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Profiling Cancer-Associated Fibroblasts in Melanoma

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Profiling Cancer-Associated Fibroblasts in Melanoma International Journal of Molecular Sciences Article Profiling Cancer-Associated Fibroblasts in Melanoma Federica Papaccio 1,*,† , Daniela Kovacs 1,† , Barbara Bellei 1,† , Silvia Caputo 1, Emilia Migliano 2 , Carlo Cota 3 and Mauro Picardo 1 1 Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy; [email protected] (D.K.); [email protected] (B.B.); [email protected] (S.C.); [email protected] (M.P.) 2 Department of Plastic and Regenerative Surgery, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy; [email protected] 3 Genetic Research, Molecular Biology and Dermatopathology Unit, San Gallicano Dermatological Institute IRCCS, 00144 Rome, Italy; [email protected] * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Solid tumors are complex systems characterized by dynamic interactions between neoplas- tic cells, non-tumoral cells, and extracellular components. Among all the stromal cells that populate tumor microenvironment, fibroblasts are the most abundant elements and are critically involved in disease progression. Cancer-associated fibroblasts (CAFs) have pleiotropic functions in tumor growth and extracellular matrix remodeling implicated in local invasion and distant metastasis. CAFs additionally participate in the inflammatory response of the tumor site by releasing a vari- ety of chemokines and cytokines. It is becoming clear that understanding the dynamic, mutual melanoma–fibroblast relationship would enable treatment options to be amplified. To better charac- terize melanoma-associated fibroblasts, here we analyzed low-passage primary CAFs derived from Citation: Papaccio, F.; Kovacs, D.; advanced-stage primary skin melanomas, focusing on the immuno-phenotype. Furthermore, we Bellei, B.; Caputo, S.; Migliano, E.; assessed the expression of several CAF markers and the production of growth factors. To deepen Cota, C.; Picardo, M. Profiling the study of CAF–melanoma cell crosstalk, we employed CAF-derived supernatants and trans-well Cancer-Associated Fibroblasts in co-culture systems to evaluate the influences of CAFs on (i) the motogenic ability of melanoma cells, Melanoma. Int. J. Mol. Sci. 2021, 22, (ii) the chemotherapy-induced cytotoxicity, and (iii) the release of mediators active in modulating 7255. https://doi.org/10.3390/ tumor growth and spread. ijms22147255 Keywords: melanoma; CAF; tumor microenvironment; stroma; inflammation Academic Editor: Terrence Piva Received: 14 May 2021 Accepted: 25 June 2021 1. Introduction Published: 6 July 2021 Melanoma is an aggressive melanocytic neoplasm with an increasing annual number Publisher’s Note: MDPI stays neutral of cases, more so than other solid tumors, and treatment resistant [1–3]. Despite accounting with regard to jurisdictional claims in for about 4% of skin cancers, melanoma is responsible for the majority of cutaneous cancer published maps and institutional affil- mortality and about 1–2% of all cancer deaths [4,5]. The survival of patients is closely iations. associated with early detection. However, little is understood about predicting biomarkers to identify a prognostic subtype of melanoma, including the specific contribution of the tumor microenvironment. Although a tumor is a complex system resulting from the inter- actions between transformed cells and the surrounding tissue, studies of oncogenesis have mainly focused on the former [6], particularly in melanoma due to the highest mutational Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. burden of any cancer, partially attributed to UV-induced DNA damage. However, recent This article is an open access article studies have shown that stromal cells surrounding the cancer nest play a major role in distributed under the terms and progression and invasion [7]. Activated fibroblast, called cancer-associated fibroblast (CAF), conditions of the Creative Commons is a recurrent cell type present in the tumor microenvironment [8,9]. This type of fibroblast Attribution (CC BY) license (https:// demonstrated a distinct phenotype compared to its “normal” counterpart [10]. Starting creativecommons.org/licenses/by/ from the early tumor stage, due to continuous paracrine stimulation by transformed cells, 4.0/). enclosing stromal fibroblasts are induced to initiate phenotypic, molecular, and biochemical Int. J. Mol. Sci. 2021, 22, 7255. https://doi.org/10.3390/ijms22147255 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 7255 2 of 14 transitions and to transdifferentiate into CAFs. These cells are frequently described as simi- lar to myofibroblasts abundantly expressing the highly contractile protein α-smooth muscle actin (α-SMA) seen during the wound healing process and in fibrotic conditions [11]. CAFs are distinguished from their normal counterparts by the expression of several markers, such as fibroblast-specific protein-1 (FSP-1, also referred to as S100A4), fibroblast-activating protein (FAP), platelet-derived growth factor receptor-alpha/beta (PDGFR α/β), tenascin- C, desmin, collagen 11-α1 (COL11A1), vimentin, and fibronectin. However, a univocal molecular definition of a CAF profile is as yet lacking. Several studies have revealed CAF heterogeneity, which implies cancer type-specific features, inter-patient and stage-linked variability, and intra-tumoral subsets [12–14]. A specific profile of fibroblast-associated melanoma genesis has not yet been defined. On the other hand, chronic and long-term exposure to UV radiation, the major etiological factor in skin cancer, causes changes in dermal fibroblasts, resulting in increased secretion of growth factors and in the acquisition of the senescent-like phenotype similar to that observed in cancer-activated ones [15–17]. Therefore, modification in the stroma can act independently of melanocytic cell alterations, thus moving as a driver of the tumorigenic process. Consequently, in the skin, activation of fibroblasts might precede the recruitment of stromal cells by tumoral cells, a process that includes paracrine stimulation due to the pro-mitogenic tumor milieu, considering also the extraordinary secretory activity of melanoma cells [18,19]. The presence of a large number of CAFs in the tumor stroma is associated with an increased risk of invasion, metastasis, and poor prognosis of several different types of cancers [20–22]. Because of the great capac- ity of fibroblasts to secrete extracellular matrix (ECM) components and ECM-remodeling enzymes, both CAF expression profile and CAF density drive the architecture modification of host tissue. In melanoma, the stiffness of the surrounding ECM has been linked to tumor aggressiveness and the acquisition of drug resistance [1]. The capacity to sustain cancer depends largely on augmented pro-mitogenic peptides that facilitate tumor growth, whereas secreted inflammatory mediators operate in con- flicting modalities: both tumor-antagonizing and tumor-promoting [23,24]. The balance between pro-inflammatory and anti-inflammatory cytokines in the tumor area strongly im- pacts a patient’s prognosis. Melanoma-associated fibroblasts have also been demonstrated to play an important role in the induction of immune suppression via melanoma–stroma crosstalk, and several studies have related CAF abundance with targeted drug resistance as well as checkpoint inhibitor resistance in advanced melanoma [17,25–27]. Among the immune modulators involved in CAF activation, IL-1β seems to be a driver of melanoma invasion in vitro and in vivo [28]. Cytokines produced by dermal fibroblasts, such as interleukin-6 and -8 (IL-6, IL-8), interferon-γ (INF-γ), tumor necrosis factor-alpha (TNF- α)[29,30], and a variety of C-X-C motif chemokine ligands (CXCLs) [30], can mobilize immune cells. In this study, we aimed to characterize a panel of cancer-associated fibroblast cell lines freshly isolated from melanoma lesions, focusing on their phenotypical and functional features. In addition, the influences of CAFs on melanoma cell behavior were investigated by employing cell supernatants and co-culture systems to mimic in vitro the cell–cell crosstalk existing in the tumor microenvironment. 2. Results 2.1. Expression Profile of Melanoma-Associated Fibroblast Markers We firstly characterized primary fibroblast cultures from fresh skin melanoma samples, evaluating the mRNA level of a large panel of markers commonly used to identify CAFs in various tumor types. We selected groups of genes covering biological processes linked to tumor growth and invasion and known to involve CAFs, i.e., inflammation, tissue remodeling, angiogenesis, and metabolic reprogramming. In addition, as numerous studies have recently revealed a role for CAFs in mediating anti-tumor immune response [31], we evaluated the expression of PD ligand 1 and 2 (PDL-1, PDL-2). The levels of most of the analyzed genes tended to be higher in CAFs in comparison to NHFs. Among Int. J. Mol. Sci. 2021, 22, 7255 3 of 14 them, MMP2, IL-8, and PDL-2 reached statistical significance. The high variability in basal level of gene expression may reflect the wide heterogeneity and complexity of the tumor milieu existing in vivo. Expression levels of the extensively identified CAF marker α-SMA was increased, as well as that of FSP1, whereas other commonly used markers such as PDGFRα/β did not show differences in their mRNA levels between CAFs and NHFs. No evident differences resulted in the mRNA transcripts for the CAF-associated
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