Related Experiment Video
Updated: Jun 11, 2025
Modeling Brain Metastasis Via Tail-Vein Injection of Inflammatory Breast Cancer Cells
Published on: February 4, 2021
De novo GTP synthesis is a metabolic vulnerability for the interception of brain metastases
Agata M Kieliszek1, Daniel Mobilio1, Blessing I Bassey-Archibong2
1Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
Abstract:
Patients with brain metastases (BM) face a 90% mortality rate within one year of diagnosis and the current standard of care is palliative. Targeting BM-initiating cells (BMICs) is a feasible strategy to treat BM, but druggable targets are limited. Here, we apply Connectivity Map analysis to lung-, breast-, and melanoma-pre-metastatic BMIC gene expression signatures and identify inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the de novo GTP synthesis pathway, as a target for BM. We show that pharmacological and genetic perturbation of IMPDH attenuates BMIC proliferation in vitro and the formation of BM in vivo. Metabolomic analyses and CRISPR knockout studies confirm that de novo GTP synthesis is a potent metabolic vulnerability in BM. Overall, our work employs a phenotype-guided therapeutic strategy to uncover IMPDH as a relevant target for attenuating BM outgrowth, which may provide an alternative treatment strategy for patients who are otherwise limited to palliation.
Insights
Targeting inosine monophosphate dehydrogenase (IMPDH) offers a new strategy against brain metastases (BM). Inhibiting IMPDH reduces brain metastases-initiating cell growth and formation, providing hope beyond palliative care.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Pathways
Background:
- Brain metastases (BM) have a poor prognosis with limited treatment options.
- Targeting brain metastases-initiating cells (BMICs) is a promising therapeutic strategy.
- Druggable targets for BMICs remain scarce.
Purpose of the Study:
- To identify novel therapeutic targets for brain metastases.
- To investigate the role of inosine monophosphate dehydrogenase (IMPDH) in BM development.
- To evaluate IMPDH as a potential drug target for BM treatment.
Main Methods:
- Connectivity Map analysis of BMIC gene expression signatures.
- Pharmacological and genetic inhibition of IMPDH.
- In vitro and in vivo studies of BMIC proliferation and BM formation.
- Metabolomic analyses and CRISPR knockout studies.
Main Results:
- Connectivity Map analysis identified IMPDH as a key target in BMICs.
- IMPDH inhibition (pharmacological and genetic) reduced BMIC proliferation in vitro.
- IMPDH inhibition attenuated brain metastases formation in vivo.
- De novo GTP synthesis via IMPDH was confirmed as a metabolic vulnerability in BM.
Conclusions:
- Inosine monophosphate dehydrogenase (IMPDH) is a validated therapeutic target for brain metastases.
- Targeting IMPDH offers a potential alternative treatment strategy for BM patients.
- This study provides a phenotype-guided approach to identify novel cancer therapeutics.
Related Concept Videos
02:14GTPases and their Regulation
Large G-proteins,...
02:30Metastasis
Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...
01:15Drugs that Stabilize Microtubules
01:10Drugs that Destabilize Microtubules