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The Pancreatobiliary Pathology Society (PBPS) wants to thank Alain C. Borczuk, MD, and the Archives of Pathology & Laboratory Medicine for highlighting our society by publishing 3 review articles based [...]

Context.--Alterations in the tumor microenvironment affect the response to immunotherapy and are associated with clinical outcomes. However, the role of B7 family checkpoint molecules in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Objective.--To investigate the expression of programmed death ligand-1 (PD-L1), B7 homolog 3 (B7-H3), and B7 homolog 4 (B7-H4) and the association of these molecules with pathologic features, DNA damage repair (DDR) molecules, immune infiltrates, and survival in PDAC. Design.--The expression of B7 family molecules, densities of immune cells, and DDR status were evaluated by using immunohistochemical assays in tissue microarrays. Results.--Positive PD-L1 expression on tumor cells (TCs) and stromal cells (SCs) was observed in 30.3% (80 of 264) and 20.5% (54 of 264) of patients, respectively, whereas B7-H3 showed positivity in 81.3% (195 of 240) and 87.9% (211 of 240) of patients, respectively. B7-H4 was detected exclusively in tumor cells, with a positivity rate of 76.0% (193 of 254). PD-L1 on TCs was an independent predictor of worse disease-free survival, whereas B7-H3 on TCs was an independent factor of improved survival. The prognostic significance of PD-L1 was more discriminative in lymph node-negative, p53-wild-type, and low-BRCA1/2-expression tumors. B7-H3 on SCs was negatively correlated with CD45RO T cells, whereas PD-L1 on SCs was related to high densities of CD3, CD4, CD8, CD45RO, and Foxp3 T cells and B7-H4 was more common in tumors with a low CD8 status. Conclusions.--We identified B7 family checkpoint molecules as potentially prognostic indicators, combined with different DDR molecular statuses and complex immune infiltrates, in PDAC. doi: 10.5858/arpa.2021-0471-OA, Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause and will become the second leading cause of cancer-related death in developed countries by 2030. (1,2) The prognosis of most [...]

Author(s): Shawn M Davidson [1, 2, 3]; Oliver Jonas [1, 4]; Mark A Keibler [5]; Han Wei Hou [6]; Alba Luengo [1, 2]; Jared R Mayers [1, 2]; Jeffrey Wyckoff [...]

Forward genetic screens with CRISPR-Cas9 genome editing enable high-resolution detection of genetic vulnerabilities in cancer cells. We conducted genome-wide CRISPR-Cas9 screens in RNF43-mutant pancreatic ductal adenocarcinoma (PDAC) cells, which rely on Wnt signaling for proliferation. Through these screens, we discovered a unique requirement for a Wnt signaling circuit: engaging FZD5, one of the ten Frizzled receptors encoded in the human genome. Our results uncover an underappreciated level of context-dependent specificity at the Wnt receptor level. We further derived a panel of recombinant antibodies that reports the expression of nine FZD proteins and confirms that FZD5 functional specificity cannot be explained by protein expression patterns. Additionally, antibodies that specifically bind FZD5 and FZD8 robustly inhibited the growth of RNF43-mutant PDAC cells grown in vitro and as xenografts in vivo, providing orthogonal support for the functional specificity observed genetically. Proliferation of a patient-derived PDAC cell line harboring an RNF43 variant was also selectively inhibited by the FZD5 antibodies, further demonstrating their use as a potential targeted therapy. Tumor organoid cultures from colorectal carcinoma patients that carried RNF43 mutations were also sensitive to the FZD5 antibodies, highlighting the potential generalizability of these findings beyond PDAC. Our results show that CRIPSR-based genetic screens can be leveraged to identify and validate cell surface targets for antibody development and therapy., Author(s): Zachary Steinhart [1]; Zvezdan Pavlovic [2]; Megha Chandrashekhar [2, 3]; Traver Hart [2]; Xiaowei Wang [2, 4]; Xiaoyu Zhang [2, 3]; Mélanie Robitaille [1]; Kevin R Brown [2]; Sridevi [...]

Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer in which NF-κB pathways promote biological aggressiveness. In this issue of the JCI, Lesina et al. investigated the role of RelA, the p65 partner of p50 that together form the most common NF-κB complex, in the early stages of pancreatic malignant transformation and in established PDAC. By deleting Rela in the context of an oncogenic Kras-driven autochthonous model of PDAC, the authors demonstrated that RelA is a mediator of oncogene-induced senescence (OIS) and the senescence-associated secretory phenotype (SASP) that attenuates acinar-to-ductal metaplasia, pancreatic intraepithelial neoplasia (PanIN) formation, and PanIN progression to PDAC. Loss of the tumor-suppressor function of RelA in the early stages of Kras-driven pancreatic neoplastic transformation was associated with decreased OIS and SASP and a protumorigenic tumor microenvironment that harbored more M2 macrophages and myeloid-derived suppressor cells. The beneficial effects of RelA were mediated by increased expression of CXCL1 and its activation of CXCR2. By contrast, in advanced stages of Kras-driven murine PDAC, loss of p53 or p16 was associated with senescence bypass, and RelA deficiency in this context attenuated cancer cell proliferation and prolonged mouse survival, indicating that RelA enhances tumor progression in established PDAC., Pancreatic ductal adenocarcinoma: combined factors promote aggressiveness Pancreatic ductal adenocarcinoma (PDAC) is a treatment-recalcitrant cancer with an overall 5-year survival rate of 7% (1). It is the fourth leading cause [...]

Author(s): Giulia Biffi (corresponding author) [1]; David A. Tuveson (corresponding author) [1] During cancer progression, many cancer cells delete tumour-suppressor genes that block tumour development. This deletion process often also [...]