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Crosstalk Between Tumor and Stromal Cells in Pancreatic Ductal Adenocarcinoma

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Crosstalk Between Tumor and Stromal Cells in Pancreatic Ductal Adenocarcinoma International Journal of Molecular Sciences Review Crosstalk between Tumor and Stromal Cells in Pancreatic Ductal Adenocarcinoma Nadine Sperb, Miltiadis Tsesmelis and Thomas Wirth * Institute of Physiological Chemistry, University of Ulm, 89081 Ulm, Germany; [email protected] (N.S.); [email protected] (M.T.) * Correspondence: [email protected] Received: 25 June 2020; Accepted: 29 July 2020; Published: 31 July 2020 Abstract: Pancreatic ductal adenocarcinoma (PDAC) remains a lethal cancer. The poor prognosis calls for a more detailed understanding of disease biology in order to pave the way for the development of effective therapies. Typically, the pancreatic tumor is composed of a minority of malignant cells within an excessive tumor microenvironment (TME) consisting of extracellular matrix (ECM), fibroblasts, immune cells, and endothelial cells. Research conducted in recent years has particularly focused on cancer-associated fibroblasts (CAFs) which represent the most prominent cellular component of the desmoplastic stroma. Here, we review the complex crosstalk between CAFs, tumor cells, and other components of the TME, and illustrate how these interactions drive disease progression. We also discuss the emerging field of CAF heterogeneity, their tumor-supportive versus tumor-suppressive capacity, and the consequences for designing stroma-targeted therapies in the future. Keywords: PDAC; CAF; immune microenvironment; tumor microenvironment; cancer metabolism; CAF heterogeneity 1. Cancer-Associated Fibroblasts Are Key Players in PDAC Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid cancers, with a 5-year relative survival rate of 9% [1]. Currently representing the fourth leading cause of cancer-related deaths in the United States, pancreatic cancer is predicted to become the second most lethal cancer type by 2030 [1,2]. Despite extensive research efforts over the past decades, progress in the diagnosis and treatment of the disease remains elusive. The majority of patients are diagnosed at an advanced stage when the tumor is unresectable and metastasis is already present. Large-scale cancer genomic studies have revealed a complex mutational landscape in PDAC. A total of 32 recurrently mutated genes have been identified that aggregate into 10 molecular mechanisms and primarily drive the initiation and progression of the disease [3]. The most frequent oncogenic events include activating mutations of KRAS in over 90% of cases as well as mutations in TP53, CDKN2A, and SMAD4 in over 50%, among a milieu of diverse genes mutated at low prevalence [4]. Fibrotic desmoplasia is one of the hallmarks of PDAC development, while cancer cells represent only a minority of the tissue mass in a pancreatic tumor. It is clear now that the dense fibrotic stroma is not just a bystander, but an active player during PDAC progression. This desmoplastic reaction, which may exceed 90% of the entire tumor volume, is characterized by the recruitment and activation of cancer-associated fibroblasts (CAFs), extensive extracellular matrix (ECM) deposition and remodeling, changes in immune surveillance, and altered vasculature. Multiple studies demonstrated that the stromal response and consequently the altered interactions between cancer cells and their surrounding environment promote tumor progression, invasion, metastasis, and chemoresistance [5–8]. Int. J. Mol. Sci. 2020, 21, 5486; doi:10.3390/ijms21155486 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 5486 2 of 23 CAFs are recognized as the key cell population and active component of the tumor microenvironment (TME), which undergo morphological and functional changes when compared to normal fibroblasts. They secrete ECM proteins as well as soluble factors such as chemokines and cytokines [9,10]. There exist numerous sources of CAFs that group into four major categories (Figure1). CAFs can originate from quiescent resident fibroblasts that are reprogrammed by adjacent tumor cells to form protumorigenic CAFs. For example, cancer cell-derived transforming growth factor-β (TGF-β) represents one of the most important and well-studied factors inducing CAF activation [11,12]. Interleukin-6 (IL-6), Sonic hedgehog (SHH), and platelet-derived growth factor (PDGF) are also known fibroblast-activating factors that stimulate the production of CAFs, with the latter being an essential initiator of the desmoplastic reaction in tumors [13–16]. In addition to extracellular molecules such as growth factors and cytokines, other mechanisms of CAF activation have been reported. Exosomes released by cancer cells can transfer protein, RNA, and microRNA (miRNA) to stromal fibroblasts, thereby contributing to their recruitment and activation [17,18]. The education process can be further mediated by local hypoxia and reactive oxygen species (ROS). As an example, ROS were found to promote the conversion of fibroblasts into myofibroblasts through the accumulation of the hypoxia-inducible factor (HIF)-1α transcription factor, whereas antioxidants were shown to reduce HIF-1α levels, thus inhibiting numerous myofibroblast features [19]. Moreover, widespread epigenetic reprogramming has recently emerged as a new mechanism driving de novo differentiation into CAFs [20]. Besides resident tissue fibroblasts, pancreatic stellate cells (PSCs) represent a distinct cell type and are categorized as CAFs when seen in cancer tissue. Once activated, these cells exhibit a loss of vitamin A reserves and acquire a myofibroblast-like phenotype, similar to activated normal fibroblasts. PSCs are generally considered to be the most important source of CAFs in the PDAC context and are responsible for the majority of the desmoplastic reaction [21,22]. In addition to the local CAF precursors, increasing evidence suggests that bone marrow-derived mesenchymal stem cells MSCs (BMSCs) are actively recruited to the tumor site, where they can differentiate into a substantial proportion of CAFs [23,24]. The third and fourth sources of CAFs are epithelial or endothelial cells that are in close proximity to cancer cells and undergo epithelial-to-mesenchymal transition (EMT) or endothelial-to-mesenchymal transition (EndMT), respectively [25,26]. Several cellular markers allow discriminating between quiescent fibroblasts and activated CAFs. The most commonly used CAF biomarkers to date comprise α-smooth muscle actin (α-SMA), fibroblast activation protein (FAP), fibroblast-specific protein 1 (FSP1), platelet-derived growth factor receptor-α (PDGFRα), PDGFRβ, and podoplanin (PDPN/gp38) [27–29]. α-SMA was initially considered as “the” pan-CAF marker, as, specifically, PSCs upon activation lose their vitamin A lipid droplet expression and start to exhibit myofibroblast-like characteristics staining positive for α-SMA [21]. Analysis of CAFs in a genetically engineered PDAC mouse model confirmed that approximately 75% of PDAC CAFs indeed express α-SMA. However, using a second marker, PDGFRα, the authors observed only limited overlap with the α-SMA positive fraction and an additional population (~16%) that expressed neither of the two markers [30]. In line with this, another study identified basically two separate CAF populations, being either α-SMA or Fsp1 positive [28]. Together, this indicates that there exists no unique CAF biomarker to define the entire CAF population. Instead, markers to identify CAFs have demonstrated heterogeneity in expression, pointing towards the existence of distinct subpopulations, where each subset is characterized by a specific combination of several markers. This heterogeneity is important to consider when comparing studies and interpreting results that utilized different markers or panels to either isolate or target CAFs. Int. J. J. Mol. Mol. Sci. Sci. 20202020,, 2121,, x 5486 FOR PEER REVIEW 33 of of 23 Figure 1. Heterogenous sources and activation mechanisms of cancer-associated fibroblasts (CAFs). CAFs can originate from pre-existing fibroblasts and quiescent stellate cells (via activation), bone marrow-derived mesenchymal stem cells (BMSCs) (via recruitment), epithelial cells (through epithelial-to-mesenchymal Figure 1. Heterogenous sources and activation mechanisms of cancer-associated fibroblasts (CAFs). transition (EMT)), as well as from endothelial cells (through endothelial-to-mesenchymal transition CAFs can originate from pre-existing fibroblasts and quiescent stellate cells (via activation), bone (EndMT)). Abbreviations: pancreatic ductal adenocarcinoma (PDAC); extracellular matrix (ECM). marrow-derived mesenchymal stem cells (BMSCs) (via recruitment), epithelial cells (through 2. Bidirectionalepithelial-to-mesenchymal Cancer Cell–CAF transition Crosstalk (EMT)), Promotes as well as Tumorfrom endothelial Progression cells (through endothelial- to-mesenchymal transition (EndMT)). Abbreviations: pancreatic ductal adenocarcinoma (PDAC); extracellularIn 2008, Vonlaufen matrix (ECM). et al. demonstrated for the first time the tumor-promoting interactions between cancer cells and the stromal component in a physiologically representative in vivo situation [31]. 2.Orthotopic Bidirectional co-injection Cancer ofCell–CAF pancreatic Crosstalk cancer cells Promotes with PSCs Tumor into Progression the tail of the pancreas of nude mice significantly enhanced the pancreatic tumor growth rate as well as the occurrence of regional and distantIn metastasis2008, Vonlaufen compared et toal. thedemonstrated injection ofcancer for the cells first alone. time Furthermore, the tumor-promoting they provided interactions evidence
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