Deep genomic analysis of malignant peripheral nerve sheath tumor cell lines challenges current malignant peripheral nerve sheath tumor diagnosis

Magallón-Lorenz, Míriam; Terribas, Ernest; Ortega-Bertran, Sara; Creus-Bachiller, Edgar; Fernández, Marco A.; Requena, Gerard; Rosas, Inma; Mazuelas, Helena; Uriarte-Arrázola, Itziar; Negro, Alejandro; Lausová, Tereza; Castellanos, Elisabeth; Blanco, Ignacio; DeVries, George H.; Kawashima, Hiroyuki; Legius, Eric; Brems, Hilde; Mautner, Viktor; Ratner, Nancy; Wallace, Margaret R.; Fernández-Rodríguez, Juana; Lázaro, Conxi; Fletcher, Jonathan A.; Reuß, David; Carrió, Meritxell; Gel, Bernat; Serra, Eduard

doi:10.1016/j.isci.2023.106096

Cited by 6 publications

(14 citation statements)

References 81 publications

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“…S6A). Regarding the expression of neural crest stem cell lineage markers (S100B and p75) and MPNST markers (SOX9 and EGFR) [62,63], these two cell lines were positive for SOX9 and EGFR expression and negative for S100B and p75 (only focal in the NF1‐09 cell line), similar to MPNST control cell lines (S462 and ST88‐14) [38] (Fig. 4B, Table 3, Fig.…”

Section: Resultsmentioning

confidence: 97%

“…First, the thorough genomic and histologic characterization of tumors applied in a larger number of samples may facilitate a correct diagnostic of tumors currently labeled as MPNSTs in the clinics. Second, we should reinterpret results obtained with newly rediagnosed models previously considered MPNSTs, such as the STS-26T cell line (recently reclassified as probably being a melanoma [38]) and used by many different laboratories; or the SP-01 cell line (also MPNST-SP-01 in previous works) [32,34], used in our group. Our platform also includes cellular and mouse models from MPNSTs and confounded tumor entities.…”

Section: Discussionmentioning

confidence: 99%

“…Figure 1C presents a methylome profile classifier of several sarcomas using a UMAP plot [52]. Taking a closer view of the MPNST region, SP-01's methylome profile matched that of melanoma (like STS-26T, which was recently reclassified from an MPNST to a melanoma cell line [38]), tumor NF1-08 clustered with the classic MPNST group (as for ST88-14 and S462 cell lines), and NF1-09 clustered in the rather catchall MPNST-like sarcoma group (Fig. 1D, Table 1).…”

Section: Expansion Of the Mpnst Platform: From Genuine Mpnsts To Othe...mentioning

confidence: 99%

“…In this work, the following established cell lines were also used: NF1-derived 88-14 (RRID: CVCL_8916) [35] and S462 (RRID: CVCL_1Y70) [36], and sporadic STS-26T (RRID: CVCL_8917) [37]. All details regarding these three cell lines, as well as the laboratories originating and providing these cell lines, are described in Magall on-Lorenz et al [38]. Cell lines were validated as Mycoplasma negative and were retested every 2 months.…”

Section: Establishment Of Cell Lines From Primary Human Tumorsmentioning

confidence: 99%

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Expanding a precision medicine platform for malignant peripheral nerve sheath tumors: New patient‐derived orthotopic xenografts, cell lines and tumor entities

Creus‐Bachiller,

Fernández‐Rodríguez,

Magallón‐Lorenz

et al. 2023

Molecular Oncology

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Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas with a poor survival rate, presenting either sporadically or in the context of neurofibromatosis type 1 (NF1). The histological diagnosis of MPNSTs can be challenging, with different tumors exhibiting great histological and marker expression overlap. This heterogeneity could be partly responsible for the observed disparity in treatment response due to the inherent diversity of the preclinical models used. For several years, our group has been generating a large patient‐derived orthotopic xenograft (PDOX) MPNST platform for identifying new precision medicine treatments. Herein, we describe the expansion of this platform using six primary tumors clinically diagnosed as MPNSTs, from which we obtained six additional PDOX mouse models and three cell lines, thus generating three pairs of in vitro–in vivo models. We extensively characterized these tumors and derived preclinical models, including genomic, epigenomic and histological analyses. Tumors were reclassified after these analyses: three remained as MPNSTs (two being classic MPNSTs), one was a melanoma, another an Neurotrophic tyrosine receptor kinase (NTRK)‐rearranged spindle cell neoplasm, and, finally, an unclassifiable tumor bearing Neurofibromin‐2 (NF2) inactivation, an Neuroblastoma RAS Viral Oncogene Homolog (NRAS) oncogenic mutation and a SWI/SNF‐related Matrix associated Actin‐dependent Regulator of Chromatin (SMARCA4) heterozygous truncated variant. New cell lines and PDOXs faithfully recapitulated histology, marker expression and genomic characteristics of the primary tumors. The diversity in tumor identity and their specific associated genomic alterations impacted on treatment responses obtained when we used the new cell lines for testing compounds against known altered pathways in MPNSTs. In summary, we present here an extension of our MPNST precision medicine platform, with new PDOXs and cell lines, including tumor entities confounded as MPNSTs in a real clinical scenario. This platform may constitute a useful tool for obtaining correct preclinical information to guide MPNST clinical trials.

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Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Expansion Of the Mpnst Platform: From Genuine Mpnsts To Othe...mentioning

confidence: 99%

Section: Establishment Of Cell Lines From Primary Human Tumorsmentioning

confidence: 99%

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Expanding a precision medicine platform for malignant peripheral nerve sheath tumors: New patient‐derived orthotopic xenografts, cell lines and tumor entities

Creus‐Bachiller,

Fernández‐Rodríguez,

Magallón‐Lorenz

et al. 2023

Molecular Oncology

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“…Since a pNF is a hamartoma with minimal genetic mutation compared with an MPNST, T cells probably recognize it as “self” ( 44 , 45 ). However, MPNSTs, which have more neoantigens, resemble “non-self” to T cells that infiltrate following STING activation and therefore can be targeted for immune destruction ( 46 ). Thus, it is possible that STING activation, while restraining MPNST growth, might promote pNF progression by increasing T cell infiltration.…”

Section: Discussionmentioning

confidence: 99%

STING activation reprograms the microenvironment to sensitize NF1-related malignant peripheral nerve sheath tumors for immunotherapy

Somatilaka,

Madana,

Sadek

et al. 2024

Journal of Clinical Investigation

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Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene that encodes neurofibromin, a RAS GTPase–activating protein. Inactivating NF1 mutations cause hyperactivation of RAS-mediated signaling, resulting in the development of multiple neoplasms, including malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are an aggressive tumor and the main cause of mortality in patients with NF1. MPNSTs are difficult to resect and refractory to chemo- and radiotherapy, and no molecular therapies currently exist. Immune checkpoint blockade (ICB) is an approach to treat inoperable, undruggable cancers like MPNST, but successful outcomes require an immune cell–rich tumor microenvironment. While MPNSTs are noninflamed “cold” tumors, here, we converted MPNSTs into T cell–inflamed “hot” tumors by activating stimulator of IFN genes (STING) signaling. Mouse genetic and human xenograft MPNST models treated with a STING agonist plus ICB exhibited growth delay via increased apoptotic cell death. This strategy offers a potential treatment regimen for MPNSTs.

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MPNST of the abdominal wall in a patient with lynch syndrome: A case report of a rare presentation and unique association

Hasnaoui,

Kacem,

Sassi

et al. 2023

International Journal of Surgery Case Reports

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Deep genomic analysis of malignant peripheral nerve sheath tumor cell lines challenges current malignant peripheral nerve sheath tumor diagnosis

Cited by 6 publications

References 81 publications

Expanding a precision medicine platform for malignant peripheral nerve sheath tumors: New patient‐derived orthotopic xenografts, cell lines and tumor entities

Expanding a precision medicine platform for malignant peripheral nerve sheath tumors: New patient‐derived orthotopic xenografts, cell lines and tumor entities

STING activation reprograms the microenvironment to sensitize NF1-related malignant peripheral nerve sheath tumors for immunotherapy

MPNST of the abdominal wall in a patient with lynch syndrome: A case report of a rare presentation and unique association

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