Direct transdifferentiation of tumorigenic melanoma cells to non-tumorigenic neuron-like cells
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ABSTRACT:
PROVIDER: PRJNA1020415 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26156200_1.fastq.gz | Fastqsanger.gz | |||
| SRR26156200_2.fastq.gz | Fastqsanger.gz | |||
| SRR26156201_1.fastq.gz | Fastqsanger.gz | |||
| SRR26156201_2.fastq.gz | Fastqsanger.gz | |||
| SRR26156202_1.fastq.gz | Fastqsanger.gz |
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Project description:Direct transdifferentiation of tumorigenic melanoma cells to non-tumorigenic neuron-like cells (methylation)
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Project description:Melanoma is an aggressive skin cancer and is highly lethal at advanced stages despite the availability of a variety of established therapeutic options due to the high tumorigenicity and metastatic capacity of melanoma cells. However, there is evidence that changing the lineage of cancer cells leads to a drastic reduction of their tumorigenic potential. Different approaches have been developed to change the phenotype of a cell from one lineage to another, a process called transdifferentiation. In this study, we investigated whether melanoma cells can be transdifferentiated into neurons and how that affects their properties and characteristics. For this reason, we ectopically overexpressed the neuron-specific transcription factors Ascl1, Brn2, Myt1L and NeuroD1 in melanoma cells. We could show that melanoma cells could be transdifferentiated into neuron-like cells that expressed neuronal markers and showed a neuron-like morphology. RNA sequencing and DNA methylation assay were used to further reveal the underlying mechanism. Moreover, the transdifferentiated cells had a significantly reduced tumorigenic and metastatic potential and were more sensitive to radiotherapy compared with their parental counterparts. We conclude that transdifferentiation of cancer cells into terminally differentiated cells could represent a new therapeutic alternative for the treatment of malignant melanoma.
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Project description:Melanoma is an aggressive skin cancer and is highly lethal at advanced stages despite the availability of a variety of established therapeutic options due to the high tumorigenicity and metastatic capacity of melanoma cells. However, there is evidence that changing the lineage of cancer cells leads to a drastic reduction of their tumorigenic potential. Different approaches have been developed to change the phenotype of a cell from one lineage to another, a process called transdifferentiation. In this study, we investigated whether melanoma cells can be transdifferentiated into neurons and how that affects their properties and characteristics. For this reason, we ectopically overexpressed the neuron-specific transcription factors Ascl1, Brn2, Myt1L and NeuroD1 in melanoma cells. We could show that melanoma cells could be transdifferentiated into neuron-like cells that expressed neuronal markers and showed a neuron-like morphology. RNA sequencing and DNA methylation assay were used to further reveal the underlying mechanism. Moreover, the transdifferentiated cells had a significantly reduced tumorigenic and metastatic potential and were more sensitive to radiotherapy compared with their parental counterparts. We conclude that transdifferentiation of cancer cells into terminally differentiated cells could represent a new therapeutic alternative for the treatment of malignant melanoma.
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Project description:The direct conversion of human skin fibroblasts to neurons has a low efficiency and unclear mechanism. Here, we show that the knockdown of PTBP2 (nPTB) significantly enhanced the transdifferentiation induced by ASCL1, MiR124-9/9* and p53 shRNA to generate mostly GABAergic neurons. Longitudinal RNAseq analyses identified the continuous induction of many RNA Splicing Regulators (RSRs). Among these, the knockdown of RBFOX3, which encodes the mature neuronal marker NeuN, significantly abrogated the transdifferentiation. Overexpression of RBFOX3 significantly enhanced the conversion induced by AMp; the enhancement was occluded by PTBP2 knockdown. We found that PTBP2 attenuation significantly favored neuron-specific alternative splicing (AS) of many genes involved in synaptic transmission, signal transduction, and axon formation. RBFOX3 knockdown significantly reversed the effect, while RBFOX3 overexpression enhanced it. The study reveals the critical role of neuron-specific AS in the direct conversion of human skin fibroblasts to neurons by showing that PTBP2 attenuation enhances this mechanism in concert with RBFOX3.
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Project description:Uncontrolled Transforming growth factor-beta (TGFβ) signaling promotes aggressive metastatic properties in late-stage breast cancers. However, how TGFβ-mediated cues are directed to induce late-stage tumorigenic events is poorly understood, particularly given that TGFβ has clear tumor suppressing activity in other contexts. Here we demonstrate that the transcriptional regulators TAZ and YAP (TAZ/YAP), key effectors of the Hippo pathway, are necessary to promote and maintain TGFβ-induced tumorigenic phenotypes in breast cancer cells. Interactions between TAZ/YAP, TGFβ-activated SMAD2/3, and TEAD transcription factors reveal convergent roles for these factors in the nucleus. Genome-wide expression analyses indicate that TAZ/YAP, TEADs and TGFβ-induced signals coordinate a specific pro-tumorigenic transcriptional program. Importantly, genes cooperatively regulated by TAZ/YAP, TEAD, and TGFβ, such as the novel targets NEGR1 and UCA1, are necessary for maintaining tumorigenic activity in metastatic breast cancer cells. Nuclear TAZ/YAP also cooperate with TGFβ signaling to promote phenotypic and transcriptional changes in non-tumorigenic cells to overcome TGFβ repressive effects. Our work thus identifies crosstalk between nuclear TAZ/YAP and TGFβ signaling in breast cancer cells, revealing novel insight into late-stage disease-driving mechanisms. Expression profiling was conducted following the repression of the transcriptional regulators TAZ and YAP (TAZ/YAP), the TEAD family of transcription factors (TEAD1/2/3/4), or the TGFb signaling pathway (with SB-431542, an inhibitor of the TBRI recpeptor) in human MDA-MB-231-LM2 breast cancer cells treated with TGFβ1. Human MDA-MB-231-LM2-4 breast cancer cells were transfected with control siRNA, or siRNAs targeting TAZ/YAP or all four TEADs and were treated 24 hours later with 500pM TGFβ1 or 5mM SB-431542 for an additional 24 hours. Total RNA was isolated and twelve microarrays in total were performed, with each condition carried out three times on separate days. The Boston University Microarray Core generated the data using the Affymetrix Human Gene 1.0 St Array.
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Project description:Earlier work has shown that pre-B cells can be converted into macrophages by the transcription factor C/EBP? at very high frequencies. Using this system we have now performed a systematic analysis of the question whether during transdifferentiation the cells transiently reactivate progenitor restricted genes or even retrodifferentiate. A transcriptome analysis of transdifferentiating cells showed that most genes are continuously up or downregulated, acquiring a macrophage phenotype within 5 days. In addition, we observed the transient reactivation of a subset of immature myeloid markers, as well as low levels of the progenitor markers Kit and Flt3 and a few lineage inappropriate genes. However, we were unable to observe the re-expression of cell surface marker combinations that characterize hematopoietic stem and progenitor cells (HSPCs), including c-Kit and Flt3. This was the case even when C/EBPalpha was activated in pre-B cells under culture conditions that favor HSPC growth or when the transcription factor was activated in a time limited fashion. Together, our findings are consistent with the notion that the conversion from pre-B cells to macrophages is mostly direct and does not involve overt retrodifferentiation. Our microarray data indicate that most expression changes are direct, and that transdifferentiation does not involve retrodifferentiation. Our data also show that there is a low level transient activation of selected progenitor genes, as well as myeloid precursor genes. Primary mouse pre-B cells were infected with an inducible form of C/EBPa and cells induced to transdifferentiate with beta Estradiol (b-Est) harvested at different time points to analyze expression profiles, using Affymetrix 430.2 arrays.
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