A Patient-Derived, Pan-Cancer EMT Signature Identifies Global Molecular Alterations and Immune Target Enrichment Following Epithelial-to-Mesenchymal Transition
Carregando...
Citações na Scopus
345
Tipo de produção
article
Data de publicação
2016
Título da Revista
ISSN da Revista
Título do Volume
Editora
AMER ASSOC CANCER RESEARCH
Autores
TONG, Pan
DIAO, Lixia
CARDNELL, Robert J.
GIBBONS, Don L.
WILLIAM, William N.
SKOULIDIS, Ferdinandos
PARRA, Edwin R.
RODRIGUEZ-CANALES, Jaime
WISTUBA, Ignacio I.
Citação
CLINICAL CANCER RESEARCH, v.22, n.3, p.609-620, 2016
Resumo
Purpose: We previously demonstrated the association between epithelial-to-mesenchymal transition (EMT) and drug response in lung cancer using an EMT signature derived in cancer cell lines. Given the contribution of tumor microenvironments to EMT, we extended our investigation of EMT to patient tumors from 11 cancer types to develop a pan-cancer EMT signature. Experimental Design: Using the pan-cancer EMT signature, we conducted an integrated, global analysis of genomic and proteomic profiles associated with EMT across 1,934 tumors including breast, lung, colon, ovarian, and bladder cancers. Differences in outcome and in vitro drug response corresponding to expression of the pan-cancer EMT signature were also investigated. Results: Compared with the lung cancer EMT signature, the patient-derived, pan-cancer EMT signature encompasses a set of core EMT genes that correlate even more strongly with known EMT markers across diverse tumor types and identifies differences in drug sensitivity and global molecular alterations at the DNA, RNA, and protein levels. Among those changes associated with EMT, pathway analysis revealed a strong correlation between EMT and immune activation. Further supervised analysis demonstrated high expression of immune checkpoints and other druggable immune targets, such as PD1, PD-L1, CTLA4, OX40L, and PD-L2, in tumors with the most mesenchymal EMT scores. Elevated PD-L1 protein expression in mesenchymal tumors was confirmed by IHC in an independent lung cancer cohort. Conclusions: This new signature provides a novel, patient-based, histology-independent tool for the investigation of EMT and offers insights into potential novel therapeutic targets for mesenchymal tumors, independent of cancer type, including immune checkpoints. (C)2015 AACR.
Palavras-chave
Referências
- Akbani R, 2014, NAT COMMUN, V5, DOI 10.1038/ncomms4887
- Sternberg CN, 2010, J CLIN ONCOL, V28, P1061, DOI 10.1200/JCO.2009.23.9764
- Robert C, 2011, NEW ENGL J MED, V364, P2517, DOI 10.1056/NEJMoa1104621
- Hoadley KA, 2014, CELL, V158, P929, DOI 10.1016/j.cell.2014.06.049
- Hodi FS, 2010, NEW ENGL J MED, V363, P711, DOI 10.1056/NEJMoa1003466
- Singh A, 2010, ONCOGENE, V29, P4741, DOI 10.1038/onc.2010.215
- Gregory PA, 2008, NAT CELL BIOL, V10, P593, DOI 10.1038/ncb1722
- van der Graaf WTA, 2012, LANCET, V379, P1879, DOI 10.1016/S0140-6736(12)60651-5
- Barretina J, 2012, NATURE, V483, P603, DOI 10.1038/nature11003
- Gu S, 2012, INT J MOL SCI, V13, P8449, DOI 10.3390/ijms13078449
- Brunner AM, 2013, J THORAC ONCOL, V8, P1434, DOI 10.1097/JTO.0b013e3182a47162
- Schliekelman MJ, 2011, CANCER RES, V71, P7670, DOI 10.1158/0008-5472.CAN-11-0964
- Byers LA, 2013, CLIN CANCER RES, V19, P279, DOI 10.1158/1078-0432.CCR-12-1558
- Redmond WL, 2014, CANCER IMMUNOL RES, V2, P142, DOI 10.1158/2326-6066.CIR-13-0031-T
- Ciriello G, 2013, NAT GENET, V45, P1127, DOI 10.1038/ng.2762
- Gettinger SN, 2015, J CLIN ONCOL, V33, P2004, DOI 10.1200/JCO.2014.58.3708
- Yang WJ, 2013, NUCLEIC ACIDS RES, V41, pD955, DOI 10.1093/nar/gks1111
- Zhang ZF, 2012, NAT GENET, V44, P852, DOI 10.1038/ng.2330
- Lewis NL, 2009, J CLIN ONCOL, V27, P5262, DOI 10.1200/JCO.2009.21.8487
- Yang J, 2004, CELL, V117, P927, DOI 10.1016/j.cell.2004.06.006
- Alonso SR, 2007, CANCER RES, V67, P3450, DOI 10.1158/0008-5472.CAN-06-3481
- Loboda A, 2011, BMC MED GENOMICS, V4, DOI 10.1186/1755-8794-4-9
- Pencheva N, 2012, CELL, V151, P1068, DOI 10.1016/j.cell.2012.10.028
- Sheridan C, 2013, NAT BIOTECHNOL, V31, P775, DOI 10.1038/nbt0913-775a
- Dweep H, 2011, J BIOMED INFORM, V44, P839, DOI 10.1016/j.jbi.2011.05.002
- Chung CH, 2006, CANCER RES, V66, P8210, DOI 10.1158/0008-5472.CAN-06-1213
- Hamid O, 2013, NEW ENGL J MED, V369, P134, DOI 10.1056/NEJMoa1305133
- Brahmer J, 2015, NEW ENGL J MED, V373, P123, DOI 10.1056/NEJMoa1504627
- Wei CW, 2014, P NATL ACAD SCI USA, V111, pE601, DOI 10.1073/pnas.1316255111
- De Craene B, 2013, NAT REV CANCER, V13, P97, DOI 10.1038/nrc3447
- Chen LM, 2014, NAT COMMUN, V5, DOI 10.1038/ncomms6241
- Guo ZQ, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0089350
- Cardenas CLL, 2013, PLOS GENET, V9, DOI 10.1371/journal.pgen.1003291
- Tan TZ, 2014, EMBO MOL MED, V6, P1279, DOI 10.15252/emmm.201404208