GM-CSF Mediates Mesenchymal–Epithelial Cross-talk in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDA) is characterized by a dense stroma consisting of a prevalence of activated fibroblasts whose functional contributions to pancreatic tumorigenesis remain incompletely understood. In this study, we provide the first identification and characterization of mesenchymal stem cells (MSC) within the human PDA microenvironment, highlighting the heterogeneity of the fibroblast population. Primary patient PDA samples and low-passage human pancreatic cancer–associated fibroblast cultures were found to contain a unique population of cancer-associated MSCs (CA-MSC). CA-MSCs markedly enhanced the growth, invasion, and metastatic potential of PDA cancer cells. CA-MSCs secreted the cytokine GM-CSF that was required for tumor cell proliferation, invasion, and transendothelial migration. Depletion of GM-CSF in CA-MSCs inhibited the ability of these cells to promote tumor cell growth and metastasis. Together, these data identify a population of MSCs within the tumor microenvironment that possesses a unique ability, through GM-CSF signaling, to promote PDA survival and metastasis. SIGNIFICANCE The role of stroma in pancreatic cancer is controversial. Here, we provide the first characterization of MSCs within the human PDA microenvironment and demonstrate that CA-MSCs promote tumorigenesis through the production of GM-CSF. These data identify a novel cytokine pathway that mediates mesenchymal–epithelial cross-talk and is amenable to therapeutic intervention.

The role of stromal cancer-associated fibroblasts in pancreatic cancer

“…Waghray et al identified a subpopulation of CAFs designated as cancer-associated mesenchymal stem cells (CA-MSCs) and demonstrated their role in invasion as mediated by granulocyte-macrophage colony-stimulating factor (GM-CSF) [42]. Their findings mirrored those of Heeg et al in demonstrating larger tumors with the addition of CA-MSCs for in vivo models, but they also demonstrated increased proliferation of cancer cells themselves with increased Ki67 expression as well as stromal expansion [39].…”

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

“…But recent studies also show that a subset of CAFs are derived from mesenchymal stem cells (MSCs) (figure 2). The MSCs associated with PDA show protumourigenic properties, partly because of their ability to induce tumour-promoting polarisation of macrophages,62 and by enhancing growth, invasion and the metastatic potential through secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) 63. In addition to PSCs and MSCs, there are other potential sources since CAFs have been shown to originate from activated resident fibroblasts, endothelial cells and fibrocytes in other tumour entities 59 64.…”

HNF1A is a Novel Oncogene and Central Regulator of Pancreatic Cancer Stem Cells

“…The exceeding lethality of PDA is attributed to a complex of qualities frequent to the disease including early and aggressive metastasis and limited responsiveness to current standards of care. While both aspects are in-and-of-themselves multifaceted and can be partially attributed to factors such as the tumor microenvironment (Olive et al, 2009, Provenzano et al, 2012, Waghray et al, 2016 and the mutational profile of the tumor cells (Yachida et al, 2012), cancer stem cells (CSCs) have also been identified to 5 samples (data not shown). Using previously described measures of PCSC function (Li et al, 2007, Li et al, 2011, including co-expression of the PCSC marker CD24 (Supplementary Figure 1B), the ability for isolated subpopulations to reestablish cellular heterogeneity (Supplementary Figure 1C), the ability to form tumorspheres under non-adherent/serum-free culture conditions (Supplementary Figure 1D), and initiate tumors in immune-deficient mice ( Supplementary Table 1), we found that P2 cells showed greater enrichment for cells with PCSC properties than their P1 and P3 counterparts.…”