Cells coordinate their behaviors with the mechanical properties of the extracellular matrix (ECM). Tumor cells frequently harbor an enhanced nucleotide synthesis, presumably to meet the increased demands for rapid proliferation. Nevertheless, how ECM rigidity regulates nucleotide metabolism remains elusive. Here we show that shift from stiff to soft matrix blunts glycolysis-derived nucleotide synthesis in tumor cells. Soft ECM results in TNF receptor-associated factor 2 (TRAF2)-dependent K29 ubiquitination and degradation of phosphoribosyl pyrophosphate synthetase (PRPS)1/2. Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases. Further, non-phosphoryable or non-ubiquitinatable PRPS1/2 mutations maintain PRPS1/2 expression and nucleotide synthesis at low stiffness, and promote tumor growth and metastasis. Our findings demonstrate that PRPS1/2 stability and nucleotide metabolism is ECM rigidity-sensitive, and thereby highlight a regulatory cascade underlying mechanics-guided tumor metabolism reprogramming.

细胞协调其行为与细胞外基质 (ECM) 的机械特性。肿瘤细胞经常具有增强的核苷酸合成，大概是为了满足对快速增殖增加的需求。然而，ECM 刚性如何调节核苷酸代谢仍然难以捉摸。在这里，我们表明从硬基质到软基质的转变会削弱肿瘤细胞中糖酵解衍生的核苷酸合成。软 ECM 导致 TNF 受体相关因子 2 (TRAF2) 依赖性 K29 泛素化和磷酸核糖焦磷酸合成酶 (PRPS)1/2 的降解。将 TRAF2 募集到 PRPS1/2 需要 PRPS1 S285 或 PRPS2 T285 磷酸化，这是由低刚度激活的大肿瘤抑制因子 (LATS)1/2 激酶介导的。进一步，不可磷酸化或不可泛素化的 PRPS1/2 突变维持 PRPS1/2 表达和核苷酸合成处于低刚度，并促进肿瘤生长和转移。我们的研究结果表明 PRPS1/2 稳定性和核苷酸代谢是 ECM 刚性敏感的，从而突出了力学引导的肿瘤代谢重编程的调节级联。