YAP/TAZ as master regulators in cancer: modulation, function and therapeutic approaches

Nature Cancer, Journal Year: 2022, Volume and Issue: unknown

Published: Dec. 23, 2022

Language: Английский

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Insights into recent findings and clinical application of YAP and TAZ in cancer

Nature reviews. Cancer, Journal Year: 2023, Volume and Issue: 23(8), P. 512 - 525

Published: June 12, 2023

Language: Английский

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Predictive biomarkers of immunotherapy response with pharmacological applications in solid tumors

Acta Pharmacologica Sinica, Journal Year: 2023, Volume and Issue: 44(9), P. 1879 - 1889

Published: April 13, 2023

Immune-checkpoint inhibitors show promising effects in the treatment of multiple tumor types. Biomarkers are biological indicators used to select patients for a systemic anticancer treatment, but there only few clinically useful biomarkers such as PD-L1 expression and mutational burden, which can be predict immunotherapy response. In this study, we established database consisting both gene clinical data identify response anti-PD-1, anti-PD-L1, anti-CTLA-4 immunotherapies. A GEO screening was executed datasets with simultaneously available transcriptomic regardless cancer type. The restricted studies involving administration anti-PD-1 (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, durvalumab) or (ipilimumab) agents. Receiver operating characteristic (ROC) analysis Mann-Whitney test were across all genes features related therapy consisted 1434 tissue samples from 19 esophageal, gastric, head neck, lung, urothelial cancers, plus melanoma. strongest druggable candidates linked resistance SPIN1 (AUC = 0.682, P 9.1E-12), SRC 0.667, 5.9E-10), SETD7 0.663, 1.0E-09), FGFR3 0.657, 3.7E-09), YAP1 0.655, 6.0E-09), TEAD3 0.649, 4.1E-08) BCL2 0.634, 9.7E-08). cohort, BLCAP 0.735, 2.1E-06) most candidate. No therapeutically relevant target found predictive cohort. group, able confirm significant correlation survival mismatch-repair MLH1 MSH6. web platform further validation new biomarker set up at https://www.rocplot.com/immune . summary, investigate large cohort solid samples. Our results could help patient cohorts eligible immunotherapy.

Language: Английский

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Therapeutic targeting of TEAD transcription factors in cancer

Trends in Biochemical Sciences, Journal Year: 2023, Volume and Issue: 48(5), P. 450 - 462

Published: Jan. 26, 2023

Language: Английский

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Recent Advances on Immunohistochemistry and Molecular Biology for the Diagnosis of Adnexal Sweat Gland Tumors

Cancers, Journal Year: 2022, Volume and Issue: 14(3), P. 476 - 476

Published: Jan. 18, 2022

Cutaneous sweat gland tumors are a subset of adnexal neoplasms that derive or differentiate into the apparatus. Their great diversity, rarity, and complex terminology make their pathological diagnosis challenging. Recent findings have revealed wide spectrum oncogenic drivers, several which diagnostic interest for pathologists. Most these molecular alterations represented by gene fusions, shared with other homologous occurring in organs containing exocrine glands, such as salivary breast show similarities to This review aims provide synthesis most recent immunohistochemical markers used highlight relationship similar organs. It will cover adenoid cystic carcinoma (NFIB, MYB, MYBL1 fusion), cutaneous mixed tumor (PLAG1 cylindroma spiradenoma carcinomas thereof (NF-κB activation through CYLD inactivation ALKP1 hotspot mutation), hidradenoma hidradenocarcinoma (MAML2 myoepithelioma (EWSR1 FUS poroma porocarcinoma (YAP1, MAML2, NUTM1 secretory (ETV6, NTRK3 tubular adenoma syringo-cystadenoma papilliferum (HRAS BRAF activating mutations). Sweat there no known abnormalities also be briefly discussed, well potential future developments.

Language: Английский

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Both YAP1-MAML2 and constitutively active YAP1 drive the formation of tumors that resemble NF2 mutant meningiomas in mice

Genes & Development, Journal Year: 2022, Volume and Issue: 36(13-14), P. 857 - 870

Published: July 1, 2022

YAP1 is a transcriptional coactivator regulated by the Hippo signaling pathway, including NF2. Meningiomas are most common primary brain tumors; large percentage exhibit heterozygous loss of chromosome 22 (harboring NF2 gene) and functional inactivation remaining copy, implicating oncogenic YAP activity in these tumors. Recently, fusions between MAML2 have been identified subset pediatric wild-type meningiomas. Here, we show that human YAP1-MAML2 -positive meningiomas resemble mutant global YAP-related gene expression signatures. We then mice induces tumors fusion-positive expression. demonstrate primarily functions exerting TEAD-dependent resistant to signaling. Treatment with YAP-TEAD inhibitors sufficient inhibit viability -driven mouse ex vivo. Finally, constitutively active (S127/397A-YAP1) induce similar tumors, suggesting component fusion critical driver In summary, our results implicate as causal highlight an meningioma well general.

Language: Английский

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Nuclear condensates of YAP fusion proteins alter transcription to drive ependymoma tumourigenesis

Nature Cell Biology, Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 2, 2023

Language: Английский

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Nivolumab plus chemoradiotherapy in locally-advanced cervical cancer: the NICOL phase 1 trial

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 22, 2023

Concurrent chemoradiotherapy (CRT) with blockade of the PD-1 pathway may enhance immune-mediated tumor control through increased phagocytosis, cell death, and antigen presentation. The NiCOL phase 1 trial (NCT03298893) is designed to determine safety/tolerance profile recommended phase-II dose nivolumab following concurrent CRT in 16 women locally advanced cervical cancer. Secondary endpoints include objective response rate (ORR), progression free survival (PFS), disease survival, immune correlates response. Three patients experience grade 3 dose-limiting toxicities. pre-specified are met, overall 93.8% [95%CI: 69.8-99.8%] a 2-year PFS 75% [95% CI: 56.5-99.5%]. Compared progressive (PD), progression-free (PF) subjects show brisker stromal infiltrate, higher proximity tumor-infiltrating CD3+ T cells PD-L1+ FOXP3+ proliferating CD11c+ myeloid cells. PF baseline levels ICOS-L on EMRA CD4+ tumor-associated macrophages, respectively; PD instead, display enhanced PD-L1 expression TAMs, peripheral frequencies Tregs at week 6 post-treatment initiation CD4 CD8 subsets. Concomitant plus definitive safe associated encouraging rates. Further validation subset cancer displaying pre-existing, adaptive activation warranted.

Language: Английский

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Phase separation of YAP-MAML2 differentially regulates the transcriptome

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(7)

Published: Feb. 5, 2024

Phase separation (PS) drives the formation of biomolecular condensates that are emerging biological structures involved in diverse cellular processes. Recent studies have unveiled PS-induced several transcriptional factor (TF) transcriptionally active, but how strongly PS promotes gene activation remains unclear. Here, we show oncogenic TF fusion Yes-associated protein 1-Mastermind like coactivator 2 (YAP-MAML2) undergoes and forms liquid-like bear hallmarks activity. Furthermore, examined contribution to YAP-MAML2-mediated expression by developing a chemogenetic tool dissolves condensates, allowing us compare phase-separated non-phase-separated conditions at identical YAP-MAML2 levels. We found small fraction YAP-MAML2-regulated genes is further affected PS, which include canonical YAP target CTGF CYR61 , other oncogenes. On hand, majority not highlighting transcription can be activated effectively diffuse complexes TFs with machinery. Our work opens new directions understanding role selective modulation expression, suggesting differential roles

Language: Английский

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Meningioma: current updates on genetics, classification, and mouse modeling

Upsala Journal of Medical Sciences, Journal Year: 2024, Volume and Issue: 129, P. e10579 - e10579

Published: March 18, 2024

Meningiomas, the most common primary brain tumors in adults, are often benign and curable by surgical resection. However, a subset is of higher grade, shows aggressive growth behavior as well invasion, recurs even after several rounds surgery. Increasing evidence suggests that tumor classification grading primarily based on histopathology do not always accurately predict aggressiveness recurrence behavior. The underlying biology treatment-resistant meningiomas impact specific genetic aberrations present these high-grade still only insufficiently understood. Therefore, an in-depth research into this type warranted. More recent studies large-scale molecular data such whole exome/genome sequencing, DNA methylation RNA sequencing have provided new insights revealed risk factors prognostic subtypes. aberration functional loss NF2 occurs both low- meningiomas, whereas NF2-wildtype enriched for recurrent mutations TRAF7, KLF4, AKT1, PI3KCA, SMO more frequently benign. Most meningioma mouse models patient-derived xenografts recently genetically engineered been developed will aid systematic evaluation found their In article, we review advances understanding highlight mutations, discuss meningioma.

Language: Английский

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