The mammary gland is composed of basal cells and luminal cells. It is generally believed that the mammary gland arises from embryonic multipotent progenitors, but it remains unclear when lineage ...restriction occurs and what mechanisms are responsible for the switch from multipotency to unipotency during its morphogenesis. Here, we perform multicolour lineage tracing and assess the fate of single progenitors, and demonstrate the existence of a developmental switch from multipotency to unipotency during embryonic mammary gland development. Molecular profiling and single cell RNA-seq revealed that embryonic multipotent progenitors express a unique hybrid basal and luminal signature and the factors associated with the different lineages. Sustained p63 expression in embryonic multipotent progenitors promotes unipotent basal cell fate and was sufficient to reprogram adult luminal cells into basal cells by promoting an intermediate hybrid multipotent-like state. Altogether, this study identifies the timing and the mechanisms mediating early lineage segregation of multipotent progenitors during mammary gland development.
Epithelial to mesenchymal transition (EMT) in cancer cells has been associated with metastasis, stemness, and resistance to therapy. Some tumors undergo EMT while others do not, which may reflect ...intrinsic properties of their cell of origin. However, this possibility is largely unexplored. By targeting the same oncogenic mutations to discrete skin compartments, we show that cell-type-specific chromatin and transcriptional states differentially prime tumors to EMT. Squamous cell carcinomas (SCCs) derived from interfollicular epidermis (IFE) are generally well differentiated, while hair follicle (HF) stem cell-derived SCCs frequently exhibit EMT, efficiently form secondary tumors, and possess increased metastatic potential. Transcriptional and epigenomic profiling revealed that IFE and HF tumor-initiating cells possess distinct chromatin landscapes and gene regulatory networks associated with tumorigenesis and EMT that correlate with accessibility of key epithelial and EMT transcription factor binding sites. These findings highlight the importance of chromatin states and transcriptional priming in dictating tumor phenotypes and EMT.
Display omitted
•The cancer cell of origin controls EMT•Transcriptional priming of EMT occurs in the cancer cell of origin•Epigenetic priming of EMT occurs in the cancer cell of origin•p63 restricts EMT in the cancer cell of origin
Latil and colleagues show that tumor phenotypes and propensity for EMT are dictated by cell-type-specific chomatin and transcriptional states of the cancer cell of origin. These findings provide insight into mechanisms through which chromatin landscapes and gene regulatory networks prime tumor-initiating cells to undergo EMT.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The high mortality rate in septic shock patients is likely due to environmental and genetic factors, which influence the host response to infection. Two genome-wide association studies (GWAS) on 832 ...septic shock patients were performed. We used integrative bioinformatic approaches to annotate and prioritize the sepsis-associated single nucleotide polymorphisms (SNPs). An association of 139 SNPs with death based on a false discovery rate of 5% was detected. The most significant SNPs were within the CISH gene involved in cytokine regulation. Among the 139 SNPs associated with death and the 1311 SNPs in strong linkage disequilibrium with them, we investigated 1439 SNPs within non-coding regions to identify regulatory variants. The highest integrative weighted score (IW-score) was obtained for rs143356980, indicating that this SNP is a robust regulatory candidate. The rs143356980 region is located in a non-coding region close to the CISH gene. A CRISPR-Cas9-mediated deletion of this region and specific luciferase assays in K562 cells showed that rs143356980 modulates the enhancer activity in K562 cells. These analyses allowed us to identify several genes associated with death in patients with septic shock. They suggest that genetic variations in key genes, such as CISH, perturb relevant pathways, increasing the risk of death in sepsis patients.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Introduction
In recent decades, the development of immunotherapy and targeted therapies has considerably improved the outcome of non-small cell lung cancer (NSCLC) patients. Despite these impressive ...clinical benefits, new biomarkers are needed for an accurate stratification of NSCLC patients and a more personalized management. We recently showed that the tumor suppressor fragile histidine triad (FHIT), frequently lost in NSCLC, controls HER2 receptor activity in lung tumor cells and that tumor cells from NSCLC patients harboring a FHIT
low
/pHER2
high
phenotype are sensitive to anti-HER2 drugs. Here, we sought to identify the transcriptomic signature of this phenotype and evaluate its clinical significance.
Materials and methods
We performed RNA sequencing analysis on tumor cells isolated from NSCLC (n=12) according to FHIT/pHER2 status and a functional analysis of differentially regulated genes. We also investigated the FHIT
low
/pHER2
high
signature in The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LUAD) (n=489) and lung squamous cell carcinoma (LUSC) (n=493) cohorts and used the tumor immune dysfunction and exclusion (TIDE) model to test the ability of this signature to predict response to immune checkpoint inhibitors (ICI).
Results
We showed that up-regulated genes in FHIT
low
/pHER2
high
tumors were associated with cell proliferation, metabolism and metastasis, whereas down-regulated genes were related to immune response. The FHIT
low
/pHER2
high
signature was associated with the higher size of tumors, lymph node involvement, and late TNM stages in LUAD and LUSC cohorts. It was identified as an independent predictor of overall survival (OS) in LUAD cohort. FHIT
low
/pHER2
high
tumors were also predictive of poor response to ICI in both LUAD and LUSC cohorts.
Conclusion
These data suggest that ICI might not be a relevant option for NSCLC patients with FHIT
low
/pHER2
high
tumors and that anti-HER2 targeted therapy could be a good therapeutic alternative for this molecular subclass with poorer prognosis.
Bronchiectasis is a chronic airway disease characterized by permanent and irreversible abnormal dilatation of bronchi. Several studies have reported the development of bronchiectasis after renal ...transplantation (RT), but no prospective study specifically assessed bronchiectasis in this population. This study aimed to compare features of patients with bronchiectasis associated with RT to those with idiopathic bronchiectasis.
Nineteen patients with bronchiectasis associated with RT (RT-B group) and 23 patients with idiopathic bronchiectasis (IB group) were prospectively included in this monocentric cross-sectional study. All patients underwent clinical, functional, laboratory, and CT scan assessments. Sputum was collected from 25 patients (n = 11 with RT-B and n = 14 with IB) and airway microbiota was analyzed using an extended microbiological culture.
Dyspnea (≥ 2 on mMRC scale), number of exacerbations, pulmonary function tests, total bronchiectasis score, severity and prognosis scores (FACED and E-FACED), and quality of life scores (SGRQ and MOS SF-36) were similar in the RT-B and IB groups. By contrast, chronic cough was less frequent in the RT-B group than in the IB group (68% vs. 96%, p = 0.03). The prevalence and diversity of the airway microbiota in sputum were similar in the two groups.
Clinical, functional, thoracic CT scan, and microbiological characteristics of bronchiectasis are overall similar in patients with IB and RT-B. These results highlight that in RT patients, chronic respiratory symptoms and/or airway infections should lead to consider the diagnosis of bronchiectasis. Further studies are required to better characterize the pathophysiology of RT-B including airway microbiota, its incidence, and impact on therapeutic management.
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease characterized by airflow limitation. This chronic respiratory disease represents the third leading cause of death ...worldwide. Alteration of the airway microbiota has been reported to be associated with exacerbation frequency in COPD, but its role on the symptoms in patients at stable state is still incompletely described. This study aimed to determine whether bacteria isolated in sputum can be associated with the clinical features of COPD patients within stable state. Our study highlights, for the first time, that altered microbiota with
is associated with pejorative clinical symptoms in stable COPD patients. The airway microbiota of 38 patients was analyzed using an extended culture approach and mass spectrometry identification. Cluster analysis by principal coordinate analysis of the bacterial communities showed that the patients could be classified into three distinct clusters in our cohort. The clusters showed no differences in proportions of the phylum, but one of them was associated with a high prevalence of
(71.4% in cluster 1 vs. 0% in cluster 3), loss of microbiota diversity, and higher bacterial load (10
vs. 10
CFU/ml, respectively) and characterized by predominant cough and impact on mental health. These novel findings, supported by further studies, could lead to modifying the processing of COPD sputum in the everyday practice of clinical microbiology laboratories.
Psoriasis is a common chronic skin disorder characterized by keratinocyte hyperproliferation with altered differentiation accompanied by inflammation and increased angiogenesis. It remains unclear ...whether the first events that initiate psoriasis development occur in keratinocytes or inflammatory cells. Here, using different psoriasis mouse models, we showed that conditional deletion of
or
in epidermal cells inhibited psoriasis mediated by
overexpression or
deletion. Administration of anti-Nrp1 antibody reverted the psoriasis phenotype. Using transcriptional and chromatin profiling of epidermal cells following
overexpression together with
or
deletion, we identified the gene regulatory network regulated by
/
/
during psoriasis development and uncovered a key role of Fosl1 in regulating the chromatin remodeling mediated by
overexpression in keratinocytes. In conclusion, our study identifies an epidermal autonomous function of Vegfa/Nrp1/Flt1 that mediates psoriatic-like disease and demonstrates the clinical relevance of blocking Vegfa/Nrp1/Flt1 axis in psoriasis.
In cancer, the epithelial-to-mesenchymal transition (EMT) is associated with tumour stemness, metastasis and resistance to therapy. It has recently been proposed that, rather than being a binary ...process, EMT occurs through distinct intermediate states. However, there is no direct in vivo evidence for this idea. Here we screen a large panel of cell surface markers in skin and mammary primary tumours, and identify the existence of multiple tumour subpopulations associated with different EMT stages: from epithelial to completely mesenchymal states, passing through intermediate hybrid states. Although all EMT subpopulations presented similar tumour-propagating cell capacity, they displayed differences in cellular plasticity, invasiveness and metastatic potential. Their transcriptional and epigenetic landscapes identify the underlying gene regulatory networks, transcription factors and signalling pathways that control these different EMT transition states. Finally, these tumour subpopulations are localized in different niches that differentially regulate EMT transition states.
Full text
Available for:
KISLJ, NUK, SBMB, UL, UM, UPUK
Basal cell carcinoma (BCC) is the most frequent cancer in humans and results from constitutive activation of the Hedgehog pathway
. Several Smoothened inhibitors are used to treat Hedgehog-mediated ...malignancies, including BCC and medulloblastoma
. Vismodegib, a Smoothened inhibitor, leads to BCC shrinkage in the majority of patients with BCC
, but the mechanism by which it mediates BCC regression is unknown. Here we used two genetically engineered mouse models of BCC
to investigate the mechanisms by which inhibition of Smoothened mediates tumour regression. We found that vismodegib mediates BCC regression by inhibiting a hair follicle-like fate and promoting the differentiation of tumour cells. However, a small population of tumour cells persists and is responsible for tumour relapse following treatment discontinuation, mimicking the situation found in humans
. In both mouse and human BCC, this persisting, slow-cycling tumour population expresses LGR5 and is characterized by active Wnt signalling. Combining Lgr5 lineage ablation or inhibition of Wnt signalling with vismodegib treatment leads to eradication of BCC. Our results show that vismodegib induces tumour regression by promoting tumour differentiation, and demonstrates that the synergy between Wnt and Smoothened inhibitors is a clinically relevant strategy for overcoming tumour relapse in BCC.
Full text
Available for:
KISLJ, NUK, SBMB, UL, UM, UPUK
YAP and TAZ are key downstream regulators of the Hippo pathway, regulating cell proliferation and differentiation. YAP and TAZ activation has been reported in different cancer types. However, it ...remains unclear whether they are required for the initiation of major skin malignancies like basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Here, we analyze the expression of YAP and TAZ in these skin cancers and evaluate cancer initiation in knockout mouse models. We show that YAP and TAZ are nuclear and highly expressed in different BCC types in both human and mice. Further, we find that cells with nuclear YAP and TAZ localize to the invasive front in well‐differentiated SCC, whereas nuclear YAP is homogeneously expressed in spindle cell carcinoma undergoing EMT. We also show that mouse BCC and SCC are enriched for YAP gene signatures. Finally, we find that the conditional deletion of YAP and TAZ in mouse models of BCC and SCC prevents tumor formation. Thus, YAP and TAZ are key determinants of skin cancer initiation, suggesting that targeting the YAP and TAZ signaling pathway might be beneficial for the treatment of skin cancers.
Synopsis
The Hippo pathway transcription factors YAP and TAZ are expressed and active in basal and squamous cell carcinoma in mice and humans. Conditional deletion of YAP and TAZ in mouse models prevents skin cancer initiation.
YAP and TAZ are expressed in mouse and human basal and squamous cell carcinoma.
YAP and TAZ are mainly nuclear in basal and squamous cell carcinoma.
Basal and squamous cell carcinomas express YAP gene signatures.
Conditional deletion of YAP and TAZ prevents skin cancer initiation in mice.
The Hippo pathway transcription factors YAP and TAZ are expressed and active in basal and squamous cell carcinoma in mice and humans. Conditional deletion of YAP and TAZ in mouse models prevents skin cancer initiation.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
PDF
