Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

Spain, Lavinia; Coulton, Alexander; Lobón, Irene; Rowan, Andrew N.; Schnidrig, Désirée; Shepherd, Scott T.C.; Shum, Benjamin; Byrne, Fiona; Goicoechea, Maria; Piperni, Elisa; Au, Lewis; Edmonds, Kim; Carlyle, Eleanor; Hunter, Nikki; Renn, Alexandra; Messiou, Christina; Hughes, Peta; Nobbs, J.; Foijer, Floris; Bos, Hilda van den; Wardenaar, René; Spierings, Diana C.J.; Spencer, Charlotte; Schmitt, Andreas M.; Tippu, Zayd; Lingard, Karla; Grostate, Lauren; Peat, Kema; Kelly, Kayleigh; Sarker, Sarah; Vaughan, Sarah; Mangwende, Mary; Terry, Lauren; Kelly, Denise; Biano, Jennifer; Murra, Aida; Korteweg, Justine; Lewis, Charlotte; O’Flaherty, Molly; Cattin, Anne-Laure; Emmerich, Max; Gérard, Camille L.; Pallikonda, Husayn Ahmed; Mason, Robert M.; Rogiers, Aljosja; Xu, Hang; Huebner, Ariana; McGranahan, Nicholas; Bakir, Maise Al; Murai, Jun; Naceur-Lombardelli, Cristina; Borg, Elaine; Mitchison, Miriam; Moore, David A.; Falzon, Mary; Proctor, Ian; Stamp, Gordon; Nye, Emma; Young, Kate; Furness, Andrew J.S.; Pickering, Lisa; Stewart, Ruby; Mahadeva, Ula; Green, Anna; Larkin, James; Litchfield, Kevin; Swanton, Charles; Jamal‐Hanjani, Mariam; Turajlic, Samra

doi:10.1158/2159-8290.cd-22-1427

Cited by 16 publications

(10 citation statements)

References 100 publications

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“…Stöber et al conducted a study on cells from neuroblastoma (NB) cell lines and patients and revealed that MYCN copy numbers among cells varied significantly, by orders of magnitude, and that such extensive heterogeneity was only observed in the ecDNA region [49] . Spain et al also reported the discovery of heterogeneous KIT copies in melanoma patients carrying ecDNA through single-cell whole genome sequencing (scWGS-seq) [51] . In another study, Parra et al found that in chromothriptic medulloblastoma (MB), most tumor cells carried 10–20 copies of ecDNA, while very few cells harbored more than 100 copies [42] .…”

Section: Single-cell Sequencing and Ecdna Researchmentioning

confidence: 99%

Advances in sequencing-based studies of microDNA and ecDNA: Databases, identification methods, and integration with single-cell analysis

Yang¹,

Zhang²,

Huang³

2023

Computational and Structural Biotechnology Journal

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Section: Single-cell Sequencing and Ecdna Researchmentioning

confidence: 99%

Advances in sequencing-based studies of microDNA and ecDNA: Databases, identification methods, and integration with single-cell analysis

Yang¹,

Zhang²,

Huang³

2023

Computational and Structural Biotechnology Journal

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“…FST mediates the ability of YAP to stimulate cell invasion in melanoma [ 23 , 44 ], and its expression correlates with metastasis in a breast cancer mouse model [ 45 ] and with survival outcomes in cancer patients [ 46 ]. MYC is involved in tumor progression [ 47 ] and in the response to therapy of both melanoma [ 48 ] and breast carcinoma [ 49 ]. TP73 plays a role in the progression of melanoma [ 50 ], and breast carcinoma [ 51 ], and in YAP-mediated response of breast cancer to therapy [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Bcl-2 dependent modulation of Hippo pathway in cancer cells

D’Aguanno,

Brignone,

Scalera

et al. 2024

Cell Commun Signal

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Introduction Bcl-2 and Bcl-xL are the most studied anti-apoptotic members of Bcl-2 family proteins. We previously characterized both of them, not only for their role in regulating apoptosis and resistance to therapy in cancer cells, but also for their non-canonical functions, mainly including promotion of cancer progression, metastatization, angiogenesis, and involvement in the crosstalk among cancer cells and components of the tumor microenvironment. Our goal was to identify transcriptional signature and novel cellular pathways specifically modulated by Bcl-2. Methods We performed RNAseq analysis of siRNA-mediated transient knockdown of Bcl-2 or Bcl-xL in human melanoma cells and gene ontology analysis to identify a specific Bcl-2 transcriptional signature. Expression of genes modulated by Bcl-2 and associated to Hippo pathway were validated in human melanoma, breast adenocarcinoma and non-small cell lung cancer cell lines by qRT-PCR. Western blotting analysis were performed to analyse protein expression of upstream regulators of YAP and in relation to different level of Bcl-2 protein. The effects of YAP silencing in Bcl-2 overexpressing cancer cells were evaluated in migration and cell viability assays in relation to different stiffness conditions. In vitro wound healing assays and co-cultures were used to evaluate cancer-specific Bcl-2 ability to activate fibroblasts. Results We demonstrated the Bcl-2-dependent modulation of Hippo Pathway in cancer cell lines from different tumor types by acting on upstream YAP regulators. YAP inhibition abolished the ability of Bcl-2 to increase tumor cell migration and proliferation on high stiffness condition of culture, to stimulate in vitro fibroblasts migration and to induce fibroblasts activation. Conclusions We discovered that Bcl-2 regulates the Hippo pathway in different tumor types, promoting cell migration, adaptation to higher stiffness culture condition and fibroblast activation. Our data indicate that Bcl-2 inhibitors should be further investigated to counteract cancer-promoting mechanisms.

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“…These findings are consistent with those of Lina et al, who emphasized the critical role of antigen presentation in activating autologous CD8 + T cells in the prognosis of ICIs treatment 71 . According to Lavinia et al, the loss of heterozygosity resulting from frequent genomic alterations in advanced tumors frequently affects antigen presentation 72 . Therefore, we propose that the antigen presentation signature in melanoma may serve as a target to enhance the response to ICIs treatment.…”

Section: Discussionmentioning

confidence: 99%

An advanced comprehensive muti-cell-type-specific model for predicting anti-PD-1 therapeutic effect in melanoma

Sun,

Zhu,

Zou

et al. 2024

Theranostics

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Rationale: Immune checkpoint inhibitors targeting the programmed cell death (PD)-1/PD-L1 pathway have promise in patients with advanced melanoma. However, drug resistance usually results in limited patient benefits. Recent single-cell RNA sequencing studies have elucidated that MM patients display distinctive transcriptional features of tumor cells, immune cells and interstitial cells, including loss of antigen presentation function of tumor cells, exhaustion of CD8+T and extracellular matrix secreted by fibroblasts to prevents immune infiltration, which leads to a poor response to immune checkpoint inhibitors (ICIs). However, cell subgroups beneficial to anti-tumor immunity and the model developed by them remain to be further identified. Methods: In this clinical study of neoadjuvant therapy with anti-PD-1 in advanced melanoma, tumor tissues were collected before and after treatment for single-nucleus sequencing, and the results were verified using multicolor immunofluorescence staining and public datasets. Results: This study describes four cell subgroups which are closely associated with the effectiveness of anti-PD-1 treatment. It also describes a cell-cell communication network, in which the interaction of the four cell subgroups contributes to anti-tumor immunity. Furthermore, we discuss a newly developed predictive model based on these four subgroups that holds significant potential for assessing the efficacy of anti-PD-1 treatment. Conclusions: These findings elucidate the primary mechanism of anti-PD-1 resistance and offer guidance for clinical drug administration for melanoma.

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Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

Cited by 16 publications

References 100 publications

Advances in sequencing-based studies of microDNA and ecDNA: Databases, identification methods, and integration with single-cell analysis

Advances in sequencing-based studies of microDNA and ecDNA: Databases, identification methods, and integration with single-cell analysis

Bcl-2 dependent modulation of Hippo pathway in cancer cells

An advanced comprehensive muti-cell-type-specific model for predicting anti-PD-1 therapeutic effect in melanoma

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