# Metabolic Tumor Suppressors in Renal Cancer: Unprecedented Roles in Disease Progression

> **NIH NIH R35** · UNIVERSITY OF PENNSYLVANIA · 2021 · $959,885

## Abstract

Project Summary/Abstract
Kidney cancer, or renal cell carcinoma (RCC), is among the ten most prevalent malignancies in the United
States, and has exhibited an increasing incidence rate in both men and women since 2001. The most common
subtype of RCC is “clear cell” RCC (ccRCC, 75% of all cases). ccRCC is characterized by chemotherapy and
radiation resistance; while surgical resection of early stage disease can be curative, five year relapse rates
approach 40%, with the majority of these cases developing metastases. Of note, ccRCCs lack common
genetic abnormalities observed in many other human cancers, including mutations in the PTEN, AKT, TP53,
and KRAS loci, hindering successful treatment of ccRCC by corresponding targeted therapies. In contrast,
ccRCCs feature consistent metabolic abnormalities, such as highly elevated glycogen and fat deposition.
These metabolic disorders are associated with normoxic stabilization of hypoxia-inducible factors (HIFs),
secondary to von Hippel-Lindau (VHL mutations) that occur in > 90% of ccRCC tumors. Because Vhl ablation
in mouse kidney fails to induce ccRCC formation, additional oncogenic changes may be required. By
integrating exome sequencing, copy number variation, transcriptomic, and metabolomic data, we identified
multiple metabolic enzymes as universally depleted in all ccRCC tumors (an otherwise genetically
heterogeneous disease). The first pathway involves decreased gluconeogenesis and glycogen storage, as
regulated by fructose-1,6-bisphosphatase (FBP1). FBP1 loss significantly correlates with advanced tumor
stages and poor patient survival, consistent with its tumor suppressor functions in inhibiting glycolysis, NADPH
production, and nuclear HIF activity. The second most down-regulated metabolic pathway in ccRCC is the urea
cycle, including the argininosuccinate synthase 1 (ASS1), argininosuccinate lyase (ASL), and arginase 2
(ARG2) enzymes. Of note, FBP1, ASS1, and ASL have both catalytic activity-dependent and catalytic
activity-indendent, or structural roles. For example, FBP1 exhibits both cytoplasmic metabolic activity and
nuclear transcriptional effects on HIF and other nuclear proteins. We propose to investigate the
unprecedented, non-catalytic roles of these enzymes in ccRCC and other cancers. ccRCC also exhibit
unusually high numbers of lipid droplets, organelles which store triglycerides and cholesterol esters, whose
overproduction is a hallmark of this disease. Delineating the molecular mechanisms by which changes in
gluconeogenesis, the urea cycle, and lipid homeostasis alter ccRCC tumor metabolism will provide new
therapeutic avenues to target a majority of patients diagnosed with this kidney cancer subtype. The results
obtained from ccRCC will also be applied to other malignancies, including soft-tissue sarcoma, hepatocellular
carcinoma, and Burkitt's lymphoma, which appear to engage in highly similar metabolic reprogramming.

## Key facts

- **NIH application ID:** 10214558
- **Project number:** 5R35CA220483-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** M. CELESTE SIMON
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $959,885
- **Award type:** 5
- **Project period:** 2017-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10214558

## Citation

> US National Institutes of Health, RePORTER application 10214558, Metabolic Tumor Suppressors in Renal Cancer: Unprecedented Roles in Disease Progression (5R35CA220483-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10214558. Licensed CC0.

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