WRAD core perturbation impairs DNA replication fidelity promoting immunoediting in pancreatic cancer
Year: 2024
Type: preprint
Abstract: It is unclear how cells counteract the potentially harmful effects of uncoordinated DNA replication in the context of oncogenic stress. Here, we identify the WRAD (WDR5/RBBP5/ASH2L/DPY30) core as a modulator of DNA replication in pancreatic ductal adenocarcinoma (PDAC) models. Molecular analyses demonstrated that the WRAD core interacts with the replisome complex, with disruption of DPY30 resulting in DNA re-replication, DNA damage, and chromosomal instability (CIN) without affecting cancer cell proliferation. Consequently, in immunocompetent models, DPY30 loss induced T cell infiltration and immune-mediated clearance of highly proliferating cancer cells with complex karyotypes, thus improving anti-tumor efficacy upon anti-PD-1 treatment. In PDAC patients, DPY30 expression was associated with high tumor grade, worse prognosis, and limited response to immune checkpoint blockade. Together, our findings indicate that the WRAD core sustains genome stability and suggest that low intratumor DPY30 levels may identify PDAC patients who will benefit from immune checkpoint inhibitors.
Authors: Francesca Citron, I-Lin Ho, Chiara Balestrieri, Zhaoliang Liu, Er-Yen Yen, Luca Cecchetto, Luigi Perelli, Li Zhang, Luis Castillo Montanez, Nicholas Blazanin, Charles A. Dyke, Rutvi Shah, Sergio Attanasio, Sanjana Srinivasan, Ko-Chien Chen, Ziheng Chen, Iolanda Scognamiglio, Nhung Pham, Hania Khan, Shan Jiang, Jing Pan, Ben Vanderkruk, Cecilia S. Leung, Mahinur Mattohti, Kunal Rai, Yanshuo Chu, Linghua Wang, Sisi Gao, Angela K. Deem, Alessandro Carugo, Huamin Wang, Wantong Yao, Giovanni Tonon, Yun Xiong, Philip L. Lorenzi, Chiara Bonini, M. Anna Zal, Brad G. Hoffman, Tim Heffernan, Virginia Giuliani, Collene R. Jeter, Yonathan Lissanu, Giannicola Genovese, Mauro Di Pilato, Andrea Viale, Giulio F. Draetta
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4403714557