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| Open AccessIntegrated proteogenomic and metabolomic characterization of papillary thyroid cancer with different recurrence risks
Papillary thyroid cancers (PTC) generally have good prognosis, but their recurrence rate remains high. Here, the authors use proteogenomics and metabolomics to identify molecular features in PTC tumours and determine PTC subtypes that are associated with prognosis and potential targeted therapies.
- Ning Qu
- , Di Chen
- & Rongliang Shi
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Article
| Open AccessUnraveling the role of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer by multi-omics analyses
Different types of metabolic rewiring are reported to drive cancer development and as a potential therapeutic target. Here, the authors perform multi-omics analyses in a cohort of human normal and malignant thyroid samples and show association of mitochondrial one-carbon metabolism with undifferentiated thyroid cancer.
- Seong Eun Lee
- , Seongyeol Park
- & Yea Eun Kang
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| Open AccessDurvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin
Single immune checkpoint blockade has shown limited activity in patients with neuroendocrine neoplasms (NENs). Here the authors report the results of a phase II clinical trial of durvalumab (anti-PD-L1) and tremelimumab (anti CTLA-4) in patients with advanced NENs of gastroenteropancreatic and lung origin.
- J. Capdevila
- , J. Hernando
- & J. L. Manzano
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Article
| Open AccessRecapitulating thyroid cancer histotypes through engineering embryonic stem cells
Thyroid carcinoma (TC) is the most common malignancy of endocrine organs. Here, the authors show the ability of human embryonic stem cells (hESCs) to recapitulate the different TC histotypes upon specific genomic alterations delivered by CRISPR-Cas9 and identify KISS1R and TIMP1 targeting as a therapeutic adjuvant option for undifferentiated TCs.
- Veronica Veschi
- , Alice Turdo
- & Giorgio Stassi
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Article
| Open AccessGenomic and immune landscape Of metastatic pheochromocytoma and paraganglioma
The molecular mechanisms underlying metastasis in pheochromocytoma/paraganglioma (mPPGL) remain to be explored. Here, the authors perform genomic and immunogenomic profiling of mPPGL tumors and suggest potential biomarkers for risk of metastasis and immunotherapy response.
- Bruna Calsina
- , Elena Piñeiro-Yáñez
- & Mercedes Robledo
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Article
| Open AccessSingle-nuclei and bulk-tissue gene-expression analysis of pheochromocytoma and paraganglioma links disease subtypes with tumor microenvironment
Pheochromocytomas and paragangliomas (PCPG) are rare neuroendocrine tumours. Here, the authors use single-nuclei and bulk-tissue RNA-seq to characterise PCPG tumours and their microenvironments and reveal molecular subtypes as well as expression patterns associated with metastasis.
- Magnus Zethoven
- , Luciano Martelotto
- & Richard W. Tothill
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Article
| Open AccessReprogramming of myeloid cells and their progenitors in patients with non-medullary thyroid carcinoma
Myeloid cells contribute to the tumor microenvironment of thyroid cancers, but their functional relevance is lesser known. Here authors show that myeloid cells infiltrating non-medullary thyroid carcinomas upregulate their antigen presentation-related genes, release less cytokines and over-produce reactive oxygen species, with transcriptional changes already present in extra-tumoral myeloid cells.
- Katrin Rabold
- , Martijn Zoodsma
- & Romana T. Netea-Maier
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| Open AccessSingle-cell transcriptomic analysis of the tumor ecosystems underlying initiation and progression of papillary thyroid carcinoma
The characterisation of the papillary thyroid carcinoma (PTC) tumour microenvironment remains crucial. Here, the authors perform single-cell RNA sequencing in 11 patients and identify potential opportunities for the use of immunotherapy and its combination with anti-angiogenic therapy in PTC.
- Weilin Pu
- , Xiao Shi
- & Yu-Long Wang
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Article
| Open AccessSubtype heterogeneity and epigenetic convergence in neuroendocrine prostate cancer
Neuroendocrine carcinomas (NECs) arise from different anatomic sites, but have similar histological and clinical features. Here, the authors show that the epigenetic landscape of a range of NECs converges towards a common epigenetic state, while distinct subtypes occur within neuroendocrine prostate cancer contributing to intratumor heterogeneity in clinical samples.
- Paloma Cejas
- , Yingtian Xie
- & Henry W. Long
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Article
| Open AccessThe genomic landscape of 85 advanced neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets
Metastatic and locally-advanced neuroendocrine neoplasms (aNEN) display heterogeneous clinical and genetic characteristics. Here, the authors investigate the mutational landscape of 85 aNEN by whole genome sequencing and identify distinct subpopulations, tumour mutational burden patterns, drivers and actionable somatic alterations.
- Job van Riet
- , Harmen J. G. van de Werken
- & Bianca Mostert
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Article
| Open AccessThe secreted protease Adamts18 links hormone action to activation of the mammary stem cell niche
How hormonal signaling in the mammary epithelium controls the surrounding extracellular matrix is unclear. Here, the authors show that a secreted protease, Adamts18, induced by upstream estrogen-progesterone activated Wnt4 in myoepithelial cells, remodels the basement membrane and contributes to mammary epithelial stemness.
- Dalya Ataca
- , Patrick Aouad
- & Cathrin Brisken
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Article
| Open AccessNoncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer
FOXA1 pioneer transcription factor is recurrently mutated in primary and metastatic prostate tumors. Here, authors identify a set of six cis-regulatory elements in the FOXA1 regulatory plexus harboring somatic SNVs in primary prostate tumors and characterize their role in regulating FOXA1 expression and prostate cancer cell growth.
- Stanley Zhou
- , James R. Hawley
- & Mathieu Lupien
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Article
| Open AccessMUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer
MUC1-C is overexpressed in castration-resistant prostate cancer and neuroendocrine prostate cancer. Here, the authors show that MUC1-C drives lineage plasticity through MYC and BRN2, inducing neuroendocrine features and stemness in prostate cancer.
- Yota Yasumizu
- , Hasan Rajabi
- & Donald Kufe
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Article
| Open AccessIntegrative analysis of genomic and transcriptomic characteristics associated with progression of aggressive thyroid cancer
Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) come with a dismal prognosis. Here, Yoo and colleagues reveal the genomic and transcriptomic landscape of ATC and DTC, highlighting potential therapeutic vulnerabilities.
- Seong-Keun Yoo
- , Young Shin Song
- & Jeong-Sun Seo
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| Open AccessInhibition of mTORC1 by lncRNA H19 via disrupting 4E-BP1/Raptor interaction in pituitary tumours
LncRNA H19 has been shown to be aberrantly expressed in different cancers. Here, the authors show that H19 lncRNA is downregulated in pituitary adenomas and H19 is able to impede pituitary tumorigenesis via disruption of 4E-BPB1 and Raptor interaction to inhibit the phosphorylation of 4E-BP1.
- Ze Rui Wu
- , Lichong Yan
- & Zhe Bao Wu
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Article
| Open AccessHIF-2α-pVHL complex reveals broad genotype-phenotype correlations in HIF-2α-driven disease
Hypoxia inducible factor (HIF)-2α transcription factor is mutated in polycythemia and various neuroendocrine tumors. Here the authors present the crystal structure of a HIF-2α peptide bound to the pVHL-elongin B-elongin C (VBC) heterotrimeric complex and propose a classification scheme for HIF-2α mutations that helps to predict disease phenotype outcome.
- Daniel Tarade
- , Claire M. Robinson
- & Michael Ohh
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| Open AccessIdentification of recurrent USP48 and BRAF mutations in Cushing’s disease
In this study the authors report USP48 and BRAF are frequently mutated in USP8 wild-type corticotroph adenomas, and cause Cushing’s disease mainly through promoting the promoter activity of POMC. Inhibition of BRAF may be a promising therapeutic strategy for the treatment of patients with BRAF-mutated corticotroph adenomas.
- Jianhua Chen
- , Xuemin Jian
- & Yongyong Shi
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| Open AccessRegulation of mutant TERT by BRAF V600E/MAP kinase pathway through FOS/GABP in human cancer
The mechanism of tumor progression robustly promoted by co-existing BRAF V600E and TERT promoter mutations is not known. Here, the authors show a mechanism of mutant TERT activation by BRAF V600E and MAPK pathways in which FOS, as a transcription factor of the GABPB promoter, functionally links the two oncogenes.
- Rengyun Liu
- , Tao Zhang
- & Mingzhao Xing
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Article
| Open AccessThe genetic landscape of benign thyroid nodules revealed by whole exome and transcriptome sequencing
Papillary thyroid carcinomas are often found with coincidental benign thyroid nodules. Here, the authors provide genomic evidence that papillary thyroid carcinomas and coincidental benign thyroid nodules originate and evolve independently.
- Lei Ye
- , Xiaoyi Zhou
- & Weiqing Wang
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Article
| Open AccessSenescent tumor cells lead the collective invasion in thyroid cancer
The senescence-associated secretory phenotype of stromal cells can promote tumorigenesis. Here, the authors show that senescent cancer cells are localized at the invasive front in human papillary thyroid carcinoma, and that senescent cancer cells drive collective invasion via CXCL12 in mouse models.
- Young Hwa Kim
- , Yong Won Choi
- & Tae Jun Park
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Article
| Open AccessPKA inhibits WNT signalling in adrenal cortex zonation and prevents malignant tumour development
The adrenal cortex undergoes functional zonation to generate an outer zona glomerulosa (ZG) and inner zona fasciculata (ZF), but how this is regulated at a molecular level is unclear. Here, the authors show that ZG differentiation is stimulated by WNT signalling and that PKA blocks WNT signalling to allow ZF differentiation and also prevents WNT-induced cancer development.
- Coralie Drelon
- , Annabel Berthon
- & Pierre Val
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Article
| Open AccessMulti-omics analysis defines core genomic alterations in pheochromocytomas and paragangliomas
Pheochromocytomas and paragangliomas (PCCs/PGLs) are rare neuroendocrine tumours with a significant genetic component. Here, the authors carry out a multi-omic integrative characterization of PCC/PGL and reveal potential genomic alterations and regulatory mechanisms involved in the disease.
- Luis Jaime Castro-Vega
- , Eric Letouzé
- & Anne-Paule Gimenez-Roqueplo
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Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas
Pheochromocytomas and paragangliomas (PCC/PGL) are tumours of the autonomic nervous system. Here, the authors identify ATRX mutations in PCC/PGL and suggest that ATRXloss is important for tumorigenesis in a subset of PCC/PGL.
- Lauren Fishbein
- , Sanika Khare
- & Katherine L. Nathanson
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| Open AccessTargeting β-catenin signaling for therapeutic intervention in MEN1-deficient pancreatic neuroendocrine tumours
MEN1 gene encodes menin, a nuclear scaffold protein that regulates transcription and is often inactivated in pancreatic neuroendocrine tumours (PNETs). Here Jiang et al. show that MEN1-driven PNET development involves activation of β-catenin, and that β-catenin deletion ameliorates the disease.
- Xiuli Jiang
- , Yanan Cao
- & Guang Ning
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PKA catalytic subunit mutations in adrenocortical Cushing’s adenoma impair association with the regulatory subunit
Cushing’s adenoma is associated with somatic mutations in the gene encoding the Cα subunit of protein kinase A. Calebiro et al.reveal that these mutations increase protein kinase A activity by preventing proper assembly of the protein kinase A holoenzyme.
- Davide Calebiro
- , Annette Hannawacker
- & Martin J. Lohse
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Skp2 suppresses apoptosis in Rb1-deficient tumours by limiting E2F1 activity
The pRb target E2F1 possesses contradictory activities in promoting proliferation and apoptosis. Here, the authors define a pRb-Skp2-p27-cyclin A-E2F1 survival pathway that can be disrupted to prevent Rb1-deficient tumorigenesis in the pituitary intermediate lobe.
- Zhonglei Lu
- , Frederick Bauzon
- & Liang Zhu