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Citron, Francesca; Perelli, Luigi; Chu, Yanshuo; Srinivasan, Sanjana; Ho, I-Lin; Yen, Er-Yen; Shah, Rutvi; Attanasio, Sergio; Montanez, Luis Castillo; Pilato, Mauro Di; Jiang, Shan; Yao, Wantong; Gao, Sisi; Deem, Angela; Genovese, Giannicola; Wang, Linghua; Giuliani, Virginia; Viale, Andrea; Draetta, Giulio F.

Abstract 303: DPY30 loss leads to DNA re-replication and immunoediting in pancreatic ductal adenocarcinoma

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  • Medientyp: E-Artikel
  • Titel: Abstract 303: DPY30 loss leads to DNA re-replication and immunoediting in pancreatic ductal adenocarcinoma
  • Beteiligte: Citron, Francesca; Perelli, Luigi; Chu, Yanshuo; Srinivasan, Sanjana; Ho, I-Lin; Yen, Er-Yen; Shah, Rutvi; Attanasio, Sergio; Montanez, Luis Castillo; Pilato, Mauro Di; Jiang, Shan; Yao, Wantong; Gao, Sisi; Deem, Angela; Genovese, Giannicola; Wang, Linghua; Giuliani, Virginia; Viale, Andrea; Draetta, Giulio F.
  • Erschienen: American Association for Cancer Research (AACR), 2023
  • Erschienen in: Cancer Research, 83 (2023) 7_Supplement, Seite 303-303
  • Sprache: Englisch
  • DOI: 10.1158/1538-7445.am2023-303
  • ISSN: 1538-7445
  • Schlagwörter: Cancer Research ; Oncology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: Abstract Introduction: DNA replication is a tightly regulated, multi-step process involving licensing and replication factors that faithfully orchestrate a single duplication of the entire genome exclusively during S phase of the cell cycle. Although the mechanisms that prevent uncoordinated DNA replication are well characterized, it remains unclear how cells counteract its potentially harmful effects when it does occur, such as in cancer cells driven by aberrant oncogenic signaling and loss of cell cycle checkpoints. Here, we identify DPY30, an understudied component of all COMPASS complexes, as a modulator of DNA replication. We found upregulated DPY30 expression in pancreatic ductal adenocarcinoma (PDAC) as well as a correlation between increasing DPY30 expression level and higher tumor grade and poor clinical outcomes. Experimental procedure: Human- and mouse-derived PDAC cells silenced or knockout for DPY30 expression were generated and characterized for their in vivo growth in recipient mice with increasing level of immune pressure. Chromatin immunoprecipitation followed by massive parallel sequencing was used to measure the epigenetic landscape in DPY30 or WDR5 knockdown cells. Unbiased proteomics and transcriptomics analyses were performed to elucidate molecular mechanisms. Results: The canonical function of COMPASS complexes is to regulate histone methylation. Unexpectedly, DPY30 loss did not affect histone methylation patterns compared to WDR5 loss, the core member of the COMPASS-like complex. This prompted unbiased proteomics analysis, which showed that DPY30 interacts with members of the DNA helicase, possibly stabilizing the DNA replication fork progression. We found that DPY30 overexpression, by preventing Geminin ubiquitylation, strongly stabilizes its expression, which in turn suppresses Cdt1 activity in late S-phase, buffering the risk of uncoordinated DNA replication in G2/M phase. Consistently, DPY30 loss resulted in DNA re-replication and chromosomal instability, as manifested by DNA fiber and metaphasic spread. In vivo, whole-exome sequencing analysis of DPY30-knockout tumors revealed that DPY30 loss markedly increased mutational burden in immunodeficient mice. In syngeneic models, DPY30 loss strongly inhibited tumor growth, prolonged survival, and increased T cell infiltration of tumors. Moreover, the immune system selectively cleared tumor cells with complex karyotypes, and we observed improved anti-tumor efficacy with DPY30 knockdown and anti-PD-1 treatment compared to either condition alone. Conclusions: In summary, we have identified a previously undescribed function for DPY30 to stabilize the replisome machinery and prevent excessive DNA replication. Our findings indicate that, in PDAC, DPY30 promotes genome stability, thus providing a rationale for targeting DPY30 or its effector proteins in combination with immune-checkpoint inhibitors. Citation Format: Francesca Citron, Luigi Perelli, Yanshuo Chu, Sanjana Srinivasan, I-Lin Ho, Er-Yen Yen, Rutvi Shah, Sergio Attanasio, Luis Castillo Montanez, Mauro Di Pilato, Shan Jiang, Wantong Yao, Sisi Gao, Angela Deem, Giannicola Genovese, Linghua Wang, Virginia Giuliani, Andrea Viale, Giulio F. Draetta. DPY30 loss leads to DNA re-replication and immunoediting in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 303.
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