MRTF/SRF link the cytoskeleton and hedgehog pathway in drug-resistant basal cell carcinomas
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE78497 | GEO | 2018/01/25
REPOSITORIES: GEO
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Project description:Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity. We show that cytoskeletal activation through Rho and the formin family member Diaphanous (mDia) is required for SRF-MKL-driven GLI1 activation and for tumor cell viability. Remarkably, nuclear MKL1 staining served as a biomarker in tumors from mice and human subjects to predict tumor responsiveness to MKL inhibitors, highlighting the therapeutic potential of targeting this pathway. Thus, our study illuminates, for the first time, cytoskeletal-activation-driven transcription as a personalized therapeutic target for combatting drug-resistant malignancies.
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Project description:Tumor heterogeneity and lack of knowledge about resistant cell states remain a significant barrier to effective targeted cancer therapies. Basal cell carcinomas (BCCs) uniformly depend on Hedgehog (Hh)/Gli signaling for cell growth. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies Gli1 activity, but nMRTF cell state and key factors driving its accumulation remain unknown. Here, we use three surface markers (LYPD3, TACSTD2, and LY6D) to isolate the nMRTF subpopulation and analyze chromatin accessibility profiles.
2020-08-25 | GSE156853 | GEO
Project description:Tumor heterogeneity and lack of knowledge about resistant cell states remain a significant barrier to effective targeted cancer therapies. Basal cell carcinomas (BCCs) uniformly depend on Hedgehog (Hh)/Gli signaling for cell growth. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies Gli1 activity, but nMRTF cell state and key factors driving its accumulation remain unknown. Here, we use three surface markers (LYPD3, TACSTD2, and LY6D) to isolate the nMRTF subpopulation and analyze transcriptomic profiles.
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Project description:The transcription factor SRF is a master regulator of growth factor inducible and cytoskeletal gene expression. Two transcription cofactor families, the TCFs & the MRTFs, are responsible for SRF's activity to direct transcriptional programme in response to extracellular signalling through the Ras-ERK and Rho-actin pathways respectively. We are investigating the role of the SRF network in the response to infection, using the Listeria monocytogenes model. We find that inactivation of the network impairs the ability of CD8 T cells to proliferate in response to listeria and to generate memory cells. Surprisingly, the defect reflects impaired MRTF-SRF signalling rather than the TCF-SRF signalling pathway usually associated with proliferation. Moreover, the defec doesn'tt lie downstream of the initial activation of the TCR, appearing instead to arise from an inability of CD8 T cells to present IL-2 to each other in paracrine fashion. Consistent with these observations, we find that while cultured CD8 MRTF-null T cells can be effectively activated by TCR crosslinking invitro, their ability to form clusters, which is IL-2-dependent, is impaired. Moreover, as expected, pilot experiments indicate that these cells exhibit deficits both in the basal levels of MRTF-SRF target gene expression, and in their ability to induce these genes in response to IL-2 stimulation:
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Project description:Hair follicles (HF) and BCCs can be regarded as ordered and disordered skin appendages respectively and may utilize similar molecular mechanisms of growth. We wanted to examine the similarities and differences in gene expression patterns between BCCs and HF to define common growth mechanisms and gene expression patterns that distinguish an ordered skin appendage from a disordered skin growth. Nodular BCCs (n= 8) and non-follicular skin epithelium (n=8) were obtained. Scalp hair follicle root sheath was micro dissected from between the sebaceous gland duct and the lower one third of the HF (n=7). Microarray analysis was performed using 21K cDNA arrays and selected genes were validated using qPCR and histochemistry staining. Two differentially expressed gene sets were identified by significance analysis of microarray (SAM) in BCC and HF verses skin epithelium respectively. Based on these two lists, we conducted multiple signaling pathway analyses. The results indicated that Notch, hedgehog, and WNT signaling pathways were involved in regulating formation of both HF and BCCs. However, Notch signaling, including tumor suppressor genes Notch 1, Notch 2, Jagged ligands (JAG 1, 2), notch signaling inhibitor NUMB, Lunatic Fringe (LFNG), Deltex proteins (DTX 1, 2) which serve as important signaling components downstream of Notch, and Notch target genes HES1 ,RBPSUHL, hairless protein and HES7, all showed selective differential activation in BCCs compared to HF. The components of the notch signaling pathway may be potential new targets in the development of new therapeutic approaches to BCCs.
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Project description:Basal cell carcinoma (BCC), the most common human cancer results from aberrant activation of the Hedgehog signaling pathway. Although most cases of BCC are sporadic, some forms are inherited as in Bazex-Dupré-Christol syndrome (BDCS), an X-linked, dominant, cancer-prone type of genodermatosis. We discovered mutations in the ACTRT1 gene coding for actin-related protein T1 (Arp-T1) in 2/6 BDCS families. High-throughput sequencing revealed germline mutations in non-coding sequences surrounding ACTRT1 in the remaining four families. These mutations were located in transcribed enhancer regions (eRNA) and impaired enhancer activity and ACTRT1 expression. Furthermore, we found that Arp-T1 directly binds to the Gli1 promoter, thus inhibiting its expression, while loss of Arp-T1 led to activation of Hedgehog pathway in BDCS patients. Moreover, ACTRT1 reduced in vitro and in vivo proliferation of human BCC cell line and two tumor cell lines where Hedgehog signaling pathway is aberrantly activated (MDA-MB231 breast cancer and U2OS osteosarcoma cell lines). Our study highlights a novel causative mechanism in BCCs, demonstrates that ACTRT1 could act as a tumor suppressor beyond the context of BCC, and suggests that ACTRT1 and its regulatory regions may be potential therapeutic targets in cancerology.
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Project description:Myelination of neuronal axons is essential for nervous system development. Myelination requires dramatic cytoskeletal dynamics in oligodendrocytes, but how actin is regulated during myelination is poorly understood. We recently identified serum response factor (SRF)—a transcription factor known to regulate expression of actin and actin regulators in other cell types—as a critical driver of myelination in the aged brain. Yet, a major gap remains in understanding the fundamental role of SRF in oligodendrocyte lineage cells. Here we show that SRF is required cell autonomously in oligodendrocytes for myelination during development. Combining ChIP-seq with RNA-seq identifies SRF-target genes in OPCs and oligodendrocytes that include actin and other key cytoskeletal genes. Accordingly, SRF knockout oligodendrocytes exhibit dramatically reduced actin filament levels early in differentiation, consistent with its role in actin-dependent myelin sheath initiation. Together, our findings identify SRF as a transcriptional regulator that controls the expression of cytoskeletal genes required in oligodendrocytes for myelination. This study identifies a novel pathway regulating oligodendrocyte biology with high relevance to brain development, aging, and disease.
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Project description:Myelination of neuronal axons is essential for nervous system development. Myelination requires dramatic cytoskeletal dynamics in oligodendrocytes, but how actin is regulated during myelination is poorly understood. We recently identified serum response factor (SRF)—a transcription factor known to regulate expression of actin and actin regulators in other cell types—as a critical driver of myelination in the aged brain. Yet, a major gap remains in understanding the fundamental role of SRF in oligodendrocyte lineage cells. Here we show that SRF is required cell autonomously in oligodendrocytes for myelination during development. Combining ChIP-seq with RNA-seq identifies SRF-target genes in OPCs and oligodendrocytes that include actin and other key cytoskeletal genes. Accordingly, SRF knockout oligodendrocytes exhibit dramatically reduced actin filament levels early in differentiation, consistent with its role in actin-dependent myelin sheath initiation. Together, our findings identify SRF as a transcriptional regulator that controls the expression of cytoskeletal genes required in oligodendrocytes for myelination. This study identifies a novel pathway regulating oligodendrocyte biology with high relevance to brain development, aging, and disease.
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Project description:Myelination of neuronal axons is essential for nervous system development. Myelination requires dramatic cytoskeletal dynamics in oligodendrocytes, but how actin is regulated during myelination is poorly understood. We recently identified serum response factor (SRF)—a transcription factor known to regulate expression of actin and actin regulators in other cell types—as a critical driver of myelination in the aged brain. Yet, a major gap remains in understanding the fundamental role of SRF in oligodendrocyte lineage cells. Here we show that SRF is required cell autonomously in oligodendrocytes for myelination during development. Combining ChIP-seq with RNA-seq identifies SRF-target genes in OPCs and oligodendrocytes that include actin and other key cytoskeletal genes. Accordingly, SRF knockout oligodendrocytes exhibit dramatically reduced actin filament levels early in differentiation, consistent with its role in actin-dependent myelin sheath initiation. Together, our findings identify SRF as a transcriptional regulator that controls the expression of cytoskeletal genes required in oligodendrocytes for myelination. This study identifies a novel pathway regulating oligodendrocyte biology with high relevance to brain development, aging, and disease.
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