracellular matrix (ECM) composition of normal lung, fibrotic lung, lung tumors, and metastases. Using quantitative proteomics, we identified and assayed the abundance of 113 ECM proteins, which revealed robust ECM protein signatures unique to fibrosis, primary tumors, or metastases. These analyses indicated significantly increased abundance of several S100 proteins, including Fibronectin and Tenascin-C (Tnc), in primary lung tumors and associated lymph node metastases compared with normal tissue. We further showed that Tnc expression is repressed by the transcription factor Nkx2-1, a well-established suppressor of metastatic progression. We found that increasing the levels of Tnc, via CRISPR-mediated transcriptional activation of the endogenous gene, enhanced the metastatic dissemination of lung adenocarcinoma cells. Interrogation of human cancer gene expression data revealed that high TNC expression correlates with worse prognosis for lung adenocarcinoma, and that a three-gene expression signature comprising TNC, S100A10, and S100A11 is a robust predictor of patient survival independent of age, sex, smoking history, and mutational load. Our findings suggest that the poorly understood ECM composition of the fibrotic and tumor microenvironment is an underexplored source of diagnostic markers and potential therapeutic targets for cancer patients. FAU - Gocheva, Vasilena AU - Gocheva V AD - David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139. FAU - Naba, Alexandra AU - Naba A AD - David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; anaba@uic.edu tjacks@mit.edu. AD - Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139. FAU - Bhutkar, Arjun AU - Bhutkar A AD - David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139. FAU - Guardia, Talia AU - Guardia T AD - David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139. FAU - Miller, Kathryn M AU - Miller KM AD - David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139. FAU - Li, Carman Man-Chung AU - Li CM AD - David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139. FAU - Dayton, Talya L AU - Dayton TL AD - David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139. FAU - Sanchez-Rivera, Francisco J AU - Sanchez-Rivera FJ AD - David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139. FAU - Kim-Kiselak, Caroline AU - Kim-Kiselak C AD - David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139. FAU - Jailkhani, Noor AU - Jailkhani N AD - David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139. FAU - Winslow, Monte M AU - Winslow MM AD - David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139. FAU - Del Rosario, Amanda AU - Del Rosario A AD - David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139. FAU - Hynes, Richard O AU - Hynes RO AD - David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139. FAU - Jacks, Tyler AU - Jacks T AD - David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; anaba@uic.edu tjacks@mit.edu. AD - Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139. AD - Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139. LA - eng GR - P30 CA014051/CA/NCI NIH HHS/United States GR - U54 CA126515/CA/NCI NIH HHS/United States GR - U54 CA163109/CA/NCI NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20170626 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Annexin A2) RN - 0 (NKX2-1 protein, human) RN - 0 (S100 Proteins) RN - 0 (S100 calcium binding protein A10) RN - 0 (Tenascin) RN - 0 (Thyroid Nuclear Factor 1) RN - 146909-89-9 (S100A11 protein, human) SB - IM CIN - J Thorac Dis. 2017 Nov;9(11):4300-4304. PMID: 29268496 MH - Adenocarcinoma/metabolism MH - Animals MH - Annexin A2/metabolism MH - CRISPR-Cas Systems MH - Disease Progression MH - Extracellular Matrix/metabolism MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Lung Neoplasms/genetics/*metabolism/*mortality MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Multivariate Analysis MH - Neoplasm Metastasis MH - Prognosis MH - Proteomics/*methods MH - S100 Proteins/metabolism MH - Tenascin/*physiology MH - Thyroid Nuclear Factor 1/metabolism MH - Treatment Outcome MH - Tumor Microenvironment PMC - PMC5514763 OTO - NOTNLM OT - Tenascin-C OT - extracellular matrix OT - lung cancer OT - quantitative proteomics OT - tumor microenvironment COIS- The authors declare no conflict of interest. EDAT- 2017/06/28 06:00 MHDA- 2018/06/14 06:00 PMCR- 2018/01/11 CRDT- 2017/06/28 06:00 PHST- 2017/06/28 06:00 [pubmed] PHST- 2018/06/14 06:00 [medline] PHST- 2017/06/28 06:00 [entrez] PHST- 2018/01/11 00:00 [pmc-release] AID - 1707054114 [pii] AID - 201707054 [pii] AID - 10.1073/pnas.1707054114 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2017 Jul 11;114(28):E5625-E5634. doi: 10.1073/pnas.1707054114. Epub 2017 Jun 26.