Fibroblast MMP14-Dependent Collagen Processing Is Necessary for Melanoma Growth

Pach, Elke; Brinckmann, Jürgen; Rübsam, Matthias; Kümper, Maike; Mauch, Cornelia; Zigrino, Paola

doi:10.3390/cancers13081984

Cited by 10 publications

(20 citation statements)

References 57 publications

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“…It is increasingly clear that in vitro macrophage polarization protocols do not re-capitulate the complex macrophage phenotypes observed in vivo [ 45 , 46 ]. Single-cell approaches have provided a more complete look into macrophage heterogeneity in tumor infiltrates [ 47 , 48 ], with surrounding cells and cues that influence their behavior and shape their functional response [ 12 , 49 , 50 ]. Developing experimental models to study TAMs in vitro is not as simple as inducing a cell program through a signaling pathway, especially when the definition of polarization state, such as the M2-like profile, has expanded over the years to fit the pathophysiology of the macrophages [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

3D Model of the Early Melanoma Microenvironment Captures Macrophage Transition into a Tumor-Promoting Phenotype

Pizzurro

Liu

Bridges

et al. 2021

Cancers

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Tumor immune response is shaped by the tumor microenvironment (TME), which often evolves to be immunosuppressive, promoting disease progression and metastasis. An important example is melanoma tumors, which display high numbers of tumor-associated macrophages (TAMs) that are immunosuppressive but also have the potential to restore anti-tumor activity. However, to therapeutically target TAMs, there is a need to understand the early events that shape their tumor-promoting profile. To address this, we built and optimized 3D in vitro co-culture systems, composed of a collagen-I matrix scaffolding murine bone-marrow-derived macrophages (BMDMs), YUMM1.7 melanoma cells, and fibroblasts to recreate the early melanoma TME and study how interactions with fibroblasts and tumor cells modulate macrophage immune activity. We monitored BMDM behavior and interactions through time-lapse imaging and characterized their activation and secretion. We found that stromal cells induced a rapid functional activation, with increased motility and response from BMDMs. Over the course of seven days, BMDMs acquired a phenotype and secretion profile that resembled melanoma TAMs in established tumors. Overall, the direct cell–cell interactions with the stromal components in a 3D environment shape BMDM transition to a TAM-like immunosuppressive state. Our systems will enable future studies of changes in macrophage–stromal cross-talk in the melanoma TME

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Section: Discussionmentioning

confidence: 99%

3D Model of the Early Melanoma Microenvironment Captures Macrophage Transition into a Tumor-Promoting Phenotype

Pizzurro

Liu

Bridges

et al. 2021

Cancers

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“…Extensive deposition of extracellular matrix, with enhanced collagen accumulation, is linked to the growth of many cancers [24][25][26], although the influence of collagen is diverse on the different types of cancers. Mice lacking MMP14 in stromal fibroblasts (MMP14 Sf−/− ) display skin fibrosis and reduced melanoma growth due to enhanced collagen I accumulation and increased skin stiffness [13,14]. However, it was unclear whether additional extracellular matrix alterations due to MMP14 deletion in fibroblasts, the primary producer of extracellular matrix in tissues, contribute to the observed effect.…”

Section: Negative Effect Of Mmp14 Sf−/− Fibroblast Matrix On Melanoma Proliferation and Migrationmentioning

confidence: 99%

“…Indeed, MMP14 deletion in fibroblasts led to the development of a fibrosis-like skin phenotype [13]. Dermal alterations, collagen I accumulation, and increased tissue stiffness also restrained melanoma growth [14]. In addition to collagen I, likely other collagens were altered around these tumors, as increased hydroxyproline would result from all types of collagens [14].…”

Section: Introductionmentioning

confidence: 99%

“…Dermal alterations, collagen I accumulation, and increased tissue stiffness also restrained melanoma growth [14]. In addition to collagen I, likely other collagens were altered around these tumors, as increased hydroxyproline would result from all types of collagens [14]. Collagens are a large superfamily of 28 different types presenting the most abundant proteins in the extracellular matrix of vertebrates.…”

Section: Introductionmentioning

confidence: 99%

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Extracellular Matrix Remodeling by Fibroblast-MMP14 Regulates Melanoma Growth

Pach

Kümper

Fromme

et al. 2021

IJMS

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Maintaining a balanced state in remodeling the extracellular matrix is crucial for tissue homeostasis, and this process is altered during skin cancer progression. In melanoma, several proteolytic enzymes are expressed in a time and compartmentalized manner to support tumor progression by generating a permissive environment. One of these proteases is the matrix metalloproteinase 14 (MMP14). We could previously show that deletion of MMP14 in dermal fibroblasts results in the generation of a fibrotic-like skin in which melanoma growth is impaired. That was primarily due to collagen I accumulation due to lack of the collagenolytic activity of MMP14. However, as well as collagen I processing, MMP14 can also process several extracellular matrices. We investigated extracellular matrix alterations occurring in the MMP14-deleted fibroblasts that can contribute to the modulation of melanoma growth. The matrix deposited by cultured MMP14-deleted fibroblast displayed an antiproliferative and anti-migratory effect on melanoma cells in vitro. Analysis of the secreted and deposited-decellularized fibroblast’s matrix identified a few altered proteins, among which the most significantly changed was collagen XIV. This collagen was increased because of post-translational events, while de novo synthesis was unchanged. Collagen XIV as a substrate was not pro-proliferative, pro-migratory, or adhesive, suggesting a negative regulatory role on melanoma cells. Consistent with that, increasing collagen XIV concentration in wild-type fibroblast-matrix led to reduced melanoma proliferation, migration, and adhesion. In support of its anti-tumor activity, enhanced accumulation of collagen XIV was detected in peritumoral areas of melanoma grown in mice with the fibroblast’s deletion of MMP14. In advanced human melanoma samples, we detected reduced expression of collagen XIV compared to benign nevi, which showed a robust expression of this molecule around melanocytic nests. This study shows that loss of fibroblast-MMP14 affects melanoma growth through altering the peritumoral extracellular matrix (ECM) composition, with collagen XIV being a modulator of melanoma progression and a new proteolytic substrate to MMP14.

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“…Studies have shown that MMP14 is involved in the progression of cervical cancer (CC) by promoting angiogenesis, invasion, and lymph node metastasis, and it has also been reported that MMP14 overexpression is associated with poor prognosis of cervical cancer (7)(8)(9). At the same time, a large number of studies have shown that MMP14 is closely related to the invasion, migration, and angiogenesis of ovarian cancer (10), gastric cancer (11), glioma (12), pancreatic cancer (12), hepatocellular carcinoma (13), colon cancer (14), and melanoma (15). However, there has been no study on the effect of MMP14 on the immune infiltration and prognosis of pan tumor cells, which needs to be addressed.…”

Section: Introductionmentioning

confidence: 99%

Immune Infiltration of MMP14 in Pan Cancer and Its Prognostic Effect on Tumors

Zhou

et al. 2021

Front. Oncol.

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BackgroundMatrix metalloproteinase 14 (MMP14) is a member of the MMP family, which interacts with tissue inhibitors of metalloproteinase (TIMPs), and is involved in normal physiological functions such as cell migration, invasion, metastasis, angiogenesis, and proliferation, as well as tumor genesis and progression. However, there has been a lack of relevant reports on the effect of MMP14 across cancers. This study aims to explore the correlation between MMP14 and pan-cancer prognosis, immune infiltration, and the effects of pan-cancer gene mismatch repair (MMR), microsatellite instability (MSI), tumor mutational burden (TMB), DNA methylation, and immune checkpoint genes.MethodsIn this study, we used bioinformatics to analyze data from multiple databases, including The Cancer Genome Atlas (TCGA), ONCOMINE, and Kaplan–Meier plotter. We investigated the relationship between the expression of MMP14 in tumors and tumor prognosis, the relationship between MMP14 expression and tumor cell immune infiltration, and the relationship between MMR gene MMR, MSI, TMB, DNA methylation, and immune checkpoint genes.ResultsMMP14 expression is highly associated with the prognosis of a variety of cancers and tumor immune invasion and has important effects on pan oncologic MMR, MSI, TMB, DNA methylation, and immune checkpoint genes.ConclusionMMP14 is highly correlated with tumor prognosis and immune invasion and affects the occurrence and progression of many tumors. All of these results fully indicate that MMP14 may be a biomarker for the prognosis, diagnosis, and treatment of many tumors and provide new ideas and direction for subsequent tumor immune research and treatment strategies.

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Fibroblast MMP14-Dependent Collagen Processing Is Necessary for Melanoma Growth

Cited by 10 publications

References 57 publications

3D Model of the Early Melanoma Microenvironment Captures Macrophage Transition into a Tumor-Promoting Phenotype

3D Model of the Early Melanoma Microenvironment Captures Macrophage Transition into a Tumor-Promoting Phenotype

Extracellular Matrix Remodeling by Fibroblast-MMP14 Regulates Melanoma Growth

Immune Infiltration of MMP14 in Pan Cancer and Its Prognostic Effect on Tumors

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