Faculty Bibliography

Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis. Conversely, cancer cells often disrupt apoptosis to survive. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs. Here we report that the principal components of the necrosome, receptor-interacting protein (RIP)1 and RIP3, are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumour microenvironment associated with intact RIP1/RIP3 signalling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SAP130 (a subunit of the histone deacetylase complex) was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle-its cognate receptor-was upregulated in tumour-infiltrating myeloid cells. Ligation of Mincle by SAP130 promoted oncogenesis, whereas deletion of Mincle protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumour microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or Mincle is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or Mincle signalling, are reprogrammed into indispensable mediators of anti-tumour immunity in the absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signalling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.

A salient feature of pancreatic ductal adenocarcinoma (PDA) is an abundant fibroinflammatory response characterized by the recruitment of immune and mesenchymal cells and the consequent establishment of a pro-tumorigenic microenvironment. Here we report the prominent presence of B cells in human pancreatic intraepithelial neoplasia (PanIN) and PDA lesions as well as in oncogenic K-Ras-driven pancreatic neoplasms in the mouse. The growth of orthotopic pancreatic neoplasms harboring oncogenic K-Ras was significantly compromised in B cell-deficient mice (muMT), and this growth deficiency could be rescued by the reconstitution of a CD1dhighCD5+ B cell subset. The pro-tumorigenic effect of B cells was mediated by their expression of IL-35 through a mechanism involving IL-35-mediated stimulation of tumor cell proliferation. Our results identify a previously unrecognized role for IL-35-producing CD1dhighCD5+ B cells in the pathogenesis of pancreatic cancer and underscore the potential significance of a B cell/IL-35 axis as a therapeutic target.

Background: Certain nutritional and herbal supplements may have potential hepatotoxic effects. With increasing use of these supplements in the general population, supplements-induced liver injury (SILI) has become a common problem clinically. However, there is not much data about the clinical and pathologic features of SILI, and pathological characteristics of SILI have not been defined. Design: All liver biopsy cases with diagnoses of hepatitis or liver injury were reviewed from our pathology database from 2014-2015. The cases of SILI were confirmed by pathological and clinical correlation. Pre-biopsy liver function tests (LFTs) were collected from the electronic medical record system. The H&E and Trichrome stain slides were re-assessed for pathologic changes. The morphologic patterns of liver injury, including bile duct injury, portal inflammation, interface hepatitis, lobular inflammation, fibrosis, presence of granulomas, and plasma cell and eosinophil infiltrates were recorded and analyzed. Results: Total 17 cases of SILI were identified from 323 liver biopsy cases of hepatitis and liver injury. Two of 17 patients with SILI developed acute fulminant hepatic failure and succumbed to the illness. The hepatotoxic nutritional/herbal supplements identified included boswellic acid, carnosyn beta-alanine, whey protein, maca extract, rhodiola, holy basil, creatine, and some unspecified tea and anti-itching supplements. Histologically, the major pattern of liver injury was combined bile duct damage and hepatitis, and the majority of cases showed significant cholestasis. Fibrosis ranged from mild portal fibrosis to cirrhosis. No granulomas were identified. Plasma cells were rare to minimal in all cases, while eosinophils ranged from none up to 12 per high power field. Serologically, the mean values of alanine transaminase, aspartate transaminase, alkaline phosphatase, and total bilirubin were 625 U/L, 447 U/L, 241 U/L, and 12 mg/d, respectively. Conclusions: Nutritional and herbal supplements have become a common cause of drug induced liver injury that may be under recognized. Histologically, the pattern of SILI in this study is the combination of bile duct and hepatocytic damage, ranging from mild disease to fulminant hepatitis. Significant elevation of LFTs, in combination with mixed pattern of liver injury should trigger the consideration of SILI

The role of senescence as a tumor suppressor is well established; however, recent evidence has revealed novel paracrine functions for senescent cells in relation to their microenvironment, most notably protumorigenic roles in certain contexts. Senescent cells are capable of altering the inflammatory microenvironment through the senescence-associated secretory phenotype, which could have important consequences for tumorigenesis. The role of senescent cells in a highly inflammatory cancer like pancreatic cancer is still largely undefined, apart from the fact that senescence abrogation increases tumorigenesis in vivo. This review will summarize our current knowledge of the phenomenon of cellular senescence in pancreatic ductal adenocarcinoma, its overlapping link with inflammation, and some urgent unanswered questions in the field.