# A new bladder cancer model based on tissue reprogramming and gene targeting

> **NIH NIH R21** · STATE UNIVERSITY NEW YORK STONY BROOK · 2021 · $181,790

## Abstract

Project Summary:
 With recent advances in cellular reprogramming and gene editing it became possible to envision new
approaches for tissue modeling in normal and disease contexts. Specifically, we propose to use
transdifferentiation and gene targeting to generate a novel genetically-engineered model system for studies of
human cancer. We recently developed a highly innovative methodology for generating fully functional prostate
tissue in renal grafts based on a computational system approach that identifies synergistic specification genes
(Talos et al., Nat Commun, 2017). We propose here to apply and expand these methods for modeling human
bladder cancer by combining lineage conversion of fibroblasts with tissue recombination assays, advanced
computational systems biology algorithms and CRIPSR/Cas9-mediated gene targeting of clinically-relevant
mutations. In our preliminary studies, we have shown that fibroblasts can be directly converted into epithelial
cells following transient expression of the pluripotency factors in pro-epithelial culture conditions. Moreover,
these induced epithelial cells are amenable to further terminal differentiation into bladder tissue in tissue
recombination assays in vivo under the inductive force of bladder specific mesenchyme. Based on these
preliminary data, we hypothesize that the inherent plasticity of readily-accessible fibroblasts can be exploited to
generate bladder epithelia through a combination of key bladder specification genes, reprogramming techniques
and tissue recombination assays. Moreover, we hypothesize that the reprogrammed bladder tissue is amenable
to malignant transformation through CRISPR-mediated gene targeting.
To test this hypothesis and generate a new model of human cancer, we propose to perform (1) Direct
conversion of human fibroblasts into bladder epithelium by activation of master regulator genes of normal
bladder epithelium, identified by bioinformatic analysis of regulatory genetic networks of bladder or by a
candidate gene approach and (2) Modeling human bladder cancer by CRISPR-mediated gene targeting in
the reprogrammed tissue of tumor suppressors and oncogenes relevant for human disease. Our studies will
provide novel insights into the mechanisms underlying bladder tumorigenesis and a novel platform for drug
screening and for discovery of patient-specific early prognostic biomarkers.

## Key facts

- **NIH application ID:** 10084281
- **Project number:** 5R21CA237955-02
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Flaminia Talos
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $181,790
- **Award type:** 5
- **Project period:** 2020-01-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10084281

## Citation

> US National Institutes of Health, RePORTER application 10084281, A new bladder cancer model based on tissue reprogramming and gene targeting (5R21CA237955-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10084281. Licensed CC0.

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