Interferon signaling promotes tolerance to chromosomal instability during metastatic evolution in renal cancer

Perelli, Luigi; Carbone, Federica; Zhang, Li; Huang, Justin K.; Le, Courtney N.; Khan, Hania; Citron, Francesca; Poggetto, Edoardo Del; Gutschner, Tony; Tomihara, Hideo; Soeung, Melinda; Minelli, Rosalba; Srinivasan, Sanjana; Peoples, Michael; Lam, Truong; Lundgren, Sebastian; Xia, Ruohan; Zhu, Cihui; Mohamed, Alaa M. T.; Zhang, Jianhua; Sircar, Kanishka; Sgambato, Alessandro; Gao, Jianjun; Jonasch, Eric; Draetta, Giulio; Futreal, Andrew; Bakouny, Ziad; Allen, Eliezer M. Van; Choueiri, Toni K.; Signoretti, Sabina; Msaouel, Pavlos; Litchfield, Kevin; Turajlic, Samra; Wang, Linghua; Chen, Ying-Bei; DiNatale, Renzo G.; Hakimi, A. Ari; Giuliani, Virginia; Heffernan, Timothy; Viale, Andrea; Bristow, Christopher A.; Tannir, Nizar M.; Carugo, Alessandro; Genovese, Giannicola

doi:10.1038/s43018-023-00584-1

Cited by 16 publications

(4 citation statements)

References 72 publications

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“…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: Resultsmentioning

confidence: 99%

“…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%

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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“…4A, Supplementary Table 8). INFG acts as a gatekeeper of ccRCC progression by restraining the clonal expansion of ccRCC cells (Perelli et al, 2023). The suppression of INFG response associated with latent factor 6 might also have contributed to formation of a permissive environment for the expansion of these tumour cells and disease progression.…”

Section: Latent Factor 6 Epigenetic Regulation Of Gstp1 and Genotoxicitymentioning

confidence: 99%

Disease aetiology and progression shape the inter-patient multi-omics profile of clear cell renal carcinoma

Penha,

Sexton-Oates,

Senkin

et al. 2024

Preprint

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Endogenous and exogenous processes are associated with distinctive molecular marks in somatic tissues, including human tumours. Here, we used integrative multi-omics analyses to infer sources of inter-patient somatic variation within clear cell renal cell carcinomas (ccRCC) and used them to explore how the disease aetiology and progression are reflected in the tumour DNA methylome, transcriptome, and somatic mutation profile. The main source of inter-patient variation within ccRCC tumours was associated with ageing, particularly cellular mitotic age estimated by DNA methylation (epiTOC2), clock-like DNA mutational signatures (SBS1/ID1), and telomere attrition, independent to chronological age. This component was associated with PBRM1 and SETD2 somatic cancer driver mutations, genome instability, tumor stage, grade, and ccRCC patient survival. Pan-cancer analysis supported the similar role of this molecular component in other cancer types. The ccRCC tumour microenvironment was another source of inter-patient variation, including a component associated with BAP1 driver mutations, epigenetic regulation of epithelial-mesenchymal transition genes (i.e., IL20RB, WT1) and patient survival. An additional source of ccRCC inter-patient variation was linked to the epigenetic regulation of the xenobiotic metabolism gene GSTP1. This molecular component was associated with tobacco usage and tobacco-related genomic features, implying a relationship with tobacco-related carcinogenesis, but also present in tumours of never-smoking patients, potentially implicating it in other genotoxic effects. By considering how the tumour DNA methylome, transcriptome, and somatic mutation profile vary across patients, we provide novel insights into the endogenous and exogenous processes acting within ccRCC tumours and their relation to the disease aetiology and progression.

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“…In particular, the loss of mouse chromosome 16q along with the initial 9p loss results in a proliferative advantage. 64 …”

Section: Specific Aneuploidy Patterns Have Been Identified At All Sta...mentioning

confidence: 99%

Selection forces underlying aneuploidy patterns in cancer

Klockner,

Campbell

2024

Molecular & Cellular Oncology

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Interferon signaling promotes tolerance to chromosomal instability during metastatic evolution in renal cancer

Cited by 16 publications

References 72 publications

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

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

Disease aetiology and progression shape the inter-patient multi-omics profile of clear cell renal carcinoma

Selection forces underlying aneuploidy patterns in cancer

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