ISG15 is a critical microenvironmental factor for pancreatic cancer stem cells.

Bruno Sainz,Marianthi Tatari,Beatriz Martín,Christopher Heeschen,Susana Guerra

doi:10.1158/0008-5472.can-14-1354

Abstract

Cancer stem cells (CSC) are thought to play a major role in the development and metastatic progression of pancreatic ductal adenocarcinoma (PDAC), one of the deadliest solid tumors. Likewise, the tumor microenvironment contributes critical support in this setting, including from tumor stromal cells and tumor-associated macrophages (TAM) that contribute structural and paracrine-mediated supports, respectively. Here, we show that TAMs secrete the IFN-stimulated factor ISG15, which enhances CSC phenotypes in PDAC in vitro and in vivo. ISG15 was preferentially and highly expressed by TAM present in primary PDAC tumors resected from patients. ISG15 was secreted by macrophages in response to secretion of IFNβ by CSC, thereby reinforcing CSC self-renewal, invasive capacity, and tumorigenic potential. Overall, our work demonstrates that ISG15 is a previously unrecognized support factor for CSC in the PDAC microenvironment with a key role in pathogenesis and progression.

Highlights

The importance of the stroma in promoting cancer initiation and solid tumor growth has been increasingly recognized during recent years [1,2,3]
First- and second-generation sphere formation increased when cells were cultured in the presence of macrophage conditioned media (CM) by about 1.5- to 2-fold, with the greatest increase observed when pancreatic adenocarcinoma (PDAC) cells were cultured with CM from M2-polarized macrophages (Fig. 1A)
tumor-associated macrophages (TAM), known as M2, "alternatively activated" or "protumorigenic" macrophages, are the major cell type of the inflammatory infiltrates present in PDAC tumors [32, 40] and are believed to promote tumorigenesis, matrix remodeling, and metastasis [36, 41, 42]. In accordance with the latter, we observed that compared with M1 macrophages, M2 macrophages were able to promote the self-renewal capacity, modulate the expression of pluripotency- and EMT-associated genes, increase the migratory potential, and enhance the tumorigenic capacity of PDAC cancer stem cells (CSC) in a contactindependent manner

Summary

Introduction

The importance of the stroma in promoting cancer initiation and solid tumor growth has been increasingly recognized during recent years [1,2,3]. We have come to understand that apart from providing structural support for tumor development, the tumor-associated microenvironment of many solid tumors provides cues to a subpopulation of tumor-initiating cells, known as cancer stem cells (CSC), which regulates their self-renewal and tumorigenic and metastatic potential [4]. This is certainly the case for pancreatic adenocarcinoma (PDAC), which consists of a heterogeneous population of tumor cells including (i) CSCs [5, 6], (ii) more differentiated cancer cells, and (iii) an extremely high proportion of desmoplastic stromal tissue and immune cells, which accounts for up to 90% of the tumor mass [7]. Recent but less conclusive evidence suggests that inflammatory cells, such as tumor-associated macrophages (TAM; refs. 1, 8), may play critical roles in the development and progression of numerous tumors, such as PDAC, and the immunomodulatory factors they secrete may be paracrine-mediated

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