Browsing by Author "Wistuba, Ignacio I."

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    Diminished Immune Surveillance during Histologic Progression of Intraductal Papillary Mucinous Neoplasms Offers a Therapeutic Opportunity for Cancer Interception
    (American Association for Cancer Research, 2022) Hernandez, Sharia; Parra, Edwin Roger; Uraoka, Naohiro; Tang, Ximing; Shen, Yu; Qiao, Wei; Jiang, Mei; Zhang, Shanyu; Mino, Barbara; Lu, Wei; Pandurengan, Renganayaki; Haymaker, Cara; Affolter, Kajsa; Scaife, Courtney L.; Yip-Schneider, Michele; Schmidt, C. Max; Firpo, Matthew A.; Mulvihill, Sean J.; Koay, Eugene J.; Wang, Huamin; Wistuba, Ignacio I.; Maitra, Anirban; Solis, Luisa M.; Sen, Subrata; Surgery, School of Medicine
    Purpose: Intraductal papillary mucinous neoplasms (IPMN) are bona fide precursors to pancreatic ductal adenocarcinoma (PDAC). While genomic alterations during multistep IPMN progression have been well cataloged, the accompanying changes within the tumor immune microenvironment (TIME) have not been comprehensively studied. Herein, we investigated TIME-related alterations during IPMN progression, using multiplex immunofluorescence (mIF) coupled with high-resolution image analyses. Experimental design: Two sets of formalin-fixed, paraffin-embedded tissue samples from surgically resected IPMNs were analyzed. The training set of 30 samples consisted of 11 low-grade IPMN (LG-IPMN), 17 high-grade IPMN (HG-IPMN), and 2 IPMN with PDAC, while a validation set of 93 samples comprised of 55 LG-IPMN and 38 HG-IPMN. The training set was analyzed with two panels of immuno-oncology-related biomarkers, while the validation set was analyzed with a subset of markers found significantly altered in the training set. Results: Cell types indicative of enhanced immune surveillance, including cytotoxic and memory T cells, and antigen-experienced T cells and B cells, were all found at higher densities within isolated LG-IPMNs compared with HG-IPMNs. Notably, the TIME of LG-IPMNs that had progressed at the time of surgical resection (progressor LGD) resembled that of the synchronous HG-IPMNs, underscoring that attenuated immune surveillance occurs even in LG-IPMNs destined for progression. Conclusions: Our findings provide a basis for interception of cystic neoplasia to PDAC, through maintenance of sustained immune surveillance using vaccines and other prevention approaches.
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    The mutational landscape and functional effects of noncoding ultraconserved elements in human cancers
    (American Association for the Advancement of Science, 2025) Bayraktar, Recep; Tang, Yitao; Dragomir, Mihnea P.; Ivan, Cristina; Peng, Xinxin; Fabris, Linda; Zhang, Jianhua; Carugo, Alessandro; Aneli, Serena; Liu, Jintan; Chen, Mei-Ju M.; Srinivasan, Sanjana; Sahnoune, Iman; Bayraktar, Emine; Akdemir, Kadir C.; Chen, Meng; Narayanan, Pranav; Huang, Wilson; Ott, Leonie Florence; Eterovic, Agda Karina; Villarreal, Oscar Eduardo; Mohammad, Mohammad Moustaf; Peoples, Michael D.; Walsh, Danielle M.; Hernandez, Jon Andrew; Morgan, Margaret B.; Shaw, Kenna R.; Davis, Jennifer S.; Menter, David; Tam, Constantine S.; Yeh, Paul; Dawson, Sarah-Jane; Rassenti, Laura Z.; Kipps, Thomas J.; Kunej, Tanja; Estrov, Zeev; Joosse, Simon A.; Pagani, Luca; Alix-Panabières, Catherine; Pantel, Klaus; Ferajoli, Alessandra; Futreal, Andrew; Wistuba, Ignacio I.; Radovich, Milan; Kopetz, Scott; Keating, Michael J.; Draetta, Giulio F.; Mattick, John S.; Liang, Han; Calin, George A.; Surgery, School of Medicine
    The mutational landscape of phylogenetically ultraconserved elements (UCEs), especially those in noncoding DNAs (ncUCEs), and their functional relevance in cancers remain poorly characterized. Here, we perform a systematic analysis of whole-genome and in-house targeted UCE sequencing datasets from more than 3000 patients with cancer of 13,736 UCEs and demonstrate that ncUCE somatic alterations are common. Using a multiplexed CRISPR knockout screen in colorectal cancer cells, we show that the loss of several altered ncUCEs significantly affects cell proliferation. In-depth functional studies in vitro and in vivo further reveal that specific ncUCEs can be enhancers of tumor suppressors (such as ARID1B) and silencers of oncogenic proteins (such as RPS13). Moreover, several miRNAs located in ncUCEs are recurrently mutated. Mutations in miR-142 locus can affect the Drosha-mediated processing of precursor miRNAs, resulting in the down-regulation of the mature transcript. These results provide systematic evidence that specific ncUCEs play diverse regulatory roles in cancer.