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1.
Nature ; 562(7727): 434-438, 2018 10.
Article in English | MEDLINE | ID: mdl-30297799

ABSTRACT

Basal cell carcinoma (BCC) is the most frequent cancer in humans and results from constitutive activation of the Hedgehog pathway1. Several Smoothened inhibitors are used to treat Hedgehog-mediated malignancies, including BCC and medulloblastoma2. Vismodegib, a Smoothened inhibitor, leads to BCC shrinkage in the majority of patients with BCC3, but the mechanism by which it mediates BCC regression is unknown. Here we used two genetically engineered mouse models of BCC4 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 humans5. 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.


Subject(s)
Anilides/pharmacology , Anilides/therapeutic use , Carcinoma, Basal Cell/drug therapy , Carcinoma, Basal Cell/pathology , Neoplasm Recurrence, Local , Pyridines/pharmacology , Pyridines/therapeutic use , Receptors, G-Protein-Coupled/metabolism , Anilides/administration & dosage , Animals , Carcinoma, Basal Cell/genetics , Cell Differentiation/drug effects , Cell Lineage/drug effects , Disease Models, Animal , Female , Hair Follicle/cytology , Hair Follicle/drug effects , Hedgehog Proteins/antagonists & inhibitors , Hedgehog Proteins/metabolism , Humans , Male , Mice , Neoplasm Recurrence, Local/prevention & control , Patched-1 Receptor/deficiency , Pyridines/administration & dosage , Recurrence , Secondary Prevention , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Smoothened Receptor/antagonists & inhibitors , Withholding Treatment , Wnt Proteins/antagonists & inhibitors , Wnt Proteins/metabolism , Wnt Signaling Pathway/drug effects
2.
Nature ; 536(7616): 298-303, 2016 08 18.
Article in English | MEDLINE | ID: mdl-27459053

ABSTRACT

The changes in cell dynamics after oncogenic mutation that lead to the development of tumours are currently unknown. Here, using skin epidermis as a model, we assessed the effect of oncogenic hedgehog signalling in distinct cell populations and their capacity to induce basal cell carcinoma, the most frequent cancer in humans. We found that only stem cells, and not progenitors, initiated tumour formation upon oncogenic hedgehog signalling. This difference was due to the hierarchical organization of tumour growth in oncogene-targeted stem cells, characterized by an increase in symmetric self-renewing divisions and a higher p53-dependent resistance to apoptosis, leading to rapid clonal expansion and progression into invasive tumours. Our work reveals that the capacity of oncogene-targeted cells to induce tumour formation is dependent not only on their long-term survival and expansion, but also on the specific clonal dynamics of the cancer cell of origin.


Subject(s)
Carcinoma, Basal Cell/pathology , Clone Cells/pathology , Neoplastic Stem Cells/pathology , Skin Neoplasms/pathology , Animals , Apoptosis , Carcinoma, Basal Cell/genetics , Cell Self Renewal , Cell Survival , Disease Progression , Epidermis/pathology , Female , Hedgehog Proteins/metabolism , Homeostasis , Male , Mice , Mutation/genetics , Oncogenes/genetics , Signal Transduction , Skin Neoplasms/genetics , Tail/pathology , Tumor Suppressor Protein p53/metabolism
3.
Nat Cell Biol ; 18(1): 100-10, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26595384

ABSTRACT

Aneuploidy is found in most solid tumours, but it remains unclear whether it is the cause or the consequence of tumorigenesis. Using Plk4 overexpression (PLK4OE) during epidermal development, we assess the impact of centrosome amplification and aneuploidy on skin development and tumorigenesis. PLK4OE in the developing epidermis induced centrosome amplification and multipolar divisions, leading to p53 stabilization and apoptosis of epidermal progenitors. The resulting delayed epidermal stratification led to skin barrier defects. Plk4 transgene expression was shut down postnatally in the surviving mice and PLK4OE mice never developed skin tumours. Concomitant PLK4OE and p53 deletion (PLK4OE/p53cKO) rescued the differentiation defects, but did not prevent the apoptosis of PLK4OE cells. Remarkably, the short-term presence of cells with supernumerary centrosomes in PLK4OE/p53cKO mice was sufficient to generate aneuploidy in the adult epidermis and triggered spontaneous skin cancers with complete penetrance. These results reveal that aneuploidy induced by transient centrosome amplification can accelerate tumorigenesis in p53-deficient cells.


Subject(s)
Cell Transformation, Neoplastic/metabolism , Centrosome/metabolism , Epidermis/metabolism , Protein Serine-Threonine Kinases/metabolism , Skin Neoplasms/pathology , Tumor Suppressor Protein p53/metabolism , Animals , Apoptosis/genetics , Cell Transformation, Neoplastic/genetics , Mice , Protein Serine-Threonine Kinases/genetics , Skin Neoplasms/genetics , Tumor Suppressor Protein p53/deficiency
4.
Cell Stem Cell ; 17(1): 60-73, 2015 Jul 02.
Article in English | MEDLINE | ID: mdl-26095047

ABSTRACT

Sox9 is a transcription factor expressed in most solid tumors. However, the molecular mechanisms underlying Sox9 function during tumorigenesis remain unclear. Here, using a genetic mouse model of basal cell carcinoma (BCC), the most frequent cancer in humans, we show that Sox9 is expressed from the earliest step of tumor formation in a Wnt/ß-catenin-dependent manner. Deletion of Sox9 together with the constitutive activation of Hedgehog signaling completely prevents BCC formation and leads to a progressive loss of oncogene-expressing cells. Transcriptional profiling of oncogene-expressing cells with Sox9 deletion, combined with in vivo ChIP sequencing, uncovers a cancer-specific gene network regulated by Sox9 that promotes stemness, extracellular matrix deposition, and cytoskeleton remodeling while repressing epidermal differentiation. Our study identifies the molecular mechanisms regulated by Sox9 that link tumor initiation and invasion.


Subject(s)
Cell Self Renewal/physiology , Cell Transformation, Neoplastic/genetics , Neoplastic Stem Cells/physiology , Oncogenes , SOX9 Transcription Factor/physiology , Actin Cytoskeleton/physiology , Animals , Carcinogenesis , Carcinoma, Basal Cell/etiology , Carcinoma, Basal Cell/genetics , Carcinoma, Basal Cell/physiopathology , Cell Adhesion , Cell Self Renewal/genetics , Extracellular Matrix/physiology , Female , Gene Deletion , Hedgehog Proteins/physiology , Humans , Male , Mice , Mice, Knockout , Mice, Transgenic , Models, Biological , Mutation , Neoplasm Invasiveness , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/physiology , SOX9 Transcription Factor/genetics , Signal Transduction , Skin Neoplasms/etiology , Skin Neoplasms/genetics , Skin Neoplasms/physiopathology , Smoothened Receptor
5.
EMBO Mol Med ; 7(4): 366-7, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25724199

ABSTRACT

Stem cell gene therapy followed by transplantation into damaged regions of the skin has been successfully used to treat genetic skin blistering disorder. Usually, many stem cells are virally transduced to obtain a sufficient number of genetically corrected cells required for successful transplantation, as genetic insertion in every stem cell cannot be precisely defined. In this issue of EMBO Molecular Medicine, Droz-Georget Lathion et al developed a new strategy for ex vivo single cell gene therapy that allows extensive genomic and functional characterization of the genetically repaired individual cells before they can be used in clinical settings.


Subject(s)
Collagen Type VII , Epidermolysis Bullosa Dystrophica/therapy , Genetic Therapy/methods , Stem Cells/metabolism , Transduction, Genetic , Animals , Female , Humans , Male
6.
Nat Cell Biol ; 14(12): 1282-94, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23178882

ABSTRACT

Basal cell carcinoma, the most frequent human skin cancer, arises from activating hedgehog (HH) pathway mutations; however, little is known about the temporal changes that occur in tumour-initiating cells from the first oncogenic hit to the development of invasive cancer. Using an inducible mouse model enabling the expression of a constitutively active Smoothened mutant (SmoM2) in the adult epidermis, we carried out transcriptional profiling of SmoM2-expressing cells at different times during cancer initiation. We found that tumour-initiating cells are massively reprogrammed into a fate resembling that of embryonic hair follicle progenitors (EHFPs). Wnt/ ß-catenin signalling was very rapidly activated following SmoM2 expression in adult epidermis and coincided with the expression of EHFP markers. Deletion of ß-catenin in adult SmoM2-expressing cells prevents EHFP reprogramming and tumour initiation. Finally, human basal cell carcinomas also express genes of the Wnt signalling and EHFP signatures.


Subject(s)
Carcinoma, Basal Cell/pathology , Hair Follicle/cytology , Neoplastic Stem Cells/cytology , Animals , Carcinoma, Basal Cell/metabolism , Flow Cytometry , Hair Follicle/metabolism , Immunohistochemistry , Keratinocytes/cytology , Keratinocytes/metabolism , Mice , Mice, Transgenic , Neoplastic Stem Cells/metabolism , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , beta Catenin/metabolism
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