Abstract Pancreatic ductal adenocarcinoma (PDAC), which accounts for over 90% of pancreatic cancers, remains among the most lethal malignancies. Traditionally, tumors have been classified by tissue of origin under the assumption that those arising from the same organ share more similarities than those from different sites. However, recent advances in transcriptomic profiling have enabled molecular subtyping strategies that better reflect tumor biology and therapeutic vulnerabilities. In PDAC, a relatively consistent subtype framework has emerged, with the Classical and Basal-like/Squamous subtypes demonstrating the greatest clinical relevance. The Basal-like subtype in particular is associated with poorer outcomes and exhibits transcriptional signatures linked to squamous differentiation, epithelial–mesenchymal transition, and therapy resistance. One recurrent feature of the Basal-like subtype is the aberrant expression of p63, specifically the ΔNp63 isoform. Normally restricted to basal cells of stratified epithelia such as the epidermis, squamous mucosa, and urothelium, ΔNp63 is not expressed in the normal pancreas but becomes pathologically activated in Basal-like PDAC and other squamous tumors. Its expression drives dysregulated gene networks associated with stem-like programs and squamous trans-differentiation. Recent studies have identified MED12 as a modulator of ΔNp63 in PDAC, highlighting the essential role of p63 in maintaining the Basal-like transcriptional program. However, beyond MED12, the broader regulatory mechanisms controlling ΔNp63 expression in PDAC and related squamous cancers remain poorly understood. To address this gap, we applied a systematic approach to identify cancer-specific regulators of ΔNp63 using genome-scale CRISPR-Cas12a knockout screening. The screens were performed across PDAC, head and neck squamous cell carcinoma (HNSCC), and normal squamous epithelial cell lines that endogenously express ΔNp63. By integrating pooled CRISPR perturbation with p63-specific antibody labeling and high-throughput fluorescence-activated cell sorting (FACS), we isolated populations with altered p63 protein levels and identified both positive and negative regulators of its expression. Top-ranked candidates will be prioritized based on their expression specificity in cancer and potential druggability. Hits will undergo detailed validation in PDAC and HNSCC models to assess effects on ΔNp63 expression and downstream transcriptional programs across these distinct cancer types. In parallel, we will test small-molecule inhibitors targeting selected regulators to determine whether pharmacologic approaches can mimic genetic disruption. Functional relevance will be assessed in patient-derived organoid cultures and xenograft models. Through this integrated strategy, we aim to uncover the regulatory network sustaining ΔNp63 in Basal-like PDAC, advancing our understanding of subtype-specific biology and providing new therapeutic entry points for a highly refractory patient population. Citation Format: Shengmiao Chen, Evelyn Yuzhou. Tong, Sharon Bader, Hongming Shang, Tsukasa Shibue, Peter Winter, Srivatsan Raghavan. Identification of cancer-specific regulators of ΔNp63 through CRISPR-Cas12a screening in pancreatic and head and neck cancers abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr A028.
Chen et al. (Sun,) studied this question.
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