Abstract
Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest cancers due to its aggressive and metastatic nature. PDA is characterized by a rich tumor stroma with abundant macrophages, fibroblasts, and collagen deposition that can represent up to 90% of the tumor mass. Activation of the tyrosine kinase receptor AXL and expression of its ligand growth arrest-specific protein 6 (Gas6) correlate with a poor prognosis and increased metastasis in pancreatic cancer patients. Gas6 is a multifunctional protein that can be secreted by several cell types and regulates multiple processes, including cancer cell plasticity, angiogenesis, and immune cell functions. However, the role of Gas6 in pancreatic cancer metastasis has not been fully investigated. In these studies we find that, in pancreatic tumors, Gas6 is mainly produced by tumor associated macrophages (TAMs) and cancer associated fibroblasts (CAFs) and that pharmacological blockade of Gas6 signaling partially reverses epithelial-to-mesenchymal transition (EMT) of tumor cells and supports NK cell activation, thereby inhibiting pancreatic cancer metastasis. Our data suggest that Gas6 simultaneously acts on both the tumor cells and the NK cells to support pancreatic cancer metastasis. This study supports the rationale for targeting Gas6 in pancreatic cancer and use of NK cells as a potential biomarker for response to anti-Gas6 therapy.
Highlights
Growth arrest-specific gene 6 (Gas6) is a multifunctional factor that regulates several processes in normal physiology and pathophysiology [1]
The data presented in this study describe a dual anti-tumor effect of growth arrest-specific protein 6 (Gas6) blockade in pancreatic tumors, shedding light on the anti-cancer mechanism of action of inhibitors of the Gas6Axl pathway and supporting the rationale for using anti-Gas6 therapy in pancreatic cancer patients
In these studies we show that blockade of Gas6 in pancreatic tumors, with either an antiGas6 neutralizing antibody or with warfarin, acts simultaneously on both the tumor cells, altering their epithelial-mesenchymal phenotype, as well as on natural killer (NK) cells, promoting their activation and recruitment to the metastatic site (Figures 6, 7)
Summary
Growth arrest-specific gene 6 (Gas6) is a multifunctional factor that regulates several processes in normal physiology and pathophysiology [1]. Gas binds to the Tyro, Axl, and Mer (TAM) family of receptor tyrosine kinases (TAM receptors) with the highest affinity for Axl [2]. Platelet aggregation, angiogenesis, efferocytosis and inhibits the immune response [3]. Gas and its main receptor Axl are overexpressed in several cancer types including, breast, ovarian, gastric, glioblastoma, lung, and pancreatic cancer and their expression correlates with a poor prognosis [5]. Axl is ubiquitously expressed in all tissues [6] but is notable in cancer cells, macrophages, dendritic cells and natural killer cells for its role in driving immunosuppression and tumor progression [7,8,9]. Several cancer studies have focused on the role of Gas6-Axl signaling on the tumor cells and have demonstrated that Axl activation supports tumor cell proliferation, epithelial-mesenchymal
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