{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T13:44:17Z","timestamp":1785937457941,"version":"3.56.0"},"reference-count":53,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T00:00:00Z","timestamp":1785024000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T00:00:00Z","timestamp":1785024000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Anim Models and Exp Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cancer cell lines are widely used in preclinical oncology, yet their fidelity in modeling primary tumors remains uncertain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed a systematic pathway\u2010level transcriptomic comparison of lung adenocarcinoma (LUAD) primary tumors from The Cancer Genome Atlas (TCGA;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009513) and LUAD cell lines from the Cancer Cell Line Encyclopedia (CCLE;\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200945). Single\u2010sample gene set enrichment analysis (ssGSEA) combined with L1\u2010penalized logistic regression was applied to identify a discriminatory pathway signature.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Five Hallmark pathways (E2F targets, interferon\u2010gamma response, epithelial\u2010mesenchymal transition, coagulation, and G2M checkpoint) distinguished primary lung tumors from cell line models. Cell lines exhibited significant enrichment of proliferation\u2010associated pathways, whereas primary tumors retained immune\u2010 and microenvironment\u2010related programs. Tumor\u2013normal comparisons revealed significant pathway alterations in TCGA samples that were not fully recapitulated in CCLE models. Gene\u2010level analyses confirmed depletion of stromal and vascular markers in cell lines. CCLE samples also demonstrated significantly higher tumor mutational burden and increased frequencies of\n                      <jats:italic>TP53<\/jats:italic>\n                      and\n                      <jats:italic>STK11<\/jats:italic>\n                      mutations. These pathway\u2010level distinctions were conserved in lung squamous cell carcinoma, indicating generalizability across major NSCLC subtypes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings define a pathway\u2010based framework for evaluating transcriptional fidelity between cell lines and primary tumors, highlighting fundamental transcriptional divergence with implications for rational model selection in lung cancer research.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ame2.70258","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:02:16Z","timestamp":1785128536000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Systematic pathway\u2010level analysis defines conserved transcriptional divergence between primary lung 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