The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression

Seifert, L., Werba, G., Tiwari, S., Giao Ly, N. N., Alothman, S., Alqunaibit, D., Avanzi, A., Barilla, R., Daley, D., Greco, S. H., Torres-Hernandez, A., Pergamo, M., Ochi, A., Zambirinis, C. P., Pansari, M., Rendon, M., Tippens, D., Hundeyin, M., Mani, V. R., Hajdu, C., Engle, D., Miller, G. (2016) The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature, 532 (7598). pp. 245-9. ISSN 1476-4687 (Electronic)0028-0836 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/27049944
DOI: 10.1038/nature17403

Abstract

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.

Item Type: Paper
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell types > macrophages
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > macrophages
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > macrophages

bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > Tuveson lab
Depositing User: Matt Covey
Date Deposited: 26 Apr 2016 19:35
Last Modified: 26 Apr 2016 19:35
PMCID: PMC4833566
Related URLs:
URI: http://repository.cshl.edu/id/eprint/32612

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