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Here, we investigated whether NFs are passive stromal bystanders or active participants in early bladder cancer microenvironmental remodeling. Analysis of an early\u2010stage non\u2010muscle\u2010invasive bladder cancer transcriptomic cohort revealed that fibroblast\u2010associated scores were higher in T1 than Ta tumors, enriched in European Organisation for Research and Treatment of Cancer high\u2010risk disease, positively correlated with epithelial\u2010mesenchymal transition (EMT) scores, and associated with increased expression of resistance\u2010linked genes. Experimentally, fibroblast\u2010conditioned medium reduced bladder cancer cell proliferation while accelerating wound closure, indicating a less proliferative but more motile phenotype. This was accompanied by EMT\u2010like cadherin remodeling, including reduced E\u2010cadherin and increased N\u2010cadherin staining. Reciprocally, tumor\u2010derived signals rapidly induced cancer\u2010associated fibroblast (CAF)\u2010like activation features in NFs within 48\u00a0h, including increased \u03b1\u2010smooth muscle actin, fibroblast activation protein, and PDGFR\u03b2 expression. Functionally, increasing fibroblast\u2010to\u2010tumor cell ratios progressively attenuated mitomycin C (MMC)\u2010induced cytotoxicity, demonstrating that stromal context can modify chemotherapy response in vitro. Together, these findings show that NF\u2010tumor crosstalk is rapid, bidirectional and functionally relevant to MMC response in vitro. Rather than acting only after stable CAF formation, NFs can rapidly acquire CAF\u2010like activation features following tumor\u2010derived stimulation and contribute to a stromal context associated with EMT\u2010like plasticity and reduced MMC\u2010induced cytotoxicity in vitro.<\/jats:p>","DOI":"10.1002\/ccs3.70110","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:35:32Z","timestamp":1787564132000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Rapid normal fibroblast\u2010tumor crosstalk promotes cancer\u2010associated fibroblast\u2010like activation and attenuates mitomycin C cytotoxicity in bladder cancer"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9588-7561","authenticated-orcid":false,"given":"Jinhui","family":"Gao","sequence":"first","affiliation":[{"name":"Division of Medicine University College London  London 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Engineering Science Institute of Biomedical Engineering University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2853-4293","authenticated-orcid":false,"given":"Richard T.","family":"Bryan","sequence":"additional","affiliation":[{"name":"Department of Cancer and Genomic Sciences, Bladder Cancer Research Centre, College of Medicine and Health University of Birmingham  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8766-6056","authenticated-orcid":false,"given":"Jennifer L.","family":"Rohn","sequence":"additional","affiliation":[{"name":"Division of Medicine University College London  London 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