# Discoidin Domain Receptor Tyrosine Kinase 2 in bladder cancer progression

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2022 · $405,059

## Abstract

PROJECT SUMMARY
Even with immune checkpoint blockade therapy (ICBT), most patients with metastatic bladder cancer (BC) die
of their disease. In the previous funding period, we studied CD24, a metastasis driver and prognostic marker.
Our most translationally significant finding is induction of CD24 expression by Discoidin Domain Receptor
Tyrosine Kinase 2 (DDR2), a collagen-activated receptor that is therapeutically actionable. In human BC, DDR2
expression was associated with poor patient prognosis, the aggressive and ICBT insensitive basal squamous
tumor subtype (BSS), TGFβ signaling, immunosuppressive (M2) macrophages (Mφ) and a fibroblast-enriched,
tumor microenvironment. These results raised the intriguing possibility that DDR2 is a lynchpin driver of both
metastasis and ICBT resistance. To explore this possibility, we developed an shRNA based functional screen in
syngeneic murine BC models to probe DDR2 and other selected “druggable” targets evaluated in BC clinical
trials for their synergism with αPD-1, a common ICBT in BC. We found the most robust tumor reduction with
depletion of DDR2 and this was recapitulated with the Tyr kinase inhibitor, dasatinib. This result was compelling
because it defined a novel synergistic combination therapy with αPD-1 that, unlike CD24 targeting, is actionable
in the near term in patients. To begin elucidating the mechanisms DDR2 may use to drive tumor metastasis and
ICBT resistance, we profiled DDR2-silenced murine BC tumors with RNA-seq. We identified 69 genes
downregulated >2 fold by DDR2 depletion and used these to construct a DDR2 Effector Signature (DES). Low
tumor DES scores of surgically or αPD-L1 treated patients associated with better outcome, supporting a role for
DES genes in progression and αPD-L1 response. Remarkably, MMP10 or S100A2 expression each alone
stratified outcome nearly as well as the DES score in surgery and αPD-L1 treatment and they were implicated
in Mφ, TGFβ and fibroblast biology. These findings and the lack of genes associated with T-cell exhaustion in
DES, lead us to propose our innovative Guiding Hypothesis that cancer cell DDR2 establishes the BSS and
uses MMP10 and S100A2 to engage M2 Mφ and cancer-associated fibroblasts (CAFs) to promote metastasis
and αPD-(L)1 resistance. Specific Aims test this hypothesis with the Objective to develop new effective
treatments for metastatic BC. Aim 1 will use full and conditional DDR2-null mice exposed to chemical
carcinogens to test the hypothesis that DDR2 expression in basal urothelial cells is necessary for BSS tumor
development and progression. Aim 2 will treat murine tumors with alterations in DDR2, MMP10 and S100A2
expression grown in genetically engineered mice with fibroblast and Mφ defects, with αPD-1, to test the
hypothesis that cancer cell DDR2 drives MMP10 and S100A2 and via their actions in Mφ and fibroblasts
contribute to metastasis and αPD-1 resistance. Since even with DDR2+PD-1 blockade, not all tumors are cured,
Aim 3 wil...

## Key facts

- **NIH application ID:** 10374936
- **Project number:** 5R01CA075115-23
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Dan Theodorescu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $405,059
- **Award type:** 5
- **Project period:** 1997-09-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10374936

## Citation

> US National Institutes of Health, RePORTER application 10374936, Discoidin Domain Receptor Tyrosine Kinase 2 in bladder cancer progression (5R01CA075115-23). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10374936. Licensed CC0.

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