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Metabolic memory underlying minimal residual disease in breast cancer

ABSTRACT:

Tumor relapse from treatment-resistant cells (minimal residual disease, MRD) underlies most breast cancer related deaths. Yet, the molecular characteristics defining their malignancy have largely remained elusive. Here we integrated multi-omics data from a tractable organoid system with a metabolic modelling approach to uncover the metabolic and regulatory idiosyncrasies of the MRD. We find that the resistant cells, despite their non-proliferative phenotype and the absence of oncogenic signaling, feature increased glycolysis and activity of certain urea cycle enzymes reminiscent of the tumor. This metabolic distinctiveness was also evident in a mouse model and in transcriptomic data from patients following neo-adjuvant therapy. We further identified a marked similarity in DNA methylation profiles between tumor and residual cells. Taken together, our data reveal a metabolic and epigenetic memory of the treatment-resistant cells. We further demonstrate that the memorized elevated glycolysis in MRD is crucial for their survival and can be targeted using a small molecule inhibitor without impacting normal cells. The metabolic aberrances of MRD thus offer new therapeutic opportunities for post-treatment care to prevent breast tumor recurrence.

INSTRUMENT(S): GC-(triple quadrupole)MS, TQ8040, Shimadzu

SUBMITTER: Eleni Kafkia

PROVIDER: MTBLS1507 | MetaboLights | 2021-09-14

REPOSITORIES: MetaboLights

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			Action	DRS
	MTBLS1507	Other
	FILES	Other
	a_MTBLS1507_metabolite_profiling_mass_spectrometry.txt	Txt
	files-all.json	Other
	i_Investigation.txt	Txt

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