# HIF-1alpha and FBP2 in sarcoma metabolism, progression, and metastasis

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $463,845

## Abstract

Project Summary/Abstract
Sarcomas are a heterogeneous group of malignancies arising from mesoderm-derived tissues such as
muscle, fat, and connective tissue. They are diagnosed in nearly 20,000 persons in the United States each
year, and approximately 40% of patients die of either loco-regional recurrence or distant metastasis.
Sarcomas and other solid tumors typically thrive in hypoxic and nutrient-poor conditions to proliferate and
metastasize. To survive in such environments, sarcomas hijack two adaptive mechanisms: (1) activation of
hypoxia inducible factor 1α (HIF-1α), which enhances the transcription of over 150 genes mediating tumor
metabolism, angiogenesis, and metastasis and (2) utilization of aerobic glycolysis (a.k.a. the Warburg effect),
which creates energy by means of glycolysis rather than oxidative phosphorylation. HIF-1α appears to be
particularly critical for a subset of tumor cells which we will refer to as “sarcoma stem-like cells” or SSCs,
characterized by their ability to self renew and differentiate. In preliminary studies, we have found that SSCs
reside preferentially in hypoxic regions of tumors, exhibit elevated levels of HIF-1α, and are likely to promote
chemotherapy resistance and metastasis. The reverse reaction of glycolysis is gluconeogenesis, where
fructose-1, 6-bisphosphatase (FBP) acts as a rate-limiting enzyme. We also recently determined that FBP2 is
consistently downregulated in 8 human sarcoma subtypes compared to normal human mesoderm-derived
tissues. The long-term objective of this proposal is to expand the use of agents targeting HIF-1α and FBP2 in
patients with sarcomas to reduce recurrence, distant metastasis, and chemotherapy resistance.
Consequently, this proposal is designed to test the hypothesis that HIF-1α and FBP2 play critical and inter-
related roles in regulating sarcomagenesis, metabolism, metastasis, and chemotherapy resistance. To test
this hypothesis, this research proposal will (1) define the role of FBP2 in sarcoma metabolism,
progression, and metastasis, and (2) determine the role of HIF-1α in SSC metastasis and
chemotherapy resistance. The methods of this proposal include analysis of autochthonous and xenograft
mouse models of sarcomas, analysis of sarcoma cell lines in vitro, metabolic studies, and correlative studies
of tumor samples from sarcoma patients.

## Key facts

- **NIH application ID:** 9850213
- **Project number:** 5R01CA158301-09
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** M. CELESTE SIMON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $463,845
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850213

## Citation

> US National Institutes of Health, RePORTER application 9850213, HIF-1alpha and FBP2 in sarcoma metabolism, progression, and metastasis (5R01CA158301-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9850213. Licensed CC0.

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