Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA348373 | ENA |
REPOSITORIES: ENA
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Project description:Sentinel lymph node, the first node draining the primary tumor, is a key component of tumor microenvironment promoting immune tolerance. In melanoma, sentinel node is one of the most important prognostic factors and the most frequent site of regional metastasis. To unravel the immunomodulatory pathways that are triggered by melanoma cells in the draining node that allow tumor spreading, transcriptional profiles associated to disease progression were analyzed in archival sentinel node biopsies (SNB). Gene expression profiles of melanoma-positive and negative SNB selected to maximize the differences in terms of disease stage and course, revealed subgroups correlating with regional node involvement and disease progression within positive biopsies. Transcriptional profiles revealed that genes showing differential expression between tumor-positive SNB with/without disease progression were mainly related to inflammatory response and that were mostly down regulated in patients with poor prognosis. TNFRSF8 encoding CD30 showing up regulation in SNB from patients with progressing disease displayed higher expression by immunohistochemical staining compared to SNB from non progressing patients. Subpopulations of CD30 positive CD4/CD8 double negative and CD4 Foxp3/PD-1 CD147 positive T cells were identified by flow cytometry analysis in metastatic nodes, suggesting a potential role of regulatory and tolerogenic T cells in melanoma progression. Cutaneous melanoma patients undergoing SNB biopsy in 2001-2004 with available 5M-bM-^@M-^Syear follow-up clinical data were selected. Data relative to 752 cases was extracted, 80% (n= 603) with a negative SNB and 20% (n=149) with SNB positivity for melanoma metastases. The latter underwent regional lymphadenectomy by CLND and 30% (n=44) resulted positive for melanoma metastases at non-sentinel regional lymph nodes while 70% (n=105) resulted negative. Analysis of follow-up data showed that disease recurrence at 5 yrs occurred in 9% SNB negative patients, 14% of the patients with positive SNB resulting negative at CLND, and in 57% of the patients with positive SNB resulting positive at CLND, consistent to the range of previously reported rates (Santinami M 2009, Balch CM 2009). In order to exploit gene expression profiles to unravel molecular modifications occurring in SNB from patients with progressing disease we selected two groups of cases representing the extremes of the survey, i.e. patients positive at CLND (stage IIIB-C) recurring within 5 years follow-up (SNB-PP), and patients negative at CLND (stage IIIA-B) and non-relapsing at 5 years (SNB-PN). In addition, a group of negative SNB patients without disease recurrence at 5 years was selected and analysed for comparison as tumor negative SNB (SNB-N).
2013-08-01 | E-GEOD-39945 | biostudies-arrayexpress
Project description:Sentinel lymph node, the first node draining the primary tumor, is a key component of tumor microenvironment promoting immune tolerance. In melanoma, sentinel node is one of the most important prognostic factors and the most frequent site of regional metastasis. To unravel the immunomodulatory pathways that are triggered by melanoma cells in the draining node that allow tumor spreading, transcriptional profiles associated to disease progression were analyzed in archival sentinel node biopsies (SNB). Gene expression profiles of melanoma-positive and negative SNB selected to maximize the differences in terms of disease stage and course, revealed subgroups correlating with regional node involvement and disease progression within positive biopsies. Transcriptional profiles revealed that genes showing differential expression between tumor-positive SNB with/without disease progression were mainly related to inflammatory response and that were mostly down regulated in patients with poor prognosis. TNFRSF8 encoding CD30 showing up regulation in SNB from patients with progressing disease displayed higher expression by immunohistochemical staining compared to SNB from non progressing patients. Subpopulations of CD30 positive CD4/CD8 double negative and CD4 Foxp3/PD-1 CD147 positive T cells were identified by flow cytometry analysis in metastatic nodes, suggesting a potential role of regulatory and tolerogenic T cells in melanoma progression.
2013-08-01 | GSE39945 | GEO
Project description:Gene expression profiles of tumor-positive sentinel lymph node biopsies from cutaneous melanoma patients
| PRJNA172138 | ENA
Project description:Cutaneous melanoma first metastasizes into sentinel lymph nodes that control the lymphatic drain from the area of the primary tumor. This observation is used clinically for melanoma patients with primary melanomas thicker than 1mm (tumor stage ≥T2a), for these patients sentinel lymph node biopsy has become an important and routinely performed diagnostic procedure. The importance of sentinel node analysis is reflected by a significant better prognosis of melanoma patients with tumor free sentinel nodes compared to patients with metastatic sentinel nodes. Although intensively studied, not much is known about mechanisms responsible for the development of melanoma metastasis.To analyze gene expression in mouse SLNs of M24met tumor bearing animals as compared to tumor free control animals, SLNs were taken at different time points and analyzed for the presence of human M24met to classify SLNs into control, negative, macro metastatic SLN. After categorized SLNs were subjected to microarray analysis.
2011-07-15 | GSE30688 | GEO
Project description:Cutaneous melanoma first metastasizes into sentinel lymph nodes that control the lymphatic drain from the area of the primary tumor. This observation is used clinically for melanoma patients with primary melanomas thicker than 1mm (tumor stage ≥T2a), for these patients sentinel lymph node biopsy has become an important and routinely performed diagnostic procedure. The importance of sentinel node analysis is reflected by a significant better prognosis of melanoma patients with tumor free sentinel nodes compared to patients with metastatic sentinel nodes. Although intensively studied, not much is known about mechanisms responsible for the development of melanoma metastasis.To analyze gene expression in mouse SLNs of M24met tumor bearing animals as compared to tumor free control animals, SLNs were taken at different time points and analyzed for the presence of human M24met to classify SLNs into control, negative, macro metastatic SLN. After categorized SLNs were subjected to microarray analysis. To analyze gene expression in mouse SLNs of human M24met tumor bearing animals as compared to tumor free control animals, SLNs were taken at different time points and analyzed for the presence of human M24met to classify SLNs into control, negative, macro metastatic SLN. Briefly, explanted SLNs were stored in RNA later (Ambion, Austin, TX) and DNA as well as RNA was extracted using AllPrep DNA/RNA Mini Kit and RNeasy Micro Kit (Qiagen, Valencia, CA) according to manufacturer’s instructions. To detect human cells in mouse SLNs we used a polymerase chain reaction method for the detection of a human-specific 850-bp fragment of the alpha-satellite DNA on human chromosome 17. For analysis of gene expression RNA from control SLN from tumor free animals (control), RNA from tumor negative SLN (negative), and RNA from macro metastatic SLN (positive) from tumor bearing animals was used to analyze gene expression on Mouse Genome 430A 2.0 Arrays (Affymetrix, Santa Clara, CA)
2011-07-14 | E-GEOD-30688 | biostudies-arrayexpress
Project description:We analyzed microRNA profiles in archival FFPE sentinel node biopsy (SNB) from melanoma patients with different outcomes. Tumor-negative SNB (N), and tumor-positive SNB from patients with (PP) or without disease progression at 5 years follow-up (PN) were analyzed.
2017-01-31 | GSE88727 | GEO
Project description:Several studies have demonstrated that melanoma-derived exosomes home in sentinel lymph nodes favoring metastasis. Here, we determined the proteomic signature in exosomes derived from lymph node metastatic models. We found a signature of genes over-expressed and proteins hyper-secreted in exosomes related to lymph node metastasis in the B16 mouse melanoma model. Out of these candidates, we found that Emilin1, a protein with an important function in lymph node physiology, was hyper-secreted in exosomes. Interestingly, we found that Emilin1 is degraded and secreted in exosomes as a mechanism favoring metastasis. Indeed, we found that Emilin1 has a tumor suppressor-like role regulating negatively cell viability and migration. Importantly, our in vivo studies demonstrate that Emilin1 overexpression reduced primary tumor growth and metastasis in mouse melanoma models. Analysis in human melanoma samples showed that cells expressing high levels of EMILIN1 are reduced in metastatic lesions. Overall, our analysis suggests a novel mechanism involved in the inactivation of Emilin1 in melanoma favouring melanoma progression and metastasis.
2021-07-16 | PXD018891 | Pride
Project description:Liquid biopsies are becoming imperative on early patient diagnosis, prognosis and evaluation of residual disease. The use of circulating extracellular vesicles (EVs) as surrogate markers of tumor progression could be a powerful tool in the clinical setting. EVs in plasma have emerged as a non-invasive option to detect metastatic outcome, however sensitivity is low. Here we have characterized the lymph obtained after postoperative lymphadenectomy as a novel biological fluid enriched in EVs. Our proteomic profiling and BRAFV600E/K status determination demonstrate for the first time that EVs from the lymph of melanoma patients are enriched in melanoma-associated proteins and are useful for BRAF mutations detection. Melanoma oncogenic pathways, immunomodulation and platelet activating proteins are enriched in lymph-derived exosomes from patients with distal lymph node spread compared to local/early spreading. Furthermore, patients positive for BRAFV600E mutation on lymph-circulating vesicles had a shorter time of relapse. These data encourage the analysis of lymph-circulating EVs for detection of residual disease and recurrence.
2019-03-13 | PXD012042 | Pride
Project description:Evolution of melanoma from a primary tumor to widespread metastasis is crucially dependent on lymphatic spread. The mechanisms regulating the initial step in metastatic dissemination via regional lymph nodes remain largely unknown. We have previously described a dysfunctional immune profile that precedes evidence of metastasis in the first node draining from the primary tumor, the sentinel lymph node (SLN). Herein, we explore the role of melanoma-derived extracellular vesicles (EVs) as mediators of this pre-metastatic niche through cargo-specific polarization of dendritic cells (DCs). Utilizing mass cytometry, pre-metastatic SLNs demonstrate compromised co-stimulatory CD80 expression compared to healthy lymph nodes. Similarly, DCs matured in vitro in the presence of melanoma EVs showed impaired co-stimulation and polarization towards a chronic inflammatory cytokine milieu. Profiling of melanoma EV cargo identified shared proteomic and RNA signatures including the signaling axis S100A8, S100A9 and cognate receptor TLR4. Mechanistically, S100A8 and S100A9 compromised DC maturation, a phenotype which was partially recovered following TLR4 blockade. Early evidence demonstrates similar EVs can be isolated from human afferent lymphatic fluid ex vivo. Taken together, we propose synergistic interactions among melanoma EV cargo are responsible for suppressing DC maturation, potentially explaining the survival of malignant melanocytes metastasizing into seemingly “normal” regional lymph nodes.
2018-10-26 | PXD005539 | Pride
Project description:Secreted extracellular vesicles are known to influence the tumor microenvironment and promote metastasis. In this work, we have analyzed the involvement of extracellular vesicles in establishing the lymph node pre-metastatic niche by melanoma cells. We found that small extracellular vesicles (sEVs) derived from highly metastatic melanoma cell lines spread broadly through the lymphatic system and are taken up by lymphatic endothelial cells reinforcing lymph node metastasis. Melanoma-derived sEVs induce lymphangiogenesis, a hallmark of pre-metastatic niche formation, in vitro and in lymphoreporter mice in vivo. Analysis of involved factors demonstrated that the neural growth factor receptor (NGFR) is secreted in melanoma-derived small extracellular vesicles and shuttled to lymphatic endothelial cells inducing lymphangiogenesis and tumor cell adhesion through the activation of ERK and NF-B pathways and ICAM1 expression. Importantly, ablation or inhibition of NGFR in sEVs reversed the lymphangiogenic phenotype, decreased melanoma lymph node metastasis and extended mice survival. Importantly, analysis of NGFR expression in lymph node metastases and matched primary tumors shows that levels of MITF+NGFR+ lymph node metastatic cells are correlated with disease outcome. Our data support that NGFR is secreted in sEVs favoring lymph node pre-metastatic niche formation and lymph node metastasis in melanoma.
2021-07-16 | PXD024108 | Pride