Identifying mechanisms of macrophage-induced metastasis in pancreatic ductal adenocarcinoma.

Abstract

e15705 Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal, incurable disease. Macrophages are one of the most abundant, multifunctional immune cell populations in the tumor microenvironment and a major component of the immune infiltrate in many solid tumors. Methods: Employing a multi-omics approach, PDAC cell lines and primary macrophages were CTAP (cell-type specific labelling using amino acid precursors)-labelled and admixed together for a prolonged period of time. To identify cell-of-origin of novel RNA and proteins, these mixed co-cultures were FACS sorted for downstream RNA-sequencing analysis or harvested in bulk for downstream proteome and secretome analysis. Results: Here, we provide new insight into the dichotomous relationship between epithelial and mesenchymal phenotypes of PDAC cells in 3D culture. We report the ability of PDAC mesenchymal cells to form vascular mimicry-like structures in a 3D in vitro assay of invasion. Additionally, we demonstrate that macrophages have the ability to impart a pro-invasive phenotype to PDAC cells when co-cultured in 3D, regardless of EMT (epithelial-to-mesenchymal transition) status. Preliminary integration of cell culture transcriptomes with CTAP-TMT proteomes and secretomes implicates several key epithelial- and macrophage-derived signalling molecules as principal instructing signals for mediating the observed pro-invasive phenotype. Conclusions: Blockade of these signalling molecules or their receptors disrupted the crosstalk between PDAC cells and macrophages within the tumor microenvironment and impaired the ability of macrophages to induce a pro-invasive phenotype to PDAC cells.