Lactate drives the emergence of tumor cells with centrosome amplification through CP110 lactylation

Abstract Centrosome amplification (CA) is a critical driver of tumor heterogeneity and subsequent cancer progression and metastasis. However, the cellular origin of CA has not been fully elucidated, specifically whether CA arises from progenitor cells with pre-existing centrosome abnormalities or develops de novo in initially normal tumor cells. In this study, we demonstrate that lactate, a metabolic feature commonly enriched in tumor tissues, induces the transformation of cells with two centrosomes into cells with CA, thereby providing an explanation for the widespread presence of CA in tumors. Mechanistically, through systematic screening of centrosomal proteins, we identified CP110 and its key lactylation site at lysine 690 (K690), as critical drivers of CA in tumor cells. Furthermore, CP110-K690 lactylation promotes genomic instability, accelerates cellular proliferation, and enhances metastatic potential by driving CA, collectively facilitating malignant progression. Importantly, inhibition of CP110-K690 lactylation effectively disrupts this pro-tumorigenic signaling axis. Collectively, these findings identify CP110-K690 lactylation as an upstream molecular mechanism underlying the pervasive occurrence of CA across diverse tumor types and its role in promoting aggressive tumor behavior.