The acquired capability for invasion and metastasis stands as the most complex and pathogenic hallmark of cancer. Studies involving a prototypical genetically engineered mouse model of human cancer, one that develops pancreatic neuroendocrine tumors (PanNET), are revealing new insights into and mechanisms of the invasive/metastatic phenotype. The multistage tumorigenesis pathway that unfolds in this model (RIP1-Tag2, RT2) culminates in multifocal invasive carcinomas and infrequent metastasis to liver. There are proving to be multiple components to the invasive and metastatic capabilities in this model, and two will be presented.
One mechanism affects local invasion, which we have found is mediated in part by an unexpected signaling pathway, involving an NMDA receptor and its ligand, glutamate. We previously reported (Li and Hanahan, 2013) that autocrine glutamate-to-NMDAR signaling is activated in cancer cells at the margins of tumors; ex vivo assays suggest that interstitial pressure differentials between solid tumor and surrounding tissue elicit fluid flow and consequent activation of NMDAR and secretion of glutamate. Recent unpublished studies have characterized the instrumental role of a polymorphic modifier – GKAP – that governs pro-invasive signaling, and identified downstream effectors. Additionally, we have established that the invasiveness of pancreatic ductal adenocarcinomas (PDAC) is also stimulated by this signaling circuit, and found associations between NMDAR pathway activity and comparatively poor survival in PDAC and other human cancers.
A second mechanism governs liver metastasis in the RT2 PanNET model, involving upregulated microRNAs that abrogate an invasion suppressor. By functionally interrogating microRNAs previously implicated via transcriptome profiling with the metastatic phenotype in this model (Olson et al 2009), we have in unpublished studies identified miRs that specifically contribute to metastatic seeding, by enabling disseminating cancer cells to evade a barrier to metastatic seeding present in the liver tissue microenvironment.
Finally, the aforementioned NMDAR signaling pathway is being implicated in brain-metastatic breast cancer, as will be discussed.