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Article: Np63-restricted viral mimicry response impedes cancer cell viability and remodels tumor microenvironment in esophageal squamous cell carcinoma

TitleNp63-restricted viral mimicry response impedes cancer cell viability and remodels tumor microenvironment in esophageal squamous cell carcinoma
Authors
Issue Date31-May-2024
PublisherElsevier
Citation
Cancer Letters, 2024, v. 595 How to Cite?
Abstract

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.


Persistent Identifierhttp://hdl.handle.net/10722/343878
ISSN
2023 Impact Factor: 9.1
2023 SCImago Journal Rankings: 2.595

 

DC FieldValueLanguage
dc.contributor.authorYu, Valen Zhuoyou-
dc.contributor.authorSo, Shan Shan-
dc.contributor.authorLung, Bryan Chee-chad-
dc.contributor.authorHou, George Zhaozheng-
dc.contributor.authorWong, Carissa Wing-yan-
dc.contributor.authorChow, Larry Ka-yue-
dc.contributor.authorChung, Michael King-yung-
dc.contributor.authorWong, Ian Yu-hong-
dc.contributor.authorWong, Claudia Lai-yin-
dc.contributor.authorChan, Desmond Kwan-kit-
dc.contributor.authorChan, Fion Siu-yin-
dc.contributor.authorLaw, Betty Tsz-ting-
dc.contributor.authorXu, Kaiyan-
dc.contributor.authorTan, Zack Zhen-
dc.contributor.authorLam, Ka-on-
dc.contributor.authorLo, Anthony Wing-ip-
dc.contributor.authorLam, Alfred King-yin-
dc.contributor.authorKwong, Dora Lai-wan-
dc.contributor.authorKo , Josephine Mun-yee-
dc.contributor.authorDai, Wei-
dc.contributor.authorLaw, Simon-
dc.contributor.authorLung, Maria Li-
dc.date.accessioned2024-06-13T08:14:55Z-
dc.date.available2024-06-13T08:14:55Z-
dc.date.issued2024-05-31-
dc.identifier.citationCancer Letters, 2024, v. 595-
dc.identifier.issn0304-3835-
dc.identifier.urihttp://hdl.handle.net/10722/343878-
dc.description.abstract<p>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 <em>TP63</em> 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.<br></p>-
dc.languageeng-
dc.publisherElsevier-
dc.relation.ispartofCancer Letters-
dc.titleNp63-restricted viral mimicry response impedes cancer cell viability and remodels tumor microenvironment in esophageal squamous cell carcinoma -
dc.typeArticle-
dc.identifier.doi10.1016/j.canlet.2024.216999-
dc.identifier.scopuseid_2-s2.0-85195171179-
dc.identifier.volume595-
dc.identifier.eissn1872-7980-
dc.identifier.issnl0304-3835-

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