Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with a very poor prognosis. At the same time, its incidence is on the rise, and PDAC is expected to become the second leading cause of cancer-related death by 2030. Despite extensive work on new therapeutic approaches, the median overall survival is only 6-12 months after diagnosis and the 5-year survival is less than 7%. While pancreatic cancer is particularly difficult to treat, patients usually succumb not to the growth of the primary tumor, but to extensive metastasis; therefore, strategies to reduce the migratory and metastatic capacity of pancreatic cancer cells merit close attention. The vast majority of pancreatic cancers harbor RAS mutations. The outstanding relevance of the RAS/MEK/ERK pathway in pancreatic cancer biology has been extensively shown previously. Due to their high dependency on Ras mutations, pancreatic cancers might be particularly sensitive to inhibitors acting downstream of Ras. Herein, we use a genetically engineered mouse model of pancreatic cancer and primary pancreatic cancer cells were derived from this model to demonstrate that small-molecule MEK inhibitors functionally abrogate cancer stem cell populations as demonstrated by reduced sphere and organoid formation capacity. Furthermore, we demonstrate that MEK inhibition suppresses TGFβ-induced epithelial-to-mesenchymal transition and migration in vitro and ultimately results in a highly significant reduction in circulating tumor cells in mice.

Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related mortality. Cancer stem cells (CSCs) have been shown to be the drivers of pancreatic tumor growth, metastasis, and chemoresistance, but our understanding of these cells is still limited by our inability to efficiently identify and isolate them. While a number of markers capable of identifying pancreatic CSCs (PaCSCs) have been discovered since 2007, there is no doubt that more markers are still needed. The anthrax toxin receptor 1 (ANTXR1) was identified as a functional biomarker of triple-negative breast CSCs, and PDAC patients stratified based on ANTXR1 expression levels showed increased mortality and enrichment of pathways known to be necessary for CSC biology, including TGF-β, NOTCH, Wnt/β-catenin, and IL-6/JAK/STAT3 signaling and epithelial to mesenchymal transition, suggesting that ANTXR1 may represent a putative PaCSC marker. In this study, we show that ANTXR1+ cells are not only detectable across a panel of 7 PDAC patient-derived xenograft primary cultures but ANTXR1 expression significantly increased in CSC-enriched 3D sphere cultures. Importantly, ANTXR1+ cells also coexpressed other known PaCSC markers such as CD44, CD133, and autofluorescence, and ANTXR1+ cells displayed enhanced CSC functional and molecular properties, including increased self-renewal and expression of pluripotency-associated genes, compared to ANTXR1- cells. Thus, this study validates ANTXR1 as a new PaCSC marker and we propose its use in identifying CSCs in this tumor type and its exploitation in the development of CSC-targeted therapies for PDAC.