Article Alert: Cellular Interactions in the Tumor Microenvironment Drive Pancreatic Malignancies

The tumor microenvironment (TME) is a heterogeneous, dynamic, and still poorly understood entity that drives malignancy and metastasis. Though these cellular and biochemical milieus vary between cancers, they generally consist of a complex interplay between tumor cells, stromal cells, infiltrating immune cells, vasculature, and matrix (1). Cancer biologists are realizing that defining the cell-cell associations and crosstalk that occur within TMEs may introduce novel therapeutic opportunities to block or otherwise influence these interactions.

To this end, an intriguing paper by Chen et al. has taken a major step in expanding our knowledge of the TME in pancreatic ductal cell adenocarcinomas (PDAC) (2). Using mouse models and human PDAC specimens, the authors employ a host of elegant techniques to demonstrate mechanistically how close association between tumor cells and fibroblasts promote invasion and metastasis. The essential molecular event is homophilic binding between ATP1A1 molecules found on tumor cells and fibroblasts, which results in calcium oscillations, NF-κB activation, and activin A secretion. The increased activin A exerts both juxtacrine and autocrine effects, involving induction of epithelial-mesenchymal transition (EMT) in the tumor cell and activation of peritumoral αSMA⁺ myofibroblasts, respectively. Their model presents a detailed molecular basis for TME plasticity in PDAC and a clearer picture of what is occurring at tumor invasion fronts to enable invasion and metastasis.

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