Metastasis-the disseminated growth of tumours in distant organs-underlies cancer mortality. Breast-to-brain metastasis (B2BM) is disconcertingly common and disruptive, being prevalent in the aggressive basal-like subtype, albeit evident at varying frequencies in all subtypes. Previous studies revealed parameters of breast cancer metastasis to brain, but its preference for this site remains an enigma. Herein we show that B2BM cells co-opt a neuronal signaling pathway recently implicated in invasive tumour growth, involving activation by glutamate ligand of an N-methyl-Daspartate receptor (NMDAR), whose signaling is demonstrably instrumental in model systems for metastatic colonization of the brain, and associated with poor prognosis. While NMDAR receptor activation is autocrine in some primary tumour types, human and mouse B2BM cells express Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Highlights d Map of PDAC dependencies using RNA-seq, ChIP-seq, and genome-wide CRISPR screening d Expression and direct utilization of cytokine and immune signals in PDAC stem cells d Nuclear hormone receptor RORg regulates mouse and human pancreatic cancer d Pharmacologic blockade of RORg reduces tumor burden and improves survival

Background:There is evidence that tumour–stroma interactions have a major role in the neoplastic progression of pancreatic ductal adenocarcinoma (PDAC). Tumour budding is thought to reflect the process of epithelial–mesenchymal transition (EMT); however, the relationship between tumour buds and EMT remains unclear. Here we characterize the tumour-budding- and stromal cells in PDAC at protein and mRNA levels concerning factors involved in EMT.Methods:mRNA in situ hybridisation and immunostaining for E-cadherin, β-catenin, SNAIL1, ZEB1, ZEB2, N-cadherin and TWIST1 were assessed in the main tumour, tumour buds and tumour stroma on multipunch tissue microarrays from 120 well-characterised PDACs and associated with the clinicopathological features, including peritumoural (PTB) and intratumoural (ITB) budding.Results:Tumour-budding cells showed increased levels of ZEB1 (P<0.0001) and ZEB2 (P=0.0119) and reduced E-cadherin and β-catenin (P<0.0001, each) compared with the main tumour. Loss of membranous β-catenin in the main tumour (P=0.0009) and tumour buds (P=0.0053), without nuclear translocation, as well as increased SNAIL1 in tumour and stromal cells (P=0.0002, each) correlated with high PTB. ZEB1 overexpression in the main tumour-budding and stromal cells was associated with high ITB (P=0.0084; 0.0250 and 0.0029, respectively) and high PTB (P=0.0005; 0.0392 and 0.0007, respectively). ZEB2 overexpression in stromal cells correlated with higher pT stage (P=0.03), lymphatic invasion (P=0.0172) and lymph node metastasis (P=0.0152).Conclusions:In the tumour microenvironment of phenotypically aggressive PDAC, tumour-budding cells express EMT hallmarks at protein and mRNA levels underlining their EMT-type character and are surrounded by stromal cells expressing high levels of the E-cadherin repressors ZEB1, ZEB2 and SNAIL1, this being strongly associated with the tumour-budding phenotype. Moreover, our findings suggest the existence of subtypes of stromal cells in PDAC with phenotypical and functional heterogeneity.

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