Lavi, S. | Search bioRxiv

bioRxiv2026

Dihydropyrimidines sustain aggressive cancer states by stabilizing DPYSL2

Cancer cell states are governed by coordinated signaling and metabolic networks, yet the mechanisms coupling metabolic activity to oncogenic signaling remain poorly understood. Here, we identify dihydropyrimidines (DHPs), metabolites generated during pyrimidine catabolism, as "signaling metabolites" that sustain aggressive cancer cell states. Depletion of DHPs, either by knockout of the pyrimidine catabolic enzyme DPYD or by expression of the DHP-degrading enzyme DPYS, suppressed STAT3 signaling and attenuated mesenchymal and inflammatory transcriptional programs. Mechanistically, DHPs stabilized DPYSL2, a JAK1-interacting adaptor protein required for efficient STAT3 activation. Structural modeling and thermal stability analyses further support a direct interaction between DHPs and DPYSL2. Accordingly, high DPYD expression was associated with EMT, inflammatory signaling, and poor-prognosis breast cancer subtypes across patient cohorts. Ultimately, our findings establish pyrimidine catabolism as a direct regulator of signaling competence and identify DHPs as signaling-active metabolites that couple cellular metabolic state to oncogenic transcriptional programs and mesenchymal identity.

cancer biology↗

bioRxiv2022

Depletion of FH, an essential TCA cycle enzyme, drives proliferation in a two-step model

Several tumor suppressor genes do not follow the canonical function of cell cycle repressors. For example, fumarate hydratase (FH) is an evolutionary conserved TCA cycle enzyme that reversibly catalyzes the hydration of fumarate to L-malate and has a moonlight function in the DNA damage response (DDR). Interestingly, despite this enzymes essential role in central carbon metabolism, FH is inactive or absent in several tumors, such as hereditary leiomyomatosis and renal cell cancer (HLRCC). Accordingly, FH has a contradictory cellular function, as it is pro-survival through its role in the TCA cycle, yet its loss can drive tumorigenesis. These observations have supported the role of FH as a tumor suppressor. Here, we solved this contradiction by determining the molecular mechanisms that allow the cells to survive and even proliferate upon FH loss. We found that the cells response to FH loss is separated into two distinct time frames based on cell proliferation and DNA damage repair. During the early stages of FH loss, the cells proliferation and DNA damage repair are inhibited. However, over time the cells overcome the FH loss and form knockout clones, indistinguishable from WT cells in their proliferation rate. Due to the FH loss effect on DNA damage repair, we assumed that the recovered cells bear adaptive mutations. Therefore, we applied whole-exome sequencing to identify such mutated genes systematically. Indeed, we identified recurring mutations in genes belonging to the central oncogenic signaling pathways, such as JAK/STAT, which we validated to be impaired in FH-KO clones. Intriguingly, we demonstrated that these adaptive mutations are responsible for FH-KO cell proliferation under TCA cycle malfunction.

cancer biology↗