Grants and Contracts Details
Description
Abstract
Tumor cells in TNBC tissue exhibit enhanced cell plasticity and stemness, which is crucial for cancer metastasis.
Metabolic and epigenetic reprogramming plays crucial roles in the regulation of cell plasticity. Succinate is an
intermediate metabolite of the tricarboxylic acid (TCA) cycle. Aberrant accumulation of succinate has been
detected in many cancers. However, the cellular function and regulation of succinate in breast cancer
development and progression have not been well investigated. We showed that the epithelial-to-mesenchymal
transition (EMT) was associated with profound changes in metabolites, including elevation of cytoplasmic
succinate. Importantly, treatment with the membrane permeable succinate was sufficient to induce mesenchymal
phenotypes, enhance cancer cell stemness and colonization, and reduce DNA hydroxymethylation and gene
transcription in mammary epithelial cells. Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase 2 (PLOD2)
catalyzes lysine hydroxylation in endoplasmic reticulum and generates succinate as another product. We found
that PLOD2 expression was induced in cancer cells in TNBC tissue, and increased PLOD2 expression correlates
with poor prognosis and high chances of cancer metastasis. Silence of PLOD2 in cancer cells significant reduced
cancer cell colonization and metastasis. PLOD2 expression was induced during EMT and associated with
elevation of cytoplasmic succinate levels. Using gain- and loss-of function approaches, we showed that
increased PLOD2 expression is necessary and sufficient to enhance the accumulation of cytoplasmic succinate.
Importantly, silencing PLOD2 in breast cancer cells inhibited cancer cell stemness. The overall objective of this
project is to define roles of the PLOD2/succinate axis in regulating cancer cell plasticity and stemness, and to
evaluate biological activity of the new PLOD2 inhibitor in suppressing TNBC progression and metastasis. The
central hypothesis of this proposal is that PLOD2-induced succinate accumulation enhances cancer cell
plasticity and metastasis by reducing DNA hydroxymethylation; therefore, targeting the PLOD2/succinate axis is
a potential strategy to halt TNBC progression and metastasis.
To test this hypothesis, we propose the following
aims:
Aim 1. Elucidate the molecular and cellular mechanisms by which succinate enhances cancer cell plasticity
and stemness.
Aim 2. Define roles of the PLOD2/succinate axis in regulating breast cancer progression. Aim 3.
Evaluate the potential of targeting PLOD2 to suppress breast cancer metastasis. Successfully completion of the
project will reveal novel function of collagen hydroxylation enzymes in regulating succinate-associated epigenetic
reprogramming and identify PLOD2 as a potential therapeutic target to suppress breast cancer metastasis.
Status | Active |
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Effective start/end date | 9/1/23 → 8/31/28 |
Funding
- National Cancer Institute: $713,063.00
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