# The Role of the Y Chromosome in Bladder Tumor Development, Growth And Progression

> **NIH NIH P01** · CEDARS-SINAI MEDICAL CENTER · 2023 · $543,058

## Abstract

PROJECT 2 – SUMMARY
Loss of the Y chromosome (LOY) is associated with increased risk of cancer development and death in men
with several cancer types. In bladder cancer (BC), a tobacco related malignancy, LOY is seen in ~30% of tumors,
yet the biological relevance of this is unknown. Here we address this Knowledge Gap with the Objective to
define the molecular mechanisms responsible for LOY driven growth and progression and have Impact by
translating these into effective interventions for bladder and other cancer types. Preliminary Data: We examined
TCGA BC RNAseq dataset using an LOY gene signature we developed, and found low signature scores
associated with reduced patient survival following surgery. To determine if LOY drives BC growth, we developed
lineage related male murine cell lines with (Y+) or w/o (Y-) Y chromosome. Y- tumors grew faster than Y+ tumors
in immunocompetent mice and cytometric profiling found the former to have increased immunosuppressive
tumor-associated macrophages, CD8+ T cells with exhausted phenotype while latter had increased NK cells. In
mice (Rag2-/-;Il2rg-/-) that are devoid of T, B and NK cells, Y+ and Y- tumors grew similarly. Transcriptional profiling
found four Y chromosome genes differentially expressed in these tumor types, with chromatin organization genes
Uty and Kdm5d being the only ones whose expression stratified outcome in TCGA BC patients. Thus, we
genetically deleted these genes in Y+ cells and found enhanced tumor growth only in immunocompetent mice
while their overexpression in Y- cells reduced their growth. Hence, we test the Hypothesis that Uty and Kdm5d
loss enhance BC growth and progression via creation of an immunosuppressive tumor microenvironment in
three Specific Aims. In Aim 1 we determine role of Uty and Kdm5d in tumor development and progression
using full and urothelial specific conditional Kdm5d or Uty null mice be exposed to the chemical carcinogen BBN.
With Project 3 we test the hypothesis that Uty and its X chromosome paralog Utx (aka, Kdm6a) have
independent suppressive effects on BC formation and progression by crossing full and urothelial specific
conditional Uty and Utx null mice and exposing them to BBN. In Aim 2 we define how Kdm5d and Uty suppress
BC and the role of the immune system in this process using defined LOF functional mutants to define the regions
on these proteins responsible for tumor growth suppression. With Project 1, we use spatial proteomics to
examine immunological infiltrates in relation to mutant and WT Kdm5d and Uty cancer cell expression and
various knockout mice or antibody depletion strategy to define which cellular components of the immune system
drive tumor growth differences. In Aim 3 we examine ANPEP, the most upregulated gene in Y- tumors that is
also a poor prognostic in BC patients and druggable target, as a candidate autosomal effector gene driving Y-
tumor growth. We found Y- tumors are more responsive than Y+ tumors to anti-PD-1 and ANPEP depl...

## Key facts

- **NIH application ID:** 10629079
- **Project number:** 1P01CA278732-01
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Dan Theodorescu
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $543,058
- **Award type:** 1
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10629079

## Citation

> US National Institutes of Health, RePORTER application 10629079, The Role of the Y Chromosome in Bladder Tumor Development, Growth And Progression (1P01CA278732-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10629079. Licensed CC0.

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