Convergent evolutionary trajectories uncover metastatic drivers in renal cancer

Perelli, Luigi; Zhang, Li; Le, Courtney N.; Citron, Francesca; Soeung, Melinda; Lundgren, Sebastian; Khan, Hania; Wang, Linghua; Msaouel, Pavlos; Draetta, Giulio; Hakimi, A. Ari; Carugo, Alessandro; Genovese, Giannicola

doi:10.52519/00074

Cited by 1 publication

(2 citation statements)

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“…Human ESCC samples frequently display homozygous loss of the 9p21.3 region, harboring classic tumor suppressors CDKN2A/B (32,33). Two recent studies revealed an additional selective advantage of losing 9p21.3 in cancer cells, attributed to the IFN-I gene cluster in the region (34,35). Specific disruption of the cluster resulted in substantial changes in infiltrating immune cells and escape from CD8 + T cell surveillance.…”

Section: Discussionmentioning

confidence: 99%

“…However, genes encoding several IFN-Is had negligible basal expression in ESCC PDOs and cell lines and were not upregulated upon ΔNp63 depletion (Supplementary Table 12). This is most likely due to the frequent loss of the chromosome 9p21 region containing genes encoding several IFN-Is in ESCC (32,33), which further indicates a potential tumor-suppressive role of cancer cell-derived IFN-Is (34,35).…”

Section: δNp63 Depletion Derepresses Endogenous Retrotransposon Expre...mentioning

confidence: 99%

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ΔNp63-restricted viral mimicry response impedes cancer cell viability and remodels tumor microenvironment in esophageal squamous cell carcinoma

Yu,

So,

Lung

et al. 2024

Preprint

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Tumor protein p63 isoform ΔNp63 plays roles in the squamous epithelium and squamous cell carcinomas (SCCs), including esophageal SCC (ESCC). By integrating data from cell lines and our latest patient-derived organoid cultures, derived xenograft models, and clinical sample transcriptomic analyses, we identified a novel and robust oncogenic role of ΔNp63 in ESCC. We showed that ΔNp63 maintains the repression of cancer cell endogenous retrotransposon expression and cellular double-stranded RNA sensing. These subsequently lead to a restricted cancer cell viral mimicry response and suppressed induction of tumor-suppressive type I interferon (IFN-I) signaling through the regulations of Signal transducer and activator of transcription 1, Interferon regulatory factor 1, and cGAS-STING pathway. The cancer cell ΔNp63-IFN-I signaling axis affects both the cancer cell and tumor-infiltrating immune cell (TIIC) compartments. In cancer cells, depletion of ΔNp63 resulted in reduced cell viability. ΔNp63 expression is negatively associated with the anticancer responses to viral mimicry booster treatments targeting cancer cells. In the tumor microenvironment, cancer cell TP63 expression negatively correlates with multiple TIIC signatures in ESCC clinical samples. ΔNp63 depletion leads to increased cancer cell antigen presentation molecule expression and enhanced recruitment and reprogramming of tumor-infiltrating myeloid cells. Similar IFN-I signaling and TIIC signature association with ΔNp63 were also observed in lung SCC. These results support the potential application of ΔNp63 as a therapeutic target and a biomarker to guide candidate anticancer treatments exploring viral mimicry responses.

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