Lung adenocarcinoma (LUAD) is the main non-small-cell lung cancer diagnosed in ~40–50% of all lung cancer cases. Despite the improvements in early detection and personalized medicine, even a sizable fraction of patients with early-stage LUAD would experience disease relapses and adverse prognosis. Previous reports indicated the existence of LUAD molecular subtypes characterized by specific gene expression and mutational profiles, and correlating with prognosis. However, the biological and molecular features of such subtypes have not been further explored. Consequently, the mechanisms driving the emergence of aggressive LUAD remained unclear. Here, we adopted a multi-tiered approach ranging from molecular to functional characterization of LUAD and used it on multiple cohorts of patients (for a total of 1227 patients) and LUAD cell lines. We investigated the tumor transcriptome and the mutational and immune gene expression profiles, and we used LUAD cell lines for cancer cell phenotypic screening. We found that loss of lung cell lineage and gain of stem cell-like characteristics, along with mutator and immune evasion phenotypes, explain the aggressive behavior of a specific subset of lung adenocarcinoma that we called C1-LUAD, including early-stage disease. This subset can be identified using a 10-gene prognostic signature. Poor prognosis patients appear to have this specific molecular lung adenocarcinoma subtype which is characterized by peculiar molecular and biological features. Our data support the hypothesis that transformed lung stem/progenitor cells and/or reprogrammed epithelial cells with CSC characteristics are hallmarks of this aggressive disease. Such discoveries suggest alternative, more aggressive, therapeutic strategies for early-stage C1-LUAD.
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Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer J Clinicians. 2018;68:394–424.
Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma. J Thorac Oncol. 2011;6:244–85.
Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395–409.
de Koning HJ, van der Aalst CM, de Jong PA, Scholten ET, Nackaerts K, Heuvelmans MA, et al. Reduced lung-cancer mortality with volume CT screening in a randomized trial. N Engl J Med. 2020;382:503–13.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.
Pribluda A, de la Cruz CC, Jackson EL. Intratumoral heterogeneity: from diversity comes resistance. Clin Cancer Res. 2015;21:2916–23.
Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543–50.
Zhang J, Fujimoto J, Wedge DC, Song X, Seth S, Chow CW, et al. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science. 2014;346:256–9.
Alexandrov LB, Kim J, Haradhvala NJ, Huang MN, PCAWG Mutational Signatures Working Group, PCAWG Consortium, et al. The repertoire of mutational signatures in human cancer. Nature. 2020;578:94–101.
de Bruin EC, McGranahan N, Mitter R, Salm M, Wedge DC, Yates L, et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science. 2014;346:251–6.
Chen F, Zhang Y, Parra E, Rodriguez J, Behrens C, Akbani R, et al. Multiplatform-based molecular subtypes of non-small-cell lung cancer. Oncogene. 2017;36:1384–93.
Devarakonda S, Morgensztern D, Govindan R. Genomic alterations in lung adenocarcinoma. Lancet Oncol. 2015;16:e342–51.
Yatabe Y, Mitsudomi T, Takahashi T. TTF-1 expression in pulmonary adenocarcinomas. Am J Surg Pathol. 2002;26:767–73.
Ferone G, Song J-Y, Sutherland KD, Bhaskaran R, Monkhorst K, Lambooij J-P, et al. SOX2 is the determining oncogenic switch in promoting lung squamous cell carcinoma from different cells of origin. Cancer Cell. 2016;30:519–32.
Dama E, Melocchi V, Dezi F, Pirroni S, Carletti RM, Brambilla D, et al. An aggressive subtype of stage I lung adenocarcinoma with molecular and prognostic characteristics typical of advanced lung cancers. Clin Cancer Res: Off J Am Assoc Cancer Res. 2017;23:62–72.
Bianchi F, Nuciforo P, Vecchi M, Bernard L, Tizzoni L, Marchetti A, et al. Survival prediction of stage I lung adenocarcinomas by expression of 10 genes. J Clin Invest. 2007;117:3436–44.
Takeuchi T, Tomida S, Yatabe Y, Kosaka T, Osada H, Yanagisawa K, et al. Expression profile–defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors. JCO. 2006;24:1679–88.
Bryant CM, Albertus DL, Kim S, Chen G, Brambilla C, Guedj M, et al. Clinically relevant characterization of lung adenocarcinoma subtypes based on cellular pathways: an international validation study. PLoS ONE. 2010;5:e11712.
Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, et al. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci USA. 2001;98:13790–5.
Beer DG, Kardia SLR, Huang C-C, Giordano TJ, Levin AM, Misek DE, et al. Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med. 2002;8:816–24.
Nazarov PV, Muller A, Kaoma T, Nicot N, Maximo C, Birembaut P, et al. RNA sequencing and transcriptome arrays analyses show opposing results for alternative splicing in patient derived samples. BMC Genomics. 2017;18:443.
Cheung WKC, Nguyen DX. Lineage factors and differentiation states in lung cancer progression. Oncogene. 2015;34:5771–80.
Moisés J, Navarro A, Santasusagna S, Viñolas N, Molins L, Ramirez J, et al. NKX2–1 expression as a prognostic marker in early-stage non-small-cell lung cancer. BMC Pulm Med. 2017;17:197.
Tata PR, Chow RD, Saladi SV, Tata A, Konkimalla A, Bara A, et al. Developmental history provides a roadmap for the emergence of tumor plasticity. Developmental Cell. 2018;44:679–93.
Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y. Molecular principles of metastasis: a hallmark of cancer revisited. Sig Transduct Target Ther. 2020;5:28.
Sonzogni A, Bianchi F, Fabbri A, Cossa M, Rossi G, Cavazza A, et al. Pulmonary adenocarcinoma with mucin production modulates phenotype according to common genetic traits: a reappraisal of mucinous adenocarcinoma and colloid adenocarcinoma: Reappraising mucinous and colloid adenocarcinoma of the lung. J Path: Clin Res. 2017;3:139–51.
Tammela T, Sanchez-Rivera FJ, Cetinbas NM, Wu K, Joshi NS, Helenius K, et al. A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma. Nature. 2017;545:355–9.
Marjanovic ND, Hofree M, Chan JE, Canner D, Wu K, Trakala M, et al. Emergence of a high-plasticity cell state during lung cancer evolution. Cancer Cell. 2020;38:229–46.
Ghandi M, Huang FW, Jané-Valbuena J, Kryukov GV, Lo CC, McDonald ER, et al. Next-generation characterization of the cancer cell line encyclopedia. Nature. 2019;569:503–8.
Dontu G. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 2003;17:1253–70.
Lu H, Clauser KR, Tam WL, Frose J, Ye X, Eaton EN, et al. A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol. 2014;16:1105–17.
Yan X, Luo H, Zhou X, Zhu B, Wang Y, Bian X. Identification of CD90 as a marker for lung cancer stem cells in A549 and H446 cell lines. Oncol Rep. 2013;30:2733–40.
Tokheim C, Karchin R. CHASMplus reveals the scope of somatic missense mutations driving human cancers. Cell Syst. 2019;9:9–23.
Tate JG, Bamford S, Jubb HC, Sondka Z, Beare DM, Bindal N, et al. COSMIC: the catalogue of somatic mutations in cancer. Nucleic Acids Res. 2019;47:D941–7.
Swanton C, McGranahan N, Starrett GJ, Harris RS. APOBEC enzymes: mutagenic fuel for cancer evolution and heterogeneity. Cancer Discov. 2015;5:704–12.
Bremnes RM, Busund L-T, Kilvær TL, Andersen S, Richardsen E, Paulsen EE, et al. The role of tumor-infiltrating lymphocytes in development, progression, and prognosis of non–small cell lung cancer. J Thorac Oncol. 2016;11:789–800.
Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang T-H, et al. The immune landscape of cancer. Immunity. 2018;48:812–30.
Alvisi G, Brummelman J, Puccio S, Mazza EMC, Tomada EP, Losurdo A, et al. IRF4 instructs effector Treg differentiation and immune suppression in human cancer. J Clin Investig. 2020;130:3137–50.
Yu H, Boyle TA, Zhou C, Rimm DL, Hirsch FR. PD-L1 expression in lung cancer. J Thorac Oncol. 2016;11:964–75.
Monterisi S, Lo Riso P, Russo K, Bertalot G, Vecchi M, Testa G, et al. HOXB7 overexpression in lung cancer is a hallmark of acquired stem-like phenotype. Oncogene. 2018;37:3575–88.
Care A, Valtieri M, Mattia G, Meccia E, Masella B, Luchetti L, et al. Enforced expression of HOXB7 promotes hematopoietic stem cell proliferation and myeloid-restricted progenitor differentiation. Oncogene. 1999;18:1993–2001.
Dolatshad H, Pellagatti A, Fernandez-Mercado M, Yip BH, Malcovati L, Attwood M, et al. Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells. Leukemia. 2015;29:1092–103.
Tian C, Öhlund D, Rickelt S, Lidström T, Huang Y, Hao L, et al. Cancer cell–derived matrisome proteins promote metastasis in pancreatic ductal adenocarcinoma. Cancer Res. 2020;80:1461–74.
Han B, Zhang Y-Y, Xu K, Bai Y, Wan L-H, Miao S-K, et al. NUDCD1 promotes metastasis through inducing EMT and inhibiting apoptosis in colorectal cancer. Am J Cancer Res. 2018;8:810–23.
Grindel BJ, Martinez JR, Tellman TV, Harrington DA, Zafar H, Nakhleh L, et al. Matrilysin/MMP-7 cleavage of perlecan/HSPG2 complexed with semaphorin 3A supports FAK-mediated stromal invasion by prostate cancer cells. Sci Rep. 2018;8:7262.
McCauley KB, Alysandratos K-D, Jacob A, Hawkins F, Caballero IS, Vedaie M, et al. Single-cell transcriptomic profiling of pluripotent stem cell-derived SCGB3A2+ airway epithelium. Stem Cell Rep. 2018;10:1579–95.
Naizhen X, Kido T, Yokoyama S, Linnoila RI, Kimura S. Spatiotemporal expression of three secretoglobin proteins, SCGB1A1, SCGB3A1, and SCGB3A2, in mouse airway epithelia. J Histochem Cytochem. 2019;67:453–63.
Reynolds SD, Reynolds PR, Pryhuber GS, Finder JD, Stripp BR. Secretoglobins SCGB3A1 and SCGB3A2 define secretory cell subsets in mouse and human airways. Am J Respir Crit Care Med. 2002;166:1498–509.
Kumar PA, Hu Y, Yamamoto Y, Hoe NB, Wei TS, Mu D, et al. Distal airway stem cells yield alveoli in vitro and during lung regeneration following H1N1 influenza infection. Cell. 2011;147:525–38.
Zuo W, Zhang T, Wu DZ, Guan SP, Liew A-A, Yamamoto Y, et al. p63+Krt5+ distal airway stem cells are essential for lung regeneration. Nature. 2015;517:616–20.
Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, et al. Tracking the evolution of non–small-cell lung cancer. N Engl J Med. 2017;376:2109–21.
Wolf J, Seto T, Han J-Y, Reguart N, Garon EB, Groen HJM, et al. Capmatinib in MET Exon 14–mutated or MET-amplified non-small-cell lung cancer. N Engl J Med. 2020;383:944–57.
Orkin SH, Hochedlinger K. Chromatin connections to pluripotency and cellular reprogramming. Cell. 2011;145:835–50.
Schoenfeld AJ, Bandlamudi C, Lavery JA, Montecalvo J, Namakydoust A, Rizvi H, et al. The genomic landscape of SMARCA4 alterations and associations with outcomes in patients with lung cancer. Clin Cancer Res. 2020;26:5701–8.
Prasetyanti PR, Medema JP. Intra-tumor heterogeneity from a cancer stem cell perspective. Mol Cancer. 2017;16:41.
Miranda A, Hamilton PT, Zhang AW, Pattnaik S, Becht E, Mezheyeuski A, et al. Cancer stemness, intratumoral heterogeneity, and immune response across cancers. Proc Natl Acad Sci USA. 2019;116:9020–9.
Burkholder B, Huang R-Y, Burgess R, Luo S, Jones VS, Zhang W, et al. Tumor-induced perturbations of cytokines and immune cell networks. Biochim Biophys Acta. 2014;1845:182–201.
Richards CH, Mohammed Z, Qayyum T, Horgan PG, McMillan DC. The prognostic value of histological tumor necrosis in solid organ malignant disease: a systematic review. Future Oncol. 2011;7:1223–35.
Jaillon S, Ponzetta A, Di Mitri D, Santoni A, Bonecchi R, Mantovani A. Neutrophil diversity and plasticity in tumour progression and therapy. Nat Rev Cancer. 2020;20:485–503.
Stämpfli MR, Anderson GP. How cigarette smoke skews immune responses to promote infection, lung disease and cancer. Nat Rev Immunol. 2009;9:377–84.
Schabath MB, Welsh EA, Fulp WJ, Chen L, Teer JK, Thompson ZJ, et al. Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma. Oncogene. 2016;35:3209–16.
Okayama H, Kohno T, Ishii Y, Shimada Y, Shiraishi K, Iwakawa R, et al. Identification of genes upregulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas. Cancer Res. 2012;72:100–11.
We are grateful to Teresa Nittoli for technical assistance and Chiara Di Giorgio for critically editing the manuscript. This study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the Fondazione IRCCS Casa Sollievo della Sofferenza (ref. number: BIO-POLMONE – V1.0_08 Giu 16). All authors gave their consent to publication. The gene expression data used in this study are publicly available as indicated in the “Methods” and Supplementary Information sections. This work was supported by the Associazione Italiana Ricerca sul Cancro [MFAG-17568 and IG-22827 to FB; IG-20676 to EL], the Italian Ministry of Health [GR-2016-02363975 and CLEARLY to FB]. RC was supported by a fellowship from the Umberto Veronesi Foundation and the Pezcoller Foundation. TC was supported by a fellowship from the Associazione Italiana Ricerca sul Cancro (#19548) and the Umberto Veronesi Foundation.
FB has a patent US8747867B2 issued, and a patent WO2008125791A1 issued which is related to the use of the 10-gene signature described in this paper. The study funders had no role in the design of the study, the collection, analysis, and interpretation of the data, the writing of the manuscript, and the decision to submit the manuscript for publication. Other authors declare no conflict of interest.
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Melocchi, V., Dama, E., Mazzarelli, F. et al. Aggressive early-stage lung adenocarcinoma is characterized by epithelial cell plasticity with acquirement of stem-like traits and immune evasion phenotype. Oncogene 40, 4980–4991 (2021). https://doi.org/10.1038/s41388-021-01909-z