Abstract Sarcomatoid bladder cancer represents an extreme manifestation of tumor plasticity, characterized by rapid metastatic progression and limited durability of systemic therapies. Increasing evidence implicates that epithelial-mesenchymal transition (EMT) underlies this aggressive phenotype by enabling dynamic lineage state changes during tumor evolution. Enfortumab vedotin (EV), a Nectin-4-targeted antibody-drug conjugate (ADC), has emerged as a standard therapy for muscle invasive bladder cancer. However, EV response is often attenuated in in metastatic disease, where loss of Nectin-4 expression has been observed. Whether EMT-driven lineage reprogramming directly link metastatic progression, ADC target suppression, and therapeutic resistance remains poorly understood. We performed integrative clinical, genomic, and transcriptomic analyses on a real-world cohort of bladder cancers, including urothelial carcinoma, not otherwise specified (UC-NOS; n = 68) and sarcomatoid carcinoma (SARC; n = 22). Spatial transcriptomics (10x Genomics Visium) was applied to selected bladder tumors exhibiting mixed histology to resolve intratumoral heterogeneity. Bladder cancer cell lines and patient-derived organoids (PDOs) were used for mechanistic interrogation. EMT programs were functionally perturbed using CRISPR/Cas9-mediated gene editing, followed by immunoblotting, flow cytometry, and drug sensitivity assays to evaluate changes in Nectin-4 expression and response to enfortumab vedotin. Sarcomatoid tumors demonstrated robust EMT activation concomitant with transcriptional repression of epithelial lineage markers and profound reduced expression of ADC targets including Nectin-4. Spatial transcriptomic analysis revealed significant intratumoral divergence within individual tumors, with EMT-high regions displaying diminished Nectin-4 relative to adjacent urothelial components. Master regulator analysis identified EMT-associated transcription factors as dominant drivers of this lineage shift in SARC tumors. Importantly, genetic disruption of key EMT regulators reversed Nectin-4 repression and restored sensitivity to enfortumab vedotin in preclinical models, establishing EMT as a causal determinant of ADC resistance rather than a correlative feature of advanced disease. These findings uncover EMT-driven lineage plasticity as a previously underappreciated mechanism linking metastatic progression to antibody-drug conjugate resistance in bladder cancer. Our data suggest that ADC resistant cases arise from dynamic, reversible suppression of target expression rather than irreversible antigen loss. This work provides translational implications support the development of EMT-informed biomarker and rational combination strategies aimed at preventing or reversing EMT to extend the clinical benefit of ADC therapies. Citation Format: Jiaqian Luo, Sizhi P. Gao, Jacob E. Tallman, Fengshen Kuo, Merve Basar, Cansu Yol, Syed M. Alam, Hui Jiang, Xinran Tang, Alejandra Lopez Rojas, Ecenur Turkay, Jonathan E. Rosenberg, Iyer Gopakumar, Eugene J. Pietzak, David B. Solit, Hikmat Al-Ahmadie. Decoding metastasis and therapy resistance in sarcomatoid bladder cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB191.
Luo et al. (Fri,) studied this question.