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Effect of lentiviral-based shRNA-mediated knockdown of ZFX on the human medulloblastoma (MB) cell-line DAOY

ABSTRACT: The Hedgehog (Hh) signaling pathway regulates normal development and cell proliferation, whereas its aberrant activation causes tumor formation. Hh-induced tumors can arise from different tissues and can be indolent or highly aggressive, such as basal cell carcinoma (BCC) of the skin and neural progenitor-derived medulloblastoma (MB), respectively. Little is known about cell-intrinsic factors that control the development of such diverse Hh-dependent tumors. Transcription factor Zfx is required for the self-renewal of several stem cell types, whereas its role in malignant transformation remains controversial. We found that the deletion of Zfx prevented BCC formation and significantly delayed MB development caused by Hh activation in vivo. In contrast, Zfx was dispensable for the development of Hh-independent brain tumor glioblastoma. We used genome-wide expression and chromatin binding analysis in a human MB cell line to identify direct, evolutionarily conserved targets of Zfx. These targets included the Hh signal transducer Smoothened (Smo), suggesting that Zfx may directly control Hh pathway activation in tumors. Two additional targets of Zfx, Dis3L and Ube2j1, were also required for the growth of MB cells in vitro. These results identify a common cell-intrinsic regulator of diverse Hh-induced tumors, and suggest Zfx and Zfx-controlled genes as possible therapeutic targets in these malignancies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE45265 | GEO | 2014/12/31

SECONDARY ACCESSION(S): PRJNA193340

REPOSITORIES: GEO

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Anti-ZFX ChIP-seq in a human medulloblastoma cell line

Project description:The Hedgehog (Hh) signaling pathway regulates normal development and cell proliferation, whereas its aberrant activation causes tumor formation. Hh-induced tumors can arise from different tissues and can be indolent or highly aggressive, such as basal cell carcinoma (BCC) of the skin and neural progenitor-derived medulloblastoma (MB), respectively. Little is known about cell-intrinsic factors that control the development of such diverse Hh-dependent tumors. Transcription factor Zfx is required for the self-renewal of several stem cell types, whereas its role in malignant transformation remains controversial. We found that the deletion of Zfx prevented BCC formation and significantly delayed MB development caused by Hh activation in vivo. In contrast, Zfx was dispensable for the development of Hh-independent brain tumor glioblastoma. We used genome-wide expression and chromatin binding analysis in a human MB cell line to identify direct, evolutionarily conserved targets of Zfx. These targets included the Hh signal transducer Smoothened (Smo), suggesting that Zfx may directly control Hh pathway activation in tumors. Two additional targets of Zfx, Dis3L and Ube2j1, were also required for the growth of MB cells in vitro. These results identify a common cell-intrinsic regulator of diverse Hh-induced tumors, and suggest Zfx and Zfx-controlled genes as possible therapeutic targets in these malignancies.

2014-12-31 | GSE45394 | GEO

Targeting Hedgehog pathway by Smoothened Antagonist

Project description:Aberrant activation of Hedgehog pathway is responsible for initiation and maintenance of various cancers, including medulloblastoma (MB), basal cell carcinoma (BCC), and other solid and hematological tumors. Therefore, targeting Hh pathway represents promising therapeutic prospects for Hh-driven cancers. In recent years, tremendous efforts have been dedicated to the discovery of Hh pathway inhibitor. While the majority of Hh pathway inhibitors target the upstream membrane protein Smoothened (SMO). Here, we performed Next Generation Sequencing to reveal the target genes of Hh pathway by treating mouse SHH-subtype medulloblastoma cells (SmoWT) with SMO inhibitor (GDC0449) or DMSO.

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Inhibition of Medulloblastoma growth by a sonic hedgehog (SHH) inhibitor

Project description:Aberrant activation of the Hedgehog (Hh) signaling pathway is implicated in the pathogenesis of many cancers, including medulloblastoma and basal cell carcinoma (BCC). In this study, using neonatally irradiated Ptch1+/- mice as a model of Hh-dependent tumors, we investigated the in vivo effects of MK-4101, a novel SMO antagonist, for treatment of medulloblastoma and BCC. Results clearly demonstrate a robust antitumor activity of MK-4101, achieved through the inhibition of proliferation and induction of extensive apoptosis in tumor cells. Of note, beside antitumor activity on transplanted tumors, MK-4101 was highly efficacious against primary medulloblastoma and BCC developing in the cerebellum and skin of Ptch1+/- mice. By identifying the changes induced by MK-4101 in gene expression profiles in tumors, we also elucidate the mechanism of action of this novel, orally administrable compound. MK-4101 targets the Hh pathway in the tumor cells, showing the maximum inhibitory effect on Gli1 activity. MK-4101 also induced deregulation of cell cycle and block of DNA replication in tumors. Members of the IGF and Wnt signaling pathways , were among the most highly deregulated genes by MK-4101, suggesting that the interplay among Hh, IGF and Wnt is crucial in Hh-dependent tumorigenesis. Altogether, the results of this preclinical study support a therapeutic opportunity for MK-4101 in the treatment of Hh-driven cancers, also providing useful information for combination therapy with drugs targeting pathways cooperating with Hh oncogenic activity. Gene expression data was generated (in replicates) from Medulloblastoma allografts collected at various time points and following low (40mpk) or high (80 mpk) or vehicle single dose (QD) or mutiple dose (BID) treatment with a SHH pathway inhibitor.

2016-03-14 | E-GEOD-77042 | biostudies-arrayexpress

Inhibition of Medulloblastoma growth by a sonic hedgehog (SHH) inhibitor

2016-03-14 | GSE77042 | GEO

Loss of primary cilia drives switching from Hedgehog to Ras/MAPK pathway

Project description:Basal cell carcinomas (BCCs) rely on Hedgehog (HH) pathway growth signal amplification by the microtubule-based organelle, the primary cilium. Despite naïve tumors responsiveness to Smoothened inhibitors (Smoi), resistance in advanced tumors remains frequent. While the resistant BCCs usually maintain HH pathway activation, squamous cell carcinomas with Ras/MAPK pathway activation also arise, with the molecular basis of tumor type and pathway selection still obscure. Here we identify the primary cilium as a critical determinant controlling tumor pathway switching. Strikingly, Smoi-resistant BCCs possess an increased mutational load in ciliome genes, resulting in reduced primary cilia and HH pathway activation compared to naive or Gorlin patient BCCs. Gene set enrichment analysis of resistant BCCs with a low HH pathway signature reveals increased Ras/MAPK pathway activation. Tissue analysis confirms an inverse relationship between primary cilia presence and Ras/MAPK activation, and primary cilia removal in BCCs potentiates Ras/MAPK pathway activation. Moreover, activating Ras in HH-responsive cell lines confers resistance to both canonical (vismodegib) and non-canonical (aPKC and MRTF inhibitors) HH pathway inhibitors, while conferring sensitivity to MAPK inhibitors. Our results provide new insights into BCC treatment and identify the primary cilium as an important lineage gatekeeper, preventing HH to Ras/MAPK pathway switching.

2018-10-10 | GSE120954 | GEO

Sox9 controls self-renewal of oncogene targeted cells and links tumor initiation and invasion [ChIP-Seq]

Project description: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 human, we show that Sox9 is expressed from the earliest step of tumor formation in a Wnt/β-catenin dependent manner. Deletion of Sox9 together with the constitutive activation of Hedgehog (HH) 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 (ECM) deposition and cytoskeleton remodeling while repressing epidermal differentiation. Our study identifies the molecular mechanisms regulated by Sox9 that links tumor initiation and invasion. Sox9 ChIP-seq analysis in K14CreER SmoM2 cells.

2015-05-13 | E-GEOD-68755 | biostudies-arrayexpress

Expression data from mouse basal cell carcinoma (BCC) and normal epidermis, and BCC cell line treated with cyclopamine

Project description:Activation of the Sonic hedgehog (Shh) signaling pathway due to Patched 1 (PTCH1) mutation is a key event in sporadic and familial basal cell carcinoma (BCC) development. To find out the specific pathway for therapeutic intervention, we developed a mouse BCC model by skin specific Ptch1 inactivation, and sought to identify novel Shh targets. We used microarrays to identify up-regulated genes in mouse BCC. We used microarrays to identify down-regulated genes in mouse BCC cell line by cyclopamine.

2018-01-15 | GSE20065 | GEO

Genomic analysis reveals novel secondary drivers and progression pathways in skin basal cell carcinoma

Project description:Basal cell carcinoma of the skin (BCC) is the most common malignant neoplasm in humans. BCC is primarily driven by the aberrant activation of the Sonic Hedgehog (Hh) pathway. However, its extensive phenotypical variation remains to be explained. The genetic profiling of 293 BCCs revealed the highest mutation rate observed in cancer (65 Mutations/Mb), with strong prevalence of UV-light signature mutations. 85% of BCCs harbored mutations in Hh pathway genes: mutually exclusive PTCH1 (73%) and SMO (20%) (P=6.6x10-8), SUFU (8%), and in TP53 (61%). 85% of BCCs also harbored secondary driver mutations in other genes implicated in BCC tumorigenesis. Recurrent secondary driver mutations were observed in MYCN (30%), PPP6C (15%), STK19 (10%), LATS1 (8%), ERBB2 (4%), PIK3CA (2%), RAC1 (1%) and N/K/H-RAS (2%). Loss of function (LoF) and deleterious missense mutations were observed in PTPN14 (23%), RB1 (8%) and FBXW7 (5%). In line with the mutational profiles detected by RNAseq, we observed activation of the Hh pathway as well as upregulation of target genes of the Hippo-YAP pathway and activation of MYCN target genes. The functional analysis of the novel tumorigenic driver mutations in MYCN, PTPN14 and LATS1 demonstrates their relevance in BCC tumorigenesis and provides an expanded molecular understanding of BCC.

| EGAS00001001540 | EGA

Differential expression analysis of cutaneous squamous cell carcinoma and basal cell carcinoma proteomic profiles sampled with e-biopsy

Project description:Clinical misdiagnosis between cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) affects treatment plans and carries risks of potential for recurrence, metastases, morbidity and mortality. We report the development of a novel tissue sampling approach with molecular biopsy using electroporation. This method, coined e-biopsy, enables non-destructive non-thermal permeabilization of cells in the skin for efficient vacuum-assisted extraction of informative biomolecules for rapid diagnosis. We used e-biopsy for ex vivo proteome extraction from 3 locations per patient in 21 cSCC and 20 BCC pathologically validated human tissue samples. The total 123 extracted proteomes were profiled using LC/MS/MS. The obtained mass spectra presented significantly different proteome profiles for cSCC and BCC with several hundreds of proteins significantly differentially expressed in each tumor in comparison to the other. Notably, our study showed that proteomes sampled with e-biopsy from cSCC and BCC lesions are different, and that 7 proteins were significantly overexpressed in BCC in comparison to cSCC even after the Bonferroni correction (FDR=7.1e-03). Our results provide evidence that the e-biopsy approach could potentially be used as a tool to support cutaneous tumors classification with rapid molecular profiling.

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YAP-TEAD signaling promotes Basal Cell Carcinoma development via c-JUN/AP1 axis [ChIP-seq]

Project description:The mammalian Hippo signaling pathway, through its effectors YAP and TAZ, coerces epithelial progenitor cell expansion for appropriate tissue development or regeneration upon damage. Its ability to drive rapid tissue growth explains why many oncogenic events frequently exploit this pathway to promote cancer phenotypes. Indeed, several tumor types including basal cell carcinoma (BCC) show genetic aberrations in the Hippo (or YAP/TAZ) regulators. Here, we uncover that while YAP is dispensable for homeostatic epidermal regeneration, it is required for BCC development. Our clonal analyses further demonstrate that few emerging Yap-null dysplasia have lower fitness and thus are diminished as they progress to invasive BCC. Mechanistically, YAP depletion in BCC tumors leads to effective impairment of the JNK-JUN signaling, a well-established tumor driving cascade. Importantly, in this context, YAP does not influence canonical Wnt or Hedgehog signaling. Overall, we reveal the Hippo signaling as an independent promoter of BCC pathogenesis and thereby a viable target for drug-resistant BCC.

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