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Tumor‐specific metabolic rewiring, acquired to confer a proliferative and survival advantage over nontransformed cells, represents a renewed focus in cancer therapy development. Hepatocellular carcinoma (HCC), a malignancy that has hitherto been resistant to compounds targeting oncogenic signaling pathways, represents a candidate cancer to investigate the efficacy of selectively antagonizing such adaptive metabolic reprogramming. To this end, we sought to characterize metabolic changes in HCC necessary for tumorigenesis. We analyzed gene expression profiles in three independent large‐scale patient cohorts who had HCC. We identified a commonly deregulated purine metabolic signature in tumors with the extent of purine biosynthetic enzyme up‐regulation correlated with tumor grade and a predictor of clinical outcome. The functional significance of enhanced purine metabolism as a hallmark in human HCC was then validated using a combination of HCC cell lines, patient‐derived xenograft (PDX) organoids, and mouse models. Targeted ablation of purine biosynthesis by knockdown of the rate‐limiting enzyme inosine‐5′‐monophosphate dehydrogenase (IMPDH) or using the drug mycophenolate mofetil (MMF) reduced HCC proliferation in vitro and decreased the tumor burden in vivo. In comparing the sensitivities of PDX tumor organoids to MMF therapy, we found that HCC tumors defined by high levels of IMPDH and guanosine nucleosides were most susceptible to treatment. Mechanistically, a phosphoinositide 3‐kinase (PI3K)–E2F transcription factor 1 (E2F1) axis coordinated purine biosynthetic enzyme expression, deregulation of which altered the activity of mitogen‐activated protein kinase/RAS signaling. Simultaneously abolishing PI3K signaling and IMPDH activity with clinically approved inhibitors resulted in greatest efficacy in reducing tumor growth in a PDX mouse model. Conclusion: Enhanced purine metabolic activity regulated by PI3K pathway‐dependent activation of E2F1 promotes HCC carcinogenesis, suggesting the potential for targeting purine metabolic reprogramming as a precision therapeutic strategy for patients with HCC. [ABSTRACT FROM AUTHOR]

The article examines the implications of an incidental finding of pseudomyxoma peritonei (PP) in a deceased organ donor for organ donation. Pseudomyxoma peritonei is considered a rare disease characterized by the deposits of mucinous material in the peritoneal cavity secondary to rupture or metastases of a primary neoplasm. A treatment for such condition is the Sugarbaker procedure.

IL-17-producing CD8 (Tc17) T cells have been shown to play an important role in infection and chronic inflammation, however their implications in hepatocellular carcinoma (HCC) remain elusive. In this study, we performed cytometry by time-of-flight (CyTOF) and revealed the distinctive immunological phenotypes of two IFNγ+ and IFNγ- Tc17 subsets that were preferentially enriched in human HCC. Single-cell RNA-sequencing analysis further revealed regulatory circuits governing the different phenotypes of these Tc17 subsets. In particular, we discovered that IFNγ- Tc17 subset demonstrated pro-tumoral characteristics and expressed higher levels of CCL20. This corresponded to increased tumor infiltration of T regulatory cells (Treg) validated by immunohistochemistry in another independent HCC cohort, demonstrating the immunosuppressive functions of IFNγ- Tc17 subset. Most importantly, higher intra-tumoral proportions of IFNγ- Tc17 were associated with poorer prognosis in patients with HCC and this was further validated in The Cancer Genome Atlas (TCGA) HCC cohort. Taken together, this compendium of transcriptomic and proteomic data of Tc17 subsets sheds light on the immunosuppressive phenotypes of IFNγ- Tc17 and its implications in HCC progression. [ABSTRACT FROM AUTHOR]