Prognostic significance of YAP1 expression and its association with neuroendocrine markers in resected pulmonary large cell neuroendocrine carcinoma (LCNEC)

Sun, Xiaowei; Zhang, Jinyao; Dong, Jiyan; Liu, Li; Li, Xue; Xing, Puyuan; Ying, Jianming; Che, Yi-Qun; Li, Junling; Yang, Lin

doi:10.1016/j.tranon.2022.101538

Cited by 2 publications

(1 citation statement)

References 46 publications

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“…In vitro data with Ben-Men-1 benign NF2 mutant meningioma cells and HEK293 cells showed that overexpression of VGLL4 results in the significant suppression of YAP1 activity, confirming the direct link between overexpression of VGLL4 and reduced YAP activity. Functional inhibition or loss of expression of YAP1 has been observed in several cancers, such as Estrogen receptor (ER)-positive breast cancer, neuroendocrine small-cell lung cancer (SCLC), or pulmonary large cell neuroendocrine carcinoma [48][49][50][51] . YAP1 was originally identified as a tumor suppressor due to its role in activating p73-dependent apoptosis 52,53 and has been shown to suppress ER expression in ER+ breast cancer as well as suppress metastasis in SCLC 49,51 .…”

Section: Discussionmentioning

confidence: 99%

Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4

Parrish,

Arora,

Thirimanne

et al. 2024

Preprint

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Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset of meningiomas is of higher grade, shows aggressive growth behavior and recurs even after multiple surgeries. Around half of all meningiomas harbor inactivating mutations in NF2. While benign low-grade NF2 mutant meningiomas exhibit few genetic events in addition to NF2 inactivation, aggressive high-grade NF2 mutant meningiomas frequently harbor a highly aberrant genome. We and others have previously shown that NF2 inactivation leads to YAP1 activation and that YAP1 acts as the pivotal oncogenic driver in benign NF2 mutant meningiomas. Using bulk and single-cell RNA-Seq data from a large cohort of human meningiomas, we show that aggressive NF2 mutant meningiomas harbor decreased levels YAP1 activity compared to their benign counterparts. Decreased expression levels of YAP target genes are significantly associated with an increased risk of recurrence. We then identify the increased expression of the YAP1 competitor VGLL4 as well as the YAP1 upstream regulators FAT3/4 as a potential mechanism for the downregulation of YAP activity in aggressive NF2 mutant meningiomas. High expression of these genes is significantly associated with an increased risk of recurrence. In vitro, overexpression of VGLL4 resulted in the downregulation of YAP activity in benign NF2 mutant meningioma cells, confirming the direct link between VGLL4 expression and decreased levels of YAP activity observed in aggressive NF2 mutant meningiomas. Our results shed new insight on the biology of benign and aggressive NF2 mutant meningiomas and may have important implications for the efficacy of therapies targeting oncogenic YAP1 activity in NF2 mutant meningiomas.

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Section: Discussionmentioning

confidence: 99%

Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4

Parrish,

Arora,

Thirimanne

et al. 2024

Preprint

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YAP1 Status Defines Two Intrinsic Subtypes of LCNEC with Distinct Molecular Features and Therapeutic Vulnerabilities

Stewart,

Diao,

et al. 2024

Clinical Cancer Research

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Purpose: Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine malignancy that, like small cell lung cancer (SCLC), is associated with an absence of druggable oncogenic drivers and dismal prognosis. In contrast to SCLC, however, there is little evidence to guide optimal treatment strategies which are often adapted from SCLC and non-small cell lung cancer (NSCLC) approaches. Experimental design: To better define the biology of LCNEC, we analyzed cell line and patient genomic data and performed immunohistochemistry and single-cell (sc)RNAseq of core needle biopsies from LCNEC patients and preclinical models. Results: Here, we demonstrate that the presence or absence of YAP1 distinguishes two subsets of LCNEC. The YAP1-high subset is mesenchymal and inflamed and characterized, alongside TP53 mutations, by co-occurring alterations in CDKN2A/B and SMARCA4. Therapeutically, the YAP1-high subset demonstrates vulnerability to MEK and AXL targeting strategies, including a novel preclinical AXL CAR-T cell. Meanwhile, the YAP1-low subset is epithelial and immune-cold and more commonly features TP53 and RB1 co-mutations, similar to those observed in pure SCLC. Notably, the YAP1-low subset is also characterized by expression of SCLC subtype-defining transcription factors - especially ASCL1 and NEUROD1 - and, as expected given its transcriptional similarities to SCLC, exhibits putative vulnerabilities reminiscent of SCLC, including Delta-like ligand 3 (DLL3) and CD56 targeting, as with novel preclinical DLL3 and CD56 CAR T-cells, and DNA damage repair (DDR) inhibition. Conclusion: YAP1 defines distinct subsets of LCNEC with unique biology. These findings highlight the potential for YAP1 to guide personalized treatment strategies for LCNEC.

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Prognostic significance of YAP1 expression and its association with neuroendocrine markers in resected pulmonary large cell neuroendocrine carcinoma (LCNEC)

Cited by 2 publications

References 46 publications

Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4

Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4

YAP1 Status Defines Two Intrinsic Subtypes of LCNEC with Distinct Molecular Features and Therapeutic Vulnerabilities

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