# Decoding tumor metabolic and immunologic interactions driving racial disparity in African American patients with bladder cancer.

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $584,631

## Abstract

Project Summary
African American (AA) bladder cancer (BLCA) patients have worse survival and oncologic outcomes compared
to their European American (EA) counterparts. We contend that the lower survival of AA patients is driven in
part by altered tumor-specific biological activities. We have identified through mass spectrometry, genome-wide
transcriptomics, and functional biology in ancestry-verified cell lines and tumors from AA and EA BLCA patients
a pattern of mitochondrial dysregulation and immune activation disproportionately present in AA BLCA
patients. Based on this insight, we first characterized downstream metabolic changes and discovered that
mitochondrial complex I dysregulation was observed more frequently in AA BLCA patients and correlated with
more aggressive BLCA. In addition, targeted inhibition of complex I resulted in improved cancer outcomes in a
preclinical model. Moreover, we found that AA tumors containing increased complex I activity demonstrated a
higher glutamine flux into the TCA cycle by activation of GLS1, leading to accumulation of fatty acids via reductive
carboxylation. Furthermore, AA tumors with increased mitochondrial complex 1 activity showed enhanced
expression of the key complex I gene NDUFB8. Knockdown (KD) of NDUFB8 resulted in reduced mitochondrial
complex 1 activity, glutamine metabolism, ATP production, and regression of BLCA growth. Lastly, we found
that AA tumors with increased mitochondrial complex 1 activity also demonstrated concurrent activation of key
immune signaling pathways, including IFN signaling pathways, suggesting a potential interaction between tumor
metabolic activities and immune signaling. At the level of basic science, this project aims to identify the metabolic
and immunologic basis of BLCA disparities in AA patients by metabolomic analysis of the OXPHOS-GLS1
metabolic axis and by using cutting-edge single-cell RNA sequencing and imaging mass cytometry to profile the
tumor immune microenvironment and analyze tumor cell-immune cell interactions. At the translational level this
work will lay the foundation to test therapeutic strategies targeting complex 1 alone or in combination with GLS1
inhibitor in AA BLCA patients. If successful, these metabolic therapeutic strategies may be further combined with
immunotherapeutic interventions for AA BLCA patients.

## Key facts

- **NIH application ID:** 10874556
- **Project number:** 5R01CA282282-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Jianjun Gao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $584,631
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10874556

## Citation

> US National Institutes of Health, RePORTER application 10874556, Decoding tumor metabolic and immunologic interactions driving racial disparity in African American patients with bladder cancer. (5R01CA282282-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10874556. Licensed CC0.

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