ABSTRACT Chronic metabolic disorders and aging cause accumulation of dicarbonyls that glycate and render biomolecules dysfunctional. Although systemic metabolic dysregulation is associated with faster cancer progression, their mechanistic determinants remain elusive. We move between time‐lapse and end‐point experiments and tissue‐scale simulations to build a systems model of ovarian cancer colonization and show that confluent healthy serosal mesothelia can stall spheroidal adhesion and spread. However, mesothelial clearance by spheroids continues under increasing concentrations of the dicarbonyl methylglyoxal (MG). High MG levels glycate mesothelia and destabilize their adhesion and motility through mislocalization of F‐actin, ezrin, and ZO‐1. This explains preferential spheroidal spreading amidst sub‐confluent mesothelia. Confluence is dependent on mesothelial viability, which is also decreased by MG. Intriguingly, cancer cells escape glycation and its cytopathological effects by expressing relatively higher levels of glyoxalase 1 (GLO1); pharmacological GLO1 inhibition renders cancer cells vulnerable to MG. Thus, inhibition of stromal glycation holds promise for incorporation into personalized oncotherapy.
Mishra et al. (Thu,) studied this question.
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