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Receptor-independent ectopic activity of PROLACTIN predicts aggressive lung tumors and indicates HDACi-based therapeutic strategies.

ABSTRACT: Aim: PROLACTIN (PRL), normally produced by the pituitary gland, acts through its receptor (PRL-R) to initiate a signalling cascade to the genome. PRL can also be produced by cancer cells and become oncogenic by stimulating its receptor following an autocrine or paracrine route. Here we investigated the oncogenic activities of PRL in lung cancer. Results: PRL is ectopically activated in a subset of very aggressive lung tumours, associated with a rapid fatal outcome, in our cohort of 293 lung tumour patients as well as in an external independent series of patients. An investigation of the molecular basis of PRL adverse effects surprisingly showed an absence of PRL-R expression in the vast majority of PRL-expressing lung tumours. Additionally, a detailed analysis of the ectopically expressed PRL transcripts in lung tumours and cell lines revealed systematic alterations of its first exons encoding the signal peptide. Finally, the transcriptomes of two PRL expressing lung cancer cell lines, with or without silencing of PRL, showed that PRL directly or indirectly sustains the expression of a group of genes that are frequently up-regulated in a variety of unrelated cancers. Interestingly, the gene signature repressed by PRL ectopic expression in lung tumour cells is also specifically up-regulated by HDAC inhibitor treatment or HDAC1/2/3 knock-down. Innovation and conclusion: Altogether, this work sheds lights on the poorly understood impact of the recently-shown large-scale out-of-context gene activity in cancer and also suggests that PRL-expressing aggressive lung cancers could be particularly responsive to a HDAC inhibitor-based treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE49544 | GEO | 2014/08/05

SECONDARY ACCESSION(S): PRJNA214224

REPOSITORIES: GEO

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Receptor-independent ectopic activity of PROLACTIN predicts aggressive lung tumors and indicates HDACi-based therapeutic strategies.

Project description:Aim: PROLACTIN (PRL), normally produced by the pituitary gland, acts through its receptor (PRL-R) to initiate a signalling cascade to the genome. PRL can also be produced by cancer cells and become oncogenic by stimulating its receptor following an autocrine or paracrine route. Here we investigated the oncogenic activities of PRL in lung cancer. Results: PRL is ectopically activated in a subset of very aggressive lung tumours, associated with a rapid fatal outcome, in our cohort of 293 lung tumour patients as well as in an external independent series of patients. An investigation of the molecular basis of PRL adverse effects surprisingly showed an absence of PRL-R expression in the vast majority of PRL-expressing lung tumours. Additionally, a detailed analysis of the ectopically expressed PRL transcripts in lung tumours and cell lines revealed systematic alterations of its first exons encoding the signal peptide. Finally, the transcriptomes of two PRL expressing lung cancer cell lines, with or without silencing of PRL, showed that PRL directly or indirectly sustains the expression of a group of genes that are frequently up-regulated in a variety of unrelated cancers. Interestingly, the gene signature repressed by PRL ectopic expression in lung tumour cells is also specifically up-regulated by HDAC inhibitor treatment or HDAC1/2/3 knock-down. Innovation and conclusion: Altogether, this work sheds lights on the poorly understood impact of the recently-shown large-scale out-of-context gene activity in cancer and also suggests that PRL-expressing aggressive lung cancers could be particularly responsive to a HDAC inhibitor-based treatment. Total RNA was extracted from two small cell lung carcinoma (SCLC) cell lines expressing PRL (H146 and h524: si control) or not (siPRL) and the differentially expressed genes. Five replicates were analysed for each of the four conditions.

2014-08-05 | E-GEOD-49544 | biostudies-arrayexpress

Transcriptomic dysregulation in aggressive and malignant prolactin tumours

Project description:Pituitary tumours are generally benign. However, many are invasive and some of these are aggressive with high proliferation and recurrence rates. Only metastatic tumours are considered malignant and are rare (0.2%). To identify molecular events associated with the aggressive and malignant phenotypes, we combined a comparative genomic hybridization and transcriptomic analysis of 13 prolactin (PRL) tumours classified as non-invasive (NI; n=5), invasive (I; n=2) or aggressive-invasive (AI; n=6). Each tumour showed copy number alterations which appeared to be varied and discrete in the NI and I tumour groups, and more numerous and extensive in the AI tumour group. Allelic loss within the p arm region of chromosome 11 was detected in five of the AI tumours. This region contains the cytobands 11p15.2, 11p15.1, 11p14.3, 11p14.2, 11p14.1, 11p13, 11p12 and 11p11.2. Furthermore, an allelic loss in the 11q arm was also observed in three of these five tumours, which were considered malignant based on the presence of metastases. The comparison of genomic and transcriptomic data showed that allelic loss impacted upon the expression of genes located in the imbalanced region. An original data filtering strategy allowed us to highlight five genes (DGKZ, CD44, TSG101, GTF2H1 and HTATIP2), within the missing 11p region, potentially responsible for triggering the aggressive and malignant phenotypes of PRL tumours. Our novel combined genomic and transcriptomic analysis underlines the importance of chromosome 11 allelic loss in aggressive and malignant PRL tumours and led us to propose a new strategy to find markers of progression in rare tumours. Transcriptomic analysis of Codelink Human Whole Genome Bioarray was performed for 13 prolactin tumors: 6 aggressive-invasive, 2 invasive, and 5 non-invasive.

2011-03-16 | E-GEOD-22812 | biostudies-arrayexpress

Transcriptomic dysregulation in aggressive and malignant prolactin tumours

2011-03-16 | GSE22812 | GEO

Modeling the MYC-driven normal-to-tumour switch in breast cancer.

Project description:The potent MYC oncoprotein is deregulated in many human cancers, including breast carcinoma, and is associated with aggressive disease. To understand the mechanisms and vulnerabilities of MYC-driven breast cancer, we have generated an in vivo model that mimics human disease in response to MYC deregulation. MCF10A cells ectopically expressing a common breast cancer mutation in the PI3 kinase pathway (PIK3CAH1047R) lead to the development of organized acinar structures in mice. However, expressing both PIK3CAH1047R and deregulated-MYC lead to the development of invasive ductal carcinoma, thus creating a model in which a MYC-dependent normal-to-tumour switch occurs in vivo. These MYC-driven tumours exhibit classic hallmarks of human breast cancer at both the pathological and molecular levels. Moreover, tumour growth is dependent upon sustained deregulated MYC expression, further demonstrating addiction to this potent oncogene and regulator of gene transcription. We therefore provide a MYC-dependent model of breast cancer which can be assayed for in vivo tumour initiation, proliferation, and transformation from normal breast acini into invasive breast carcinoma. Taken together, we anticipate that this novel MYC-driven transformation model will be a useful research tool to both better understand MYC’s oncogenic function and identify therapeutic vulnerabilities.

2019-07-25 | GSE130513 | GEO

Cancer associated fibroblasts from localised prostate cancer have a distinctive DNA methylation profile [Illumina EPIC]

Project description:The current methods to distinguish slow-growing from aggressive localised prostate cancer at diagnosis are imprecise so aggressive tumours can sometimes be missed. In this study we examined whether the changes in the features of cancer associated fibroblasts (CAFs) from the surrounding tumour microenvironment can help identify high risk tumours. We show that CAFs have a distinct methylation profile versus non-malignant prostate fibroblasts (NPFs) including specific differentially methylated regions that distinguish higher grade prostate cancer.

2020-03-25 | GSE115413 | GEO

CREBBP is a novel tumour suppressor in solid tumours

Project description:The contribution of the majority of frequently mutated genes to tumourigenesis is not fully defined. Many aggressive human cancers, such as triple negative breast cancers (TNBCs), have a poor prognosis and lack tractable biomarkers and targeted therapeutic options. Here, we systematically characterize loss-of-function mutations to generate a functional map of novel driver genes in a 3-dimensional model of breast cancer heterogeneity that more readily recapitulates the unfavourable tumour microenvironment in vivo. This identified the histone acetyltransferase CREBBP as a potent tumour suppressor gene whose silencing provided a 3D-specific growth advantage only under oxygen and nutrient deplete conditions. CREBBP protein expression was altered in a substantial proportion of TNBCs as well as several other solid tumours, including endometrial, bladder, ovarian and squamous lung cancers. In multiple primary tumours and cell models, loss of CREBBP activity resulted in upregulation of the FOXM1 transcriptional network. Strikingly, treatment with a range of CDK4/6 inhibitors (CDK4/6i), that indirectly target FOXM1 activity, selectively impaired growth in both CREBBP-altered spheroids and cell line xenografts and patient derived models from multiple tumour types. This study is the first to provide rationale for CREBBP as a biomarker for CDK4/6i response in cancer representing a new treatment paradigm for tumours that harbour CREBBP alterations that have limited therapeutic options.

2022-03-23 | PXD012098 | Pride

Huntington disease protein accelerates tumour development and metastasis

Project description:Huntington disease is a severe neurological disorder caused by an abnormal polyglutamine expansion in the N-terminal of the huntingtin protein. Here we show that breast tumours appear earlier when mutant huntingtin is expressed in an activated polyomavirus middle T antigen (PyVT) mouse breast cancer model as compared to the control mice expressing wild-type huntingtin. Tumours bearing mutant huntingtin have a modified gene expression pattern revealing increases in the IGF-1/Akt signalling, epithelial-mesenchymal transition and metastatic properties. Indeed, polyQ-huntingtin expressing tumours show hyper-activation of Akt pathway. Also, when mutant huntingtin is expressed, cancer cells in culture change morphology and the levels of cell adhesion and mesenchymal markers are affected in primary tumour or corresponding derived cells. As a consequence, PyVT induced lung metastasis is higher in Huntington disease mice than in the control mice. Finally, analysis of cases of Huntington disease patients developing breast cancer may suggest an increased aggressiveness of breast cancer when compared to the control population. 8 Total samples were analyzed: 4 x MMTV-PyVT/HdhQ7/Q7 breast tumours; 4 x MMTV-PyVT/HdhQ111/Q111 breast tumours;

2014-04-14 | E-GEOD-28685 | biostudies-arrayexpress

Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer

Project description:Accumulation of senescent cells in the tumour microenvironment can drive tumourigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse line, we show that macrophages and endothelial cells are the predominant senescent cell types in murine KRAS-driven lung tumours. Single cell transcriptomics identify a population of tumour-associated macrophages, expressing a unique array of pro-tumourigenic SASP factors and surface proteins, that are also present in normal aged lungs. Genetic or senolytic ablation of senescent cells, and macrophage depletion, result in a significant reduction in tumour burden and increased mouse survival of KRAS-driven lung cancer models. Of translational relevance, we reveal the presence of macrophages with senescent features in human lung premalignant lesions, but not in adenocarcinomas. Together, our results have uncovered a population of senescent macrophages contributing to the initiation and progression of lung cancer, thus opening potential therapeutic avenues and cancer preventative strategies.

2023-06-02 | GSE230054 | GEO

Neurogenesis in Prostate Cancer is driven by Neural Precursors from the Central Nervous System

Project description:The development of autonomic nerve fibres in the tumour microenvironment is a pivotal event that regulates prostate cancer initiation and dissemination, but how nerves emerge in tumours is presently unknown. Here we show that Doublecortine-expressing (DCX+) neural precursors from the central nervous system (CNS) infiltrate prostate tumours and differentiate into neo-neurons that contribute to tumour development. In human primary prostate tumours and transgenic mouse cancer tissues, the density of DCX+ neural progenitors is strongly associated with tumour aggressiveness, invasion and recurrence. We found that DCX+ neural precursors egress from the subventricular zone, a neurogenic area of the CNS, and circulate in the blood to reach the tumour where they initiate neurogenesis. Hence, the DCX+ cells in prostate tumour can differentiate into neurons ex vivo and build up a tumour-associated neural network in vivo. Selective genetic depletion of DCX+ cells in mice significantly inhibits the early phases of prostate cancer development, whereas orthotopic transplantation of DCX+ cells purified from prostate tumour or brain tissues promotes tumour growth and cancer cell dissemination. These results unveil a unique crosstalk between the CNS and the tumour that drives a process of neurogenesis necessary for prostate cancer development, and indicate a novel neural element of the tumour microenvironment as a potential target for cancer treatment.

2019-05-16 | E-MTAB-7727 | biostudies-arrayexpress

Genome-wide analysis of ex vivo gene expression of 4T1 series mouse mammary tumors

Project description:Analysis of factors upregulated in highly aggressive 410.4 and 4T1 tumour cells compared to the less aggressive 4T07 tumour cells at gene expression level. The question addressed in the present study was which secreted factors are differentially expressed by these cells and therefore could account for the observed difference in fibroblast activation in these tumours. Results provide important characterisation of the ex vivo expression profiles of highly aggressive vs. non-aggressive tumour cells.

2016-01-18 | GSE50471 | GEO

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