31 research outputs found
TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms
[EN] Objective Hepatocellular carcinoma (HCC) is a prevalent
and aggressive cancer usually arising on a background
of chronic liver injury involving inflammatory and hepatic
regenerative processes. The triggering receptor expressed
on myeloid cells 2 (TREM-2) is predominantly expressed in
hepatic non-parenchymal
cells and inhibits Toll-like
receptor
signalling, protecting the liver from various hepatotoxic
injuries, yet its role in liver cancer is poorly defined. Here,
we investigated the impact of TREM-2 on liver regeneration
and hepatocarcinogenesis.
Design TREM-2 expression was analysed in liver tissues
of two independent cohorts of patients with HCC and
compared with control liver samples. Experimental HCC
and liver regeneration models in wild type and Trem-2-/-
mice, and in vitro studies with hepatic stellate cells (HSCs)
and HCC spheroids were conducted.
Results TREM-2 expression was upregulated in human
HCC tissue, in mouse models of liver regeneration and
HCC. Trem-2-/- mice developed more liver tumours
irrespective of size after diethylnitrosamine (DEN)
administration, displayed exacerbated liver damage,
inflammation, oxidative stress and hepatocyte proliferation.
Administering an antioxidant diet blocked DEN-induced
hepatocarcinogenesis in both genotypes. Similarly,
Trem-2-/- animals developed more and larger tumours in
fibrosis-associated
HCC models. Trem-2-/- livers showed
increased hepatocyte proliferation and inflammation after
partial hepatectomy. Conditioned media from human HSCs
overexpressing TREM-2 inhibited human HCC spheroid
growth in vitro through attenuated Wnt ligand secretion.
Conclusion TREM-2 plays a protective role in
hepatocarcinogenesis via different pleiotropic effects,
suggesting that TREM-2 agonism should be investigated
as it might beneficially impact HCC pathogenesis in a
multifactorial manner.Spanish Ministry of Economy and Competitiveness and ’Instituto de Salud
Carlos III’ grants (MJP (PI14/00399, PI17/00022 and Ramon y Cajal Programme
RYC-2015–17755); JMB (PI12/00380, PI15/01132, PI18/01075, Miguel Servet
Programme CON14/00129 and CPII19/00008) cofinanced by ’Fondo Europeo de
Desarrollo Regional’ (FEDER); CIBERehd: MJP, JMB and LB), Spain; IKERBASQUE,
Basque foundation for Science (MJP and JMB), Spain; ’Diputación Foral de Gipuzkoa’
(MJP: DFG18/114, DFG19/081; JMB: DFG15/010, DFG16/004); BIOEF (Basque
Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/
BD to JMB); Department of Health of the Basque Country (MJP: 2015111100 and
2019111024; JMB: 2017111010), Euskadi RIS3 (JMB: 2016222001, 2017222014,
2018222029, 2019222054, 2020333010) Department of Industry of the Basque
Country (JMB: Elkartek: KK-2020/00008) and AECC Scientific Foundation (JMB).
AE-B
was funded by the University of the Basque Country (UPV/EHU) (PIF2014/11)
and by the short-term
training fellowship Andrew K Burroughs (European
Association for the Study of the Liver, EASL). IL and AA-L
were funded by the
Department of Education, Language Policy and Culture of the Basque Government
(PRE_2016_1_0152 and PRE_2018_1_0184). OS and SK were funded by the
Austrian Science Fund (FWF25801-B22,
FWF-P35168
to OS and L-Mac:
F 6104-B21
to SK). FO and DAM were funded by a UK Medical Research Council programme
Grant MR/R023026/1. DAM was also funded by the CRUK programme grant
C18342/A23390, CRUK/AECC/AIRC Accelerator Award A26813 and the MRC MICA
programme grant MR/R023026/1. JBA is supported by the Danish Medical Research
Council, Danish Cancer Society, Nordisk Foundation, and APM Foundation. CJO’R
and PM-G
are supported by Marie Sklodowska-Curie
Programme and EASL Sheila
Sherlock postdoctoral fellowships
Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy
OBJECTIVE: Cytotoxic agents are the cornerstone of treatment for patients with advanced intrahepatic cholangiocarcinoma (iCCA), despite heterogeneous benefit. We hypothesised that the pretreatment molecular profiles of diagnostic biopsies can predict patient benefit from chemotherapy and define molecular bases of innate chemoresistance. DESIGN: We identified a cohort of advanced iCCA patients with comparable baseline characteristics who diverged as extreme outliers on chemotherapy (survival 23 m in long survivors, LS). Diagnostic biopsies were characterised by digital pathology, then subjected to whole-transcriptome profiling of bulk and geospatially macrodissected tissue regions. Spatial transcriptomics of tumour-infiltrating myeloid cells was performed using targeted digital spatial profiling (GeoMx). Transcriptome signatures were evaluated in multiple cohorts of resected cancers. Signatures were also characterised using in vitro cell lines, in vivo mouse models and single cell RNA-sequencing data. RESULTS: Pretreatment transcriptome profiles differentiated patients who would become RPs or LSs on chemotherapy. Biologically, this signature originated from altered tumour-myeloid dynamics, implicating tumour-induced immune tolerogenicity with poor response to chemotherapy. The central role of the liver microenviroment was confrmed by the association of the RPLS transcriptome signature with clinical outcome in iCCA but not extrahepatic CCA, and in liver metastasis from colorectal cancer, but not in the matched primary bowel tumours. CONCLUSIONS: The RPLS signature could be a novel metric of chemotherapy outcome in iCCA. Further development and validation of this transcriptomic signature is warranted to develop precision chemotherapy strategies in these settings
A Pan-cancer analysis reveals high-frequency genetic alterations in mediators of signaling by the tgf-β superfamily
We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, and BMPR2), and Smads (SMAD2 and SMAD4). Alterations in the TGF-β superfamily correlated positively with expression of metastasis-associated genes and with decreased survival. Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-β signaling in each cancer type. This study provides a broad molecular perspective relevant for future functional and therapeutic studies of the diverse cancer pathways mediated by the TGF-β superfamily
Reference-frame theory and stability region generation
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, May, 2020Cataloged from the official PDF of thesis.Includes bibliographical references (pages 87-91).Electricity provides the foundation for many of today's technological advances. The desire for energy security, a reduction in carbon dioxide emissions and a diversification of resources are all motivations for changes in how electricity is generated and transmitted. Recent alternatives to traditional centralized power-plants include technologies that are decentralized and intermittent, such as solar photovoltaic and wind power. This trend poses considerable challenges in the hardware making up these systems, the software that control and monitor power networks and their mathematical modelling. This thesis presents a set of contributions that address some of the aforementioned challenges. Firstly, we examine the fundamental theories used in modelling and controlling power systems. We expand previous work on reference-frame theory, by providing an alternative interpretation and derivation of the commonly used Park and Clarke transformations. We present a geometric interpretation that has applications in power quality. Secondly, we introduce a framework for producing regions of stability for power systems using conditional generative adversarial neural networks. This provides transmission and distribution operators with an accurate set of control options even as the system changes significantly.by Colm J. O'Rourke.Ph. D.Ph.D. Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Scienc