# Functional contributions of glycogen metabolism to ovarian cancer metastasis

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2021 · $440,454

## Abstract

PROJECT SUMMARY/ABSTRACT
 The biology of high grade serous ovarian cancer (OvCa) is distinct from that of most epithelial tumors,
in that hematogenous metastases are rare. Ovarian tumors remain confined to the peritoneal cavity and
primarily seed to the omentum and peritoneum. There, cancer cells interact with cancer associated fibroblasts
(CAFs) which promote cancer cell proliferation, invasion, and metastasis. To study bidirectional signaling
between the two cell types, we co-cultured them and used SILAC coupled with quantitative, label-free
phosphoproteomics to identify phospho-tyrosine signaling events in both OvCa cells and fibroblasts. We
identified activation of phosphoglucomutase 1 (PGM1) in the cancer cells, pointing towards regulation of
glycogen metabolism in OvCa cells by CAFs. Further, preliminary experiments showed that glycogenolysis
provides energy to cancer cells and regulates protein glycosylation and histone methylation. Based on these
data, the primary hypothesis underlying this application is that CAF-mediated glycogenolysis promotes
metastasis through several different mechanisms, including glycolysis, protein glycosylation, and epigenetics.
In Aim I, we will explore the metabolic consequences of PGM1 activation or inhibition in both OvCa cells and
normal fallopian tube epithelial cells using untargeted metabolomics and metabolic flux studies. We will use
PGM knockdown cells and investigate the effects of PGM1 inhibition on adhesion/invasion/proliferation using a
3D model and a syngeneic mouse model of metastasis. We will then utilize a high-throughput RNAi library with
the goal of identifying the upstream signaling pathways regulating glycogenolysis in response to CAFs. In Aim
II, we will systematically study glycogen-mediated glycosylation events using human protein glycosylation
arrays to identify which proteins are specifically glycosylated by CAF-mediated glycogenolysis. This
investigation will be complemented by studies determining how glycosyltransferase enzymes regulate CAF-
mediated glycosylation. We will then study the role of glycosyltransferases on in vivo metastasis assays using
primary CAF/OvCa cells and a syngeneic mouse model of OvCa metastasis. Using targeted metabolomics
data and flux analysis of CAFs co-cultured with OvCa cells, we discovered that glycogenolysis induced α-
ketoglutarate (KG). We therefore propose, in Aim III, to study how glycogenolysis alters epigenetic changes in
cancer cells. We will characterize genome-wide changes in histone methylation (ChIP-seq) and DNA
hydroxymethylation (Nano-hmC-Seal) to identify genes epigenetically regulated by glycogenolysis. The
proposed experiments aim to define the link between glycogenolysis and epigenetics to identify functional
regulators of OvCa metastasis. By understanding glycogen metabolism in the tumor organ, we may be able to
elucidate novel metabolic mechanisms important for metastasis, which could result in the identification of a
new and clinica...

## Key facts

- **NIH application ID:** 10094205
- **Project number:** 5R01CA237029-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Ernst Lengyel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $440,454
- **Award type:** 5
- **Project period:** 2020-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10094205

## Citation

> US National Institutes of Health, RePORTER application 10094205, Functional contributions of glycogen metabolism to ovarian cancer metastasis (5R01CA237029-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10094205. Licensed CC0.

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