Cysteine plays critical roles in cellular biosynthesis,
enzyme catalysis, and redox metabolism. The intracellular
cysteine pool can be sustained by
cystine uptake or de novo synthesis from
serine and
homocysteine. Demand for
cysteine is increased during
tumorigenesis for generating
glutathione to deal with oxidative stress. While cultured cells have been shown to be highly dependent on exogenous
cystine for proliferation and survival, how diverse tissues obtain and use
cysteine in vivo has not been characterized. We comprehensively interrogated
cysteine metabolism in normal murine tissues and
cancers that arise from them using stable
isotope 13C1-serine and 13C6-cystine tracing. De novo
cysteine synthesis was highest in normal liver and pancreas and absent in lung tissue, while
cysteine synthesis was either inactive or downregulated during
tumorigenesis. In contrast,
cystine uptake and metabolism to downstream metabolites was a universal feature of normal tissues and
tumors. However, differences in
glutathione labeling from
cysteine were evident across
tumor types. Thus,
cystine is a major contributor to the
cysteine pool in
tumors, and
glutathione metabolism is differentially active across
tumor types.
SIGNIFICANCE: Stable
isotope 13C1-serine and 13C6-cystine tracing characterizes
cysteine metabolism in normal murine tissues and its rewiring in
tumors using genetically engineered mouse models of liver, pancreas, and
lung cancers.