Influence of Tumor Microenvironment and Fibroblast Population Plasticity on Melanoma Growth, Therapy Resistance and Immunoescape

Romano, Veronica; Belviso, Immacolata; Venuta, Alessandro; Ruocco, Maria Rosaria; Masone, Stefania; Aliotta, Federica; Fiume, Giuseppe; Montagnani, Stefania; Avagliano, Angelica; Arcucci, Alessandro

doi:10.3390/ijms22105283

Cited by 37 publications

(38 citation statements)

References 184 publications

(307 reference statements)

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“…SKCM cancer cells and the tumor microenvironment (TME) constitute the SKCM tissue [ 30 ]. The TME of SKCM includes the surrounding immune cells, fibroblasts, inflammatory cells, various signaling molecules, and extracellular matrix.…”

Section: Discussionmentioning

confidence: 99%

Low expression of endoplasmic reticulum stress-related gene SERP1 is associated with poor prognosis and immune infiltration in skin cutaneous melanoma

Fan

Liang

2021

Aging

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Stress-associated endoplasmic reticulum protein 1 (SERP1) is a gene induced by endoplasmic reticulum (ER) stress and a major contributor to multiple tumor types. Skin cutaneous melanoma (SKCM) is a highly aggressive and fatal cancer with poor treatment outcomes after progression. In this study, we evaluated SERP1’s role in tumorigenesis, prognosis, and immune infiltration in SKCM. Patients with SKCM had low SERP1 expression. We identified differentially expressed genes between high- and low-SERP1 expression groups and conducted functional, pathway, and gene enrichment analyses. Protein–protein (PPI) and gene–gene interaction (GGI) networks were constructed via STRING and GeneMANIA, respectively. SERP1 mutation information was obtained through cBioPortal; location in the skin was identified through the Human Protein Atlas. Kaplan–Meier analysis revealed an association between low SERP1 expression and overall survival (OS), disease-specific survival (DSS), progress-free interval (PFI) rates, and worse prognosis in patients with multiple clinicopathological features. Cox regression analysis and nomograms further presented SERP1 level as an independent prognostic factor for patients with SKCM. Furthermore, there were significant correlations between SERP1 expression and immune infiltrates; thus, low SERP1 expression is associated with immune cell infiltration and can be considered a poor prognostic biomarker in patients with SKCM. Stress-associated endoplasmic reticulum protein 1 (SERP1) is a gene induced by endoplasmic reticulum (ER) stress and a major contributor to multiple tumor types. Skin cutaneous melanoma (SKCM) is a highly aggressive and fatal cancer with poor treatment outcomes after progression. In this study, we evaluated SERP1’s role in tumorigenesis, prognosis, and immune infiltration in SKCM. Patients with SKCM had low SERP1 expression. We identified differentially expressed genes between high- and low-SERP1 expression groups and conducted functional, pathway, and gene enrichment analyses. Protein–protein (PPI) and gene–gene interaction (GGI) networks were constructed via STRING and GeneMANIA, respectively. SERP1 mutation information was obtained through cBioPortal; location in the skin were identified through the Human Protein Atlas. Kaplan–Meier analysis revealed an association between low SERP1 expression and overall survival (OS), disease-specific survival (DSS), progress-free interval (PFI) rates, and worse prognosis in patients with multiple clinicopathological features. Cox regression analysis and nomograms further presented SERP1 level as an independent prognostic factor for patients with SKCM. Furthermore, there were significant correlations between SERP1 expression and immune infiltrates; thus, low SERP1 expression is associated with immune cell infiltration and can be considered a poor prognostic biomarker in patients with SKCM.

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Section: Discussionmentioning

confidence: 99%

Low expression of endoplasmic reticulum stress-related gene SERP1 is associated with poor prognosis and immune infiltration in skin cutaneous melanoma

Fan

Liang

2021

Aging

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“…IL-6 is a well-known pro-inflammatory factor frequently up-regulated in serum and associated with tumor progression [ 33 ]. IL-6 is frequently overproduced by CAFs in different types of cancer [ 34 ] stimulating cancer cell proliferation, survival, invasiveness, and drug resistance [ 14 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…In MM, CAFs express high levels of the mesenchymal protein vimentin, PDGFR, or α-SMA, and they secrete soluble mediators (such as pro-inflammatory proteins IL-6, IL-8, HGF, etc.) [ 13 , 14 ]. They are the most abundant stromal cells in the cutaneous MM environment and have a major influence on melanoma growth and therapy resistance [ 13 , 14 ], especially to BRAFi [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Fibroblasts Influence Metastatic Melanoma Cell Sensitivity to Combined BRAF and MEK Inhibition

Morales

Vigneron

Ferreira

et al. 2021

Cancers

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The sensitivity of melanoma cells to targeted therapy compounds depends on the tumor microenvironment. Three-dimensional (3D) in vitro coculture systems better reflect the native structural architecture of tissues and are ideal for investigating cellular interactions modulating cell sensitivity to drugs. Metastatic melanoma (MM) cells (SK-MEL-28 BRAF V600E mutant and SK-MEL-2 BRAF wt) were cultured as a monolayer (2D) or cocultured on 3D dermal equivalents (with fibroblasts) and treated with a BRAFi (vemurafenib) combined with a MEK inhibitor (MEKi, cobimetinib). The drug combination efficiently inhibited 2D and 3D MM cell proliferation and survival regardless of their BRAF status. Two-dimensional and three-dimensional cancer-associated fibroblasts (CAFs), isolated from a cutaneous MM biopsy, were also sensitive to the targeted therapy. Conditioned media obtained from healthy dermal fibroblasts or CAFs modulated the MM cell’s response differently to the treatment: while supernatants from healthy fibroblasts potentialized the efficiency of drugs on MM, those from CAFs tended to increase cell survival. Our data indicate that the secretory profiles of fibroblasts influence MM sensitivity to the combined vemurafenib and cobimetinib treatment and highlight the need for 3D in vitro cocultures representing the complex crosstalk between melanoma and CAFs during preclinical studies of drugs.

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“…Salemi et al proposed MMP-9 as a new biomarker of response or resistance to the treatment. Moreover, the development of new selective inhibitors for MMPs (MMPs inhibitors) could represent a new promising strategy in melanoma therapy [23,[55][56][57].…”

Section: Tumor Microenvironmentmentioning

confidence: 99%

Dermoscopic Criteria, Histopathological Correlates and Genetic Findings of Thin Melanoma on Non-Volar Skin

Massone

Hofman-Wellenhof

Chiodi

et al. 2021

Genes

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Dermoscopy is a non-invasive, in vivo technique that allows the visualization of subsurface skin structures in the epidermis, at the dermoepidermal junction, and in the upper dermis. Dermoscopy brought a new dimension in evaluating melanocytic skin neoplasms (MSN) also representing a link between clinical and pathologic examination of any MSN. However, histopathology remains the gold standard in diagnosing MSN. Dermoscopic–pathologic correlation enhances the level of quality of MSN diagnosis and increases the level of confidence of pathologists. Melanoma is one of the most genetically predisposed among all cancers in humans. The genetic landscape of melanoma has been described in the last years but is still a field in continuous evolution. Melanoma genetic markers play a role not only in melanoma susceptibility, initiation, and progression but also in prognosis and therapeutic decisions. Several studies described the dermoscopic specific criteria and predictors for melanoma and their histopathologic correlates, but only a few studies investigated the correlation among dermoscopy, pathology, and genetic of MSN. The aim of this work is to review the published data about dermoscopic features of melanoma, their histopathological correlates with regards also to genetic alterations. Particularly, this review will focus on low-CSD (cumulative sun damage) melanoma or superficial spreading melanoma, high-CSD melanoma, and nevus-associated melanoma.

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Influence of Tumor Microenvironment and Fibroblast Population Plasticity on Melanoma Growth, Therapy Resistance and Immunoescape

Cited by 37 publications

References 184 publications

Low expression of endoplasmic reticulum stress-related gene SERP1 is associated with poor prognosis and immune infiltration in skin cutaneous melanoma

Low expression of endoplasmic reticulum stress-related gene SERP1 is associated with poor prognosis and immune infiltration in skin cutaneous melanoma

Fibroblasts Influence Metastatic Melanoma Cell Sensitivity to Combined BRAF and MEK Inhibition

Dermoscopic Criteria, Histopathological Correlates and Genetic Findings of Thin Melanoma on Non-Volar Skin

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