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Metabolic Drug Response Phenotyping in Colorectal Cancer Organoids by LC-QTOF-MS
Sylvia K Neef1, Nicole Janssen1, Stefan Winter1
1Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tuebingen, 70376 Tuebingen, Germany.
Metabolites
|December 4, 2020
Summary
We developed a new method for metabolic profiling of colorectal cancer organoids using mass spectrometry. This technique identifies drug responses and metabolic vulnerabilities in tumors, aiding personalized cancer treatment strategies.
Area of Science:
- Oncology
- Metabolomics
- Biochemistry
Background:
- Metabolic reprogramming is vital for cancer cell growth.
- Patient-derived organoids are valuable models for studying tumor biology and drug responses.
- Current metabolomic techniques face challenges in analyzing minimal sample amounts and complex matrices like extracellular matrix (ECM).
Purpose of the Study:
- To establish a robust protocol for metabolomic and lipidomic profiling of colorectal cancer organoids.
- To enable the identification of drug-induced metabolic changes and vulnerabilities in minimal samples.
- To apply the developed method for assessing early drug responses in 3D organoid models.
Main Methods:
- Developed a novel liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) protocol for colorectal cancer organoid metabolomics and lipidomics.
- Optimized metabolite extraction using ultrasonication without ECM removal.
- Implemented a data filtering strategy to mitigate ECM-derived background signals based on p-value and fold change.
Main Results:
- Successfully profiled minimal samples (<500 cells/injection) of colorectal cancer organoids.
- Identified dose-dependent metabolic alterations in organoids treated with 5-fluorouracil, including changes in purine and pyrimidine metabolism.
- Detected elevated levels of specific nucleosides and depleted phospholipids, consistent with 5-fluorouracil's mechanism of action.
Conclusions:
- The novel LC-QTOF-MS protocol enables sensitive metabolic and lipidomic analysis of colorectal cancer organoids.
- This method facilitates the study of metabolic drug response phenotypes in 3D organoid models.
- Provides a foundation for uncovering metabolic vulnerabilities and guiding therapeutic strategies in colorectal cancer.
