Researchers at the CSIR-National Chemical Laboratory (NCL) in Pune have found new strategies to overcome resistance to chemotherapy in brain cancer cells.
“Our work develops a novel paradigm for the use of systems biology approaches to identify metabolic switches and re-wiring in resistant cells that can be targeted to kill them,” said Dr Anu Raghunathan of CSIR-NCL’s Metabolic Inquiry and Cellular Engineering, which conducted the study.
Glioblastoma Multiforme is the most aggressive form of brain cancer. Temozolomide is the current chemotherapy drug used by oncologists and resistance to the drug is increasing at a rapid rate reducing prognosis. Drug resistance in patients can emerge through use of the routine drugs wherein cancer cells no longer respond to the drug or need very high amounts of drug to respond.
The researchers worked on a model cell line commonly used to study glioblastoma, U87MG. They have identified a critical pathway in respiration (oxidative phosphorylation) or cholesterol metabolism that can be targeted to kill temozolomide resistant brain cancer cells.
“This project grew from an initially surprising observation that there were spherical cells floating on top of the flask of neuronal star shaped cancer cells. Further probing identified these cells were alive, used different nutrients and had different molecular fingerprints,” said Dr Rupa Immanuel.
The findings were reported in an article, ‘Integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells’, published in Nature Partner Journal Systems Biology and Applications on January 8.
The article essentially talks about a pioneering holistic approach that looks at the cell in totality rather than individual components. This approach is commonly called systems biology and derives from the application of systems engineering to biology. The workflow started from isolation of a spherical cell population from within the typical star shaped neuronal cells.
Using the central dogma of biology and modern tools and measurements, the whole cell was broken down to understand individual components and how they had changed during the process of becoming chemotherapy resistant. The changes in the genome were identified through resequencing and the physiology of the cell unravelled through metabolite measurements over time. All this data was then analysed together to understand how each molecule talks to each other using a sophisticated technique called metabolic network reconstruction and then converted into a model to understand re-wiring of the networks in the cell. Targeting these re-wired networks and pathways with drug molecules allows killing the resistant cells.
“The model captures each and every component of the cell, essentially representing a virtual whole cell, which can compute how the cancer cell would behave in any situation,” said Dr Avinash Ghanate, another key contributor.
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