{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T05:01:49Z","timestamp":1790226109259,"version":"4.1.0"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"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. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      The tumor microenvironment (TME) plays a critical role in regulating cancer progression, metastasis, and therapeutic response. Conventional two-dimensional (2D) culture systems fail to accurately recapitulate the complex native TME, highlighting the need for physiologically relevant three-dimensional (3D)\n                      <jats:italic>in vitro<\/jats:italic>\n                      models. In our previous work we have developed gelatin\u2013oxidized polymannose\u2013reduced graphene oxide (Gel: OPM:rGO) scaffold as a 3D lung cancer culture model. In this study, we aimed to assess its potential to support TME-associated responses compared with conventional 2D and Matrigel-based 3D culture systems.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>A549 cells cultured on the Gel: OPM:rGO scaffold were analyzed for the secretion of growth factors and inflammatory cytokines by ELISA, the expression of TME-associated and signaling pathway-related genes by qRT-PCR, and TME-associated proteins by Western blotting. Metabolic profiling was performed by measuring glucose consumption and lactate production and the results were compared with 2D and Matrigel culture systems.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Gene expression analysis revealed the upregulation of TME-associated genes, including the hypoxia marker VEGF-A, the extracellular matrix (ECM) remodeling marker MMP9, the epithelial\u2013mesenchymal transition (EMT) marker VIM, the oncogenic marker ALK, and the growth factor receptor EGFR. Western blot analysis showed increased expression of TME-related proteins in the Gel: OPM:rGO scaffold compared with conventional 2D culture. Major signaling pathways, including mTOR, PI3K\/AKT, Wnt, c-Myc, STAT3, and TNF-\u03b1, were also modulated, indicating physiologically relevant cellular responses. Metabolic profiling in Gel: OPM:rGO culture supernatant demonstrated enhanced glucose consumption and lactate production, consistent with the Warburg effect and tumor-associated metabolic reprogramming. Overall, gene and protein expression profiles in the Gel: OPM:rGO scaffold exhibited trends similar to those observed in Matrigel-based 3D culture.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Collectively, these findings demonstrate that the Gel: OPM:rGO scaffold is a robust and physiologically relevant 3D lung cancer model. As a potential 3D culture platform that complements Matrigel-based models, it provides a valuable\n                      <jats:italic>in vitro<\/jats:italic>\n                      platform for investigating tumor-associated cellular and molecular responses, cancer progression, and preclinical anticancer drug evaluation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1955340","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:36:20Z","timestamp":1790224580000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Reduced graphene oxide-incorporated gelatin-oxidized polymannose scaffold-based 3D Lung cancer model for mimicking the tumor microenvironment"],"prefix":"10.3389","volume":"16","author":[{"given":"Hema Priya","family":"Manivannan","sequence":"first","affiliation":[{"name":"Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University","place":["Chennai, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishnu Priya","family":"Veeraraghavan","sequence":"additional","affiliation":[{"name":"Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University","place":["Chennai, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. 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