{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:29:54Z","timestamp":1786116594139,"version":"build-2736575974"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"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. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid progression, early metastasis, frequent relapse, and treatment resistance. Although chemoimmunotherapy has improved outcomes in a subset of patients, reliable molecular stratification tools reflecting tumor heterogeneity and survival risk remain limited. Chaperone-mediated autophagy (CMA) is involved in proteostasis, metabolic adaptation, and stress responses, but its cellular heterogeneity and prognostic relevance in SCLC remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This study integrated single-cell RNA sequencing data, bulk transcriptomic cohorts, and clinical information to characterize CMA-related heterogeneity in SCLC. At the single-cell level, SCLC subtypes were annotated, CMA scores were calculated, and differences among baseline, sensitive, and resistant states were evaluated. At the bulk level, tumor versus normal differential expression analysis and weighted gene co-expression network analysis were performed to identify CMA-related candidate genes. A CMA-related Risk Score was constructed through comprehensive machine learning comparison and evaluated using survival analysis, time-dependent receiver operating characteristic curves, Cox regression, nomogram analysis, functional enrichment, immune microenvironment analysis, and drug sensitivity prediction. ARRDC3 was further validated by\n                      <jats:italic>in vitro<\/jats:italic>\n                      experiments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Single-cell analysis revealed marked SCLC subtype heterogeneity and nonuniform CMA activity across cellular subtypes. Significant CMA score differences between sensitive and resistant cells were observed in the SCLC-A_NR0B1\/MYCL+ and SCLC_Hypoxia_glycolytic subtypes. Integration of CMA-related co-expression modules with tumor-associated differentially expressed genes identified 53 candidate genes. The machine learning-derived Risk Score effectively stratified patients into high-risk and low-risk groups across the combined cohort, GSE60052 cohort, and cBioPortal cohort, with high-risk patients showing significantly poorer overall survival. The Risk Score remained an independent prognostic factor and was associated with proliferative, cell-cycle, metabolic, immune, and drug sensitivity-related features.\n                      <jats:italic>In vitro<\/jats:italic>\n                      experiments showed that ARRDC3 overexpression suppressed proliferation, colony formation, migration, and invasion in H446 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study revealed CMA-related cellular heterogeneity in SCLC and established a robust prognostic Risk Score associated with survival, biological pathway activity, immune microenvironment features, and potential therapeutic responses. Functional validation of ARRDC3 further supports the biological relevance of this model, providing new insights into SCLC molecular risk stratification and CMA-associated resistance states.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1894699","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:45:54Z","timestamp":1784267154000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["CMA-associated cellular state remodeling defines prognostic heterogeneity and identifies ARRDC3 as a protective functional gene in small cell lung cancer"],"prefix":"10.3389","volume":"14","author":[{"given":"Jiahong","family":"Han","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery, Shenyang Fifth People\u2019s Hospital","place":["Shenyang, China"]},{"name":"Department of Thoracic Surgery, The First Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The First Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfeng","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The First Hospital of China Medical University","place":["Shenyang, China"]},{"name":"Department of Thoracic Surgery, Yantai Yuhuangding Hospital","place":["Yantai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3350","DOI":"10.1074\/jbc.RA117.001516","article-title":"The \u03b1-arrestin ARRDC3 suppresses breast carcinoma invasion by regulating G protein-coupled receptor lysosomal sorting and signaling","volume":"293","author":"Arakaki","year":"2018","journal-title":"J. Biol. Chem."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2482","DOI":"10.1158\/1078-0432.CCR-17-3070","article-title":"Oxidative phosphorylation as an emerging target in cancer therapy","volume":"24","author":"Ashton","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.1016\/j.jtho.2020.09.009","article-title":"SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: a comprehensive immunohistochemical and histopathologic characterization","volume":"15","author":"Baine","year":"2020","journal-title":"J. Thorac. Oncol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.lungcan.2022.11.014","article-title":"Challenges in the treatment of small cell lung cancer in the era of immunotherapy and molecular classification","volume":"175","author":"Caliman","year":"2023","journal-title":"Lung Cancer"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1479","DOI":"10.1016\/j.ccell.2021.09.008","article-title":"Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer","volume":"39","author":"Chan","year":"2021","journal-title":"Cancer Cell"},{"key":"B6","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1038\/s41392-023-01570-w","article-title":"Endoplasmic reticulum stress: molecular mechanism and therapeutic targets","volume":"8","author":"Chen","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"B7","doi-asserted-by":"publisher","first-page":"102606","DOI":"10.1016\/j.ctrv.2023.102606","article-title":"Shaping the tumor immune microenvironment of SCLC: mechanisms, and opportunities for immunotherapy","volume":"120","author":"Chen","year":"2023","journal-title":"Cancer Treat. Rev."},{"key":"B8","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1126\/science.273.5274.501","article-title":"A receptor for the selective uptake and degradation of proteins by lysosomes","volume":"273","author":"Cuervo","year":"1996","journal-title":"Science"},{"key":"B9","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/0968-0004(90)90019-8","article-title":"Peptide sequences that target cytosolic proteins for lysosomal proteolysis","volume":"15","author":"Dice","year":"1990","journal-title":"Trends Biochem. Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"5032","DOI":"10.1038\/onc.2010.250","article-title":"ARRDC3 suppresses breast cancer progression by negatively regulating integrin beta4","volume":"29","author":"Draheim","year":"2010","journal-title":"Oncogene"},{"key":"B11","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1186\/s40001-023-01300-6","article-title":"Combining bulk and single-cell RNA-Sequencing data to develop an NK cell-related prognostic signature for hepatocellular carcinoma based on an integrated machine learning framework","volume":"28","author":"Feng","year":"2023","journal-title":"Eur. J. Med. Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.6004\/jnccn.2021.0058","article-title":"Small cell lung cancer, version 2.2022, NCCN Clinical Practice Guidelines in oncology","volume":"19","author":"Ganti","year":"2021","journal-title":"J. Natl. Compr. Canc Netw."},{"key":"B13","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1016\/j.ccell.2020.12.014","article-title":"Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities","volume":"39","author":"Gay","year":"2021","journal-title":"Cancer Cell"},{"key":"B14","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1038\/nrc.2017.106","article-title":"Small-cell lung cancer: what we know, what we need to know and the path forward","volume":"17","author":"Gazdar","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"B15","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/nature14664","article-title":"Comprehensive genomic profiles of small cell lung cancer","volume":"524","author":"George","year":"2015","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","first-page":"2220","DOI":"10.1056\/nejmoa1809064","article-title":"First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer","volume":"379","author":"Horn","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s41232-021-00180-9","article-title":"Role of chaperone-mediated autophagy in the pathophysiology including pulmonary disorders","volume":"41","author":"Hosaka","year":"2021","journal-title":"Inflamm. Regen."},{"key":"B18","doi-asserted-by":"publisher","first-page":"4154","DOI":"10.1111\/cas.14629","article-title":"Chaperone-mediated autophagy receptor modulates tumor growth and chemoresistance in non-small cell lung cancer","volume":"111","author":"Ichikawa","year":"2020","journal-title":"Cancer Sci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.ccell.2020.05.001","article-title":"MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate","volume":"38","author":"Ireland","year":"2020","journal-title":"Cancer Cell"},{"key":"B20","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1093\/biostatistics\/kxj037","article-title":"Adjusting batch effects in microarray expression data using empirical Bayes methods","volume":"8","author":"Johnson","year":"2007","journal-title":"Biostatistics"},{"key":"B21","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1038\/s41580-018-0001-6","article-title":"The coming of age of chaperone-mediated autophagy","volume":"19","author":"Kaushik","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1038\/s43587-024-00799-6","article-title":"Sex-specific and cell-type-specific changes in chaperone-mediated autophagy across tissues during aging","volume":"5","author":"Khawaja","year":"2025","journal-title":"Nat. Aging"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","article-title":"Fast, sensitive and accurate integration of single-cell data with Harmony","volume":"16","author":"Korsunsky","year":"2019","journal-title":"Nat. Methods"},{"key":"B24","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.ejca.2021.03.005","article-title":"Applications of single-cell and bulk RNA sequencing in onco-immunology","volume":"149","author":"Kuksin","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"B25","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinforma."},{"key":"B26","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1200\/jco.20.01055","article-title":"Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133)","volume":"39","author":"Liu","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2050","DOI":"10.3390\/biomedicines11072050","article-title":"The complex role of chaperone-mediated autophagy in cancer diseases","volume":"11","author":"Liu","year":"2023","journal-title":"Biomedicines"},{"key":"B28","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1002\/path.5922","article-title":"Expression patterns and prognostic relevance of subtype-specific transcription factors in surgically resected small-cell lung cancer: an international multicenter study","volume":"257","author":"Megyesfalvi","year":"2022","journal-title":"J. Pathol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.ccell.2016.12.005","article-title":"MYC drives progression of small cell lung cancer to a variant neuroendocrine subtype with vulnerability to Aurora kinase inhibition","volume":"31","author":"Mollaoglu","year":"2017","journal-title":"Cancer Cell"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1929","DOI":"10.1016\/s0140-6736(19)32222-6","article-title":"Durvalumab plus platinum\u2013etoposide versus platinum\u2013etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial","volume":"394","author":"Paz-Ares","year":"2019","journal-title":"Lancet"},{"key":"B31","doi-asserted-by":"publisher","first-page":"12081","DOI":"10.3390\/ijms262412081","article-title":"Machine learning models for cancer research: a narrative review of bulk RNA-seq applications","volume":"26","author":"Pudova","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"779276","DOI":"10.3389\/fonc.2022.779276","article-title":"Prognostic implications of molecular subtypes in primary small cell lung cancer and their correlation with cancer immunity","volume":"12","author":"Qi","year":"2022","journal-title":"Front. Oncol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/s41572-020-00235-0","article-title":"Small-cell lung cancer","volume":"7","author":"Rudin","year":"2021","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B35","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1002\/pst.426","article-title":"Guidelines for accurate EC50\/IC50 estimation","volume":"10","author":"Sebaugh","year":"2011","journal-title":"Pharm. Stat."},{"key":"B36","doi-asserted-by":"publisher","first-page":"50","DOI":"10.21037\/tlcr.2018.02.03","article-title":"Targeting DNA damage repair in small cell lung cancer and the biomarker landscape","volume":"7","author":"Sen","year":"2018","journal-title":"Transl. Lung Cancer Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1038\/s41392-023-01383-x","article-title":"Tumor cell plasticity in targeted therapy-induced resistance: mechanisms and new strategies","volume":"8","author":"Shi","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive integration of single-cell data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"B39","doi-asserted-by":"publisher","first-page":"e20230317","DOI":"10.1590\/1678-4685-gmb-2023-0317","article-title":"The role of chaperone-mediated autophagy in drug resistance","volume":"47","author":"Teixeira","year":"2024","journal-title":"Genet. Mol. Biol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1038\/s41392-022-01150-4","article-title":"Single-cell transcriptomic profiling reveals the tumor heterogeneity of small-cell lung cancer","volume":"7","author":"Tian","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"B41","doi-asserted-by":"publisher","first-page":"216705","DOI":"10.1016\/j.canlet.2024.216705","article-title":"Cancer resistance and metastasis are maintained through oxidative phosphorylation","volume":"587","author":"Uslu","year":"2024","journal-title":"Cancer Lett."},{"key":"B42","doi-asserted-by":"publisher","first-page":"2778","DOI":"10.7150\/thno.107761","article-title":"Multiple regulatory mechanisms, functions and therapeutic potential of chaperone-mediated autophagy","volume":"15","author":"Wang","year":"2025","journal-title":"Theranostics"},{"key":"B43","doi-asserted-by":"publisher","first-page":"100141","DOI":"10.1016\/j.xinn.2021.100141","article-title":"clusterProfiler 4.0: a universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation"},{"key":"B44","doi-asserted-by":"publisher","first-page":"811","DOI":"10.3390\/ijms26020811","article-title":"Integrative single-cell and bulk RNA sequencing identifies a macrophage-related prognostic signature for predicting prognosis and therapy responses in colorectal cancer","volume":"26","author":"Xie","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"2612","DOI":"10.1038\/ncomms3612","article-title":"Inferring tumour purity and stromal and immune cell admixture from expression data","volume":"4","author":"Yoshihara","year":"2013","journal-title":"Nat. Commun."},{"key":"B46","doi-asserted-by":"publisher","first-page":"597651","DOI":"10.3389\/fimmu.2021.597651","article-title":"Lymphoma heterogeneity unraveled by single-cell transcriptomics","volume":"12","author":"Ysebaert","year":"2021","journal-title":"Front. Immunol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1186\/s12943-025-02472-x","article-title":"Targeting proteostasis for cancer therapy: current advances, challenges, and future perspectives","volume":"24","author":"Zhang","year":"2025","journal-title":"Mol. Cancer"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1894699\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T11:05:21Z","timestamp":1786014321000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1894699\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,17]]},"references-count":47,"alternative-id":["10.3389\/fcell.2026.1894699"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1894699","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,17]]},"article-number":"1894699"}}