Not really. We went in with an open mind and not constrained by a belief that genetics explains all in cancer biology. We are physiologists after all.

Many thanks to the very helpful reviewers and editor, and the support from @sydney.edu.au Robinson Fellowship, @sydneyprecisionds.bsky.social , @sydney-crf.bsky.social SoMS and Charles Perkins Centre

Ultimately, we believe that there is significant potential of pathway-centric approaches to reveal new aspects of cellular metabolism from metabolomic data.

Finally, In silico analyses of loss-of-function and drug sensitivity screens showed that Cluster 4 cells were more susceptible to gene deletion and drug targeting of glutamine metabolism and OXPHOS than cells in Cluster 3.

Notably, Cluster 4 cells had high TCA cycle metabolites / pyruvate ratios, produced more lactate yet consumed less glucose and glutamine, and greater OXPHOS activity compared to Cluster 3 cells with low TCA cycle metabolite ratios; explained by more glutamine cataplerotic efflux and not glycolysis.

Our starting point was to determine if cancer cells can be clustered into subtypes based on metabolic pathway activity. By calculating pathway-centric metabolite ratios, we identified 5 clusters that were not explained by media composition, tissue type or origin, or mutational status.

I am still waiting for everyone to realise that the Hallmarks of Cancer is physiology and not genetics, epigenetics, or any other stamp collecting technology.

It started in in late 2016 www.cmrijeansforgenes.org.au/research/res...

It goes straight into their reviewer database.