Aurora, A. | bioRxiv Science

bioRxiv2025

A small molecule inhibitor of NVL suppresses tumor growth by blocking ribosome biogenesis

A longstanding hypothesis, stemming from the enlarged nucleoli typical of cancer cells, posits ribosome production as a selective cancer liability. Certain genotoxic chemotherapies work partly by disrupting ribosome biogenesis, highlighting the need for selective inhibitors of this pathway. Using forward genetics, we identified mutations in the essential 60S ribosomal subunit assembly factor NVL that confer resistance to MM17, a dibenzothiazepinone with anticancer activity. Cryo-EM reconstructions of the NVL hexameric assembly reveal two MM17 docking sites adjacent to resistance mutations. NVL inhibition by MM17 arrests 60S biogenesis in the nucleolus and induces cell cycle arrest or apoptosis through both MDM2/p53-dependent and p53-independent pathways, without causing DNA damage. A bioavailable analog, MM927, suppresses tumor growth in mouse models of leukemia and colorectal cancer without observable toxicity. These findings establish NVL inhibitors as a promising new class of targeted therapeutics and validate ribosome biogenesis as a cancer-specific vulnerability.

biochemistry↗

bioRxiv2021

Heterogeneity in PHGDH protein expression potentiates cancer cell dissemination and metastasis

Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs. Genetic, transcriptional and translational intra-tumor heterogeneity contributes to this dynamic process. Beyond this, metabolic intra-tumor heterogeneity has also been observed, yet its role for cancer progression remains largely elusive. Here, we discovered that intra-tumor heterogeneity in phosphoglycerate dehydrogenase (PHGDH) protein expression drives breast cancer cell dissemination and metastasis formation. Specifically, we observed intra-tumor heterogeneous PHGDH expression in primary breast tumors, with low PHGDH expression being indicative of metastasis in patients. In mice, Phgdh protein, but not mRNA, expression is low in circulating tumor cells and early metastatic lesions, leading to increased dissemination and metastasis formation. Mechanistically, low PHGDH protein expression induces an imbalance in glycolysis that can activate sialic acid synthesis. Consequently, cancer cells undergo a partial EMT and show increased p38 as well as SRC phosphorylation, which activate cellular programs of dissemination. In turn, inhibition of sialic acid synthesis through knock-out of cytidine monophosphate N-acetylneuraminic acid synthetase (CMAS) counteracts the increased cancer cell dissemination and metastasis induced by low PHGDH expression. In conclusion, we find that heterogeneity in PHGDH protein expression promotes cancer cell dissemination and metastasis formation.

cancer biology↗