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Background <p>Bladder cancer (BLC) remains a clinically challenging malignancy due to its pronounced inter- and intra-patient heterogeneity, which contributes to therapeutic resistance and poor clinical outcomes. Capturing and modeling this complexity is essential for the development of effective, personalized therapeutic strategies.</p> Methods <p>To investigate molecularly and functionally BLC heterogeneity, this study employed three-dimensional patient-derived organoids (PDOs) and ex vivo tissue slice culture as advanced preclinical models. PDOs were established from a patient’s cohort enrolled at Regina Elena National Cancer Institute in Rome using spatially distinct tumor samples from central (TC) and peripheral (TP) tumor regions to preserve intratumoral heterogeneity. Genomic and transcriptomic fidelity between PDOs and their parental tumors was assessed through multi-omics analyses. Functional assays were conducted to evaluate therapeutic responses. A second patient cohort from the University of Bern, was used to further characterize cellular and microenvironmental features of BLC samples combining ex vivo tissue culture and multiparametric-Flow Cytometry (FACS) to address treatment-induced cancer cell plasticity and epithelial-marker expression dynamics.</p> Results <p>PDOs recapitulated the genomic and transcriptomic landscapes of the original tumors. Early passage PDOs retained components of the tumor microenvironment, including immune cell subsets, suggesting their relevance for ex vivo modeling of tumor-immune interactions. Functional assays revealed spatial heterogeneous responses to both chemotherapy and EGFR/FGFR-targeted therapies. A corresponding reduction of the EGFR-high basal-like population was observed in ex vivo tissue cultures. In contrast, treatment with a PD-1 immune checkpoint inhibitor showed consistent responses across PDOs regions but correlated with the degree of immune infiltration observed in the parental tumors.</p> Conclusion <p>This integrated dual-cohort approach demonstrates that both BLC PDOs and ex vivo tissue cultures offer a versatile and faithful platform for dissecting BLC heterogeneity and advancing functional precision medicine recapitulating patient-specific immune-tumor interactions observed in native tissues.</p>

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Bridging phenotype and function in bladder cancer using immuno-competent organoids and ex vivo drug screening

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月1日

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  • Carlotta Frascolla,
  • Riccardo Mastroianni,
  • Catarina Macedo-Silva,
  • Marta De Menna,
  • Giulia Orlandi,
  • Daniela Angela Covino,
  • Martina Minoli,
  • Martina Radic,
  • Federico La Manna,
  • Claudio Pulito,
  • Sebastiano Vaccarella,
  • Frauke Goeman,
  • Ludovica Ciuffreda,
  • Matteo Allegretti,
  • Roland Seiler,
  • Bernhard Kiss,
  • Valentina De Pascale,
  • Federica Runci,
  • Fabio Calabrò,
  • Yaron Vinik,
  • Sima Lev,
  • Sabrina Strano,
  • Maurizio Fanciulli,
  • Brindusa Ana Maria Arteni,
  • Simona Di Martino,
  • Andrea Russo,
  • Sara Donzelli,
  • Marianna Kruithof-de Julio,
  • Giovanni Blandino,
  • Giuseppe Simone

摘要

Background

Bladder cancer (BLC) remains a clinically challenging malignancy due to its pronounced inter- and intra-patient heterogeneity, which contributes to therapeutic resistance and poor clinical outcomes. Capturing and modeling this complexity is essential for the development of effective, personalized therapeutic strategies.

Methods

To investigate molecularly and functionally BLC heterogeneity, this study employed three-dimensional patient-derived organoids (PDOs) and ex vivo tissue slice culture as advanced preclinical models. PDOs were established from a patient’s cohort enrolled at Regina Elena National Cancer Institute in Rome using spatially distinct tumor samples from central (TC) and peripheral (TP) tumor regions to preserve intratumoral heterogeneity. Genomic and transcriptomic fidelity between PDOs and their parental tumors was assessed through multi-omics analyses. Functional assays were conducted to evaluate therapeutic responses. A second patient cohort from the University of Bern, was used to further characterize cellular and microenvironmental features of BLC samples combining ex vivo tissue culture and multiparametric-Flow Cytometry (FACS) to address treatment-induced cancer cell plasticity and epithelial-marker expression dynamics.

Results

PDOs recapitulated the genomic and transcriptomic landscapes of the original tumors. Early passage PDOs retained components of the tumor microenvironment, including immune cell subsets, suggesting their relevance for ex vivo modeling of tumor-immune interactions. Functional assays revealed spatial heterogeneous responses to both chemotherapy and EGFR/FGFR-targeted therapies. A corresponding reduction of the EGFR-high basal-like population was observed in ex vivo tissue cultures. In contrast, treatment with a PD-1 immune checkpoint inhibitor showed consistent responses across PDOs regions but correlated with the degree of immune infiltration observed in the parental tumors.

Conclusion

This integrated dual-cohort approach demonstrates that both BLC PDOs and ex vivo tissue cultures offer a versatile and faithful platform for dissecting BLC heterogeneity and advancing functional precision medicine recapitulating patient-specific immune-tumor interactions observed in native tissues.