{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T06:08:21Z","timestamp":1788761301696,"version":"build-2803163510"},"reference-count":88,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Only a subset of epithelial cells can initiate progressive lung adenocarcinoma (LUAD), yet the founder cell states that confer this competence remain poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We established a barcoded\n                      <jats:italic>Kras<\/jats:italic>\n                      <jats:sup>G12D<\/jats:sup>\n                      ,\n                      <jats:italic>Trp53<\/jats:italic>\n                      loss mouse LUAD organoid model that couples 15-nucleotide lineage tracing with single-cell RNA sequencing (scRNA-seq) before and after syngeneic transplantation. Candidate markers for expansion states were further evaluated using wild-type lung organoid, spatial transcriptomics, and independent human scRNA-seq datasets.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Barcoded organoids generated LUAD-like tumors. Paired barcode recovery identified expanded, diminished and failed lineages and showed that expanded lineages were enriched for surfaceome genes associated with stemness. Among candidate surface markers,\n                      <jats:italic>Plxna2<\/jats:italic>\n                      showed the strongest enrichment in baseline organoid cells that expanded after transplantation and marked cells with stronger stemness features. These cells underwent stage-specific reprogramming, with early EMT and inflammatory adaptation followed by late metabolic and MYC programs rebound within an immunosuppressive microenvironment. Wild-type lung organoid analysis showed that\n                      <jats:italic>Plxna2<\/jats:italic>\n                      marks an alveolar remodeling state sharing expansion signature. Spatial transcriptomics placed\n                      <jats:italic>Plxna2<\/jats:italic>\n                      <jats:sup>high<\/jats:sup>\n                      tumor epithelial cells in EMT-rich and stromal-interface niches. Human LUAD scRNA-seq cohorts further showed enrichment of\n                      <jats:italic>PLXNA2<\/jats:italic>\n                      <jats:sup>high<\/jats:sup>\n                      malignant cells within expansion and stemness states.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      These findings identify\n                      <jats:italic>PLXNA2<\/jats:italic>\n                      as a candidate marker of expansion state and provide a lineage-based framework for discovering tumor-initiating programs in LUAD.\n                    <\/jats:p>\n                  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