ZEB1 transcription factor promotes immune escape in melanoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE169203 | GEO | 2022/03/23
REPOSITORIES: GEO
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Project description:Cell plasticity sustains intra-tumor heterogeneity and treatment resistance in melanoma. Deciphering the transcriptional mechanisms governing reversible phenotypic transitions between proliferative/differentiated and invasive/stem-like states is required. Expression of the ZEB1 transcription factor is frequently activated in melanoma, where it fosters adaptive resistance to targeted therapies. Here, we performed a genome-wide characterization of ZEB1 transcriptional targets, by combining ChIP-sequencing and RNA-sequencing, upon phenotype switching in melanoma models. We identified and validated ZEB1 binding peaks in the promoter of key lineage-specific genes crucial for melanoma cell identity. Mechanistically, ZEB1 negatively regulates SOX10-MITF dependent proliferative/melanocytic programs and positively regulates AP-1 driven invasive and stem-like programs. Comparative analyses with breast carcinoma cells revealed lineage-specific ZEB1 binding, leading to the design of a more reliable melanoma-specific ZEB1 regulon. We then developed single-cell spatial multiplexed analyses to characterize melanoma cell states intra-tumoral heterogeneity in human melanoma samples. Combined with scRNA-Seq analyses, our findings confirmed increased ZEB1 expression in Neural-Crest-like cells and mesenchymal cells, underscoring its significance in vivo in both populations. Overall, our results define ZEB1 as a major transcriptional regulator of cell states transitions and provide a better understanding of lineage-specific transcriptional programs sustaining intra-tumor heterogeneity in melanoma.
2024-03-26 | GSE246672 | GEO
Project description:Cell plasticity sustains intra-tumor heterogeneity and treatment resistance in melanoma. Deciphering the transcriptional mechanisms governing reversible phenotypic transitions between proliferative/differentiated and invasive/stem-like states is required. Expression of the ZEB1 transcription factor is frequently activated in melanoma, where it fosters adaptive resistance to targeted therapies. Here, we performed a genome-wide characterization of ZEB1 transcriptional targets, by combining ChIP-sequencing and RNA-sequencing, upon phenotype switching in melanoma models. We identified and validated ZEB1 binding peaks in the promoter of key lineage-specific genes crucial for melanoma cell identity. Mechanistically, ZEB1 negatively regulates SOX10-MITF dependent proliferative/melanocytic programs and positively regulates AP-1 driven invasive and stem-like programs. Comparative analyses with breast carcinoma cells revealed lineage-specific ZEB1 binding, leading to the design of a more reliable melanoma-specific ZEB1 regulon. We then developed single-cell spatial multiplexed analyses to characterize melanoma cell states intra-tumoral heterogeneity in human melanoma samples. Combined with scRNA-Seq analyses, our findings confirmed increased ZEB1 expression in Neural-Crest-like cells and mesenchymal cells, underscoring its significance in vivo in both populations. Overall, our results define ZEB1 as a major transcriptional regulator of cell states transitions and provide a better understanding of lineage-specific transcriptional programs sustaining intra-tumor heterogeneity in melanoma.
2024-03-26 | GSE246603 | GEO
Project description:Melanoma is the most lethal form of skin cancer. Clinical efforts to combat melanoma include immune therapies whose benefit depends on antitumor T-cells, to target and to clear melanoma. However, most tumors lack significant immune infiltration prior to therapy, and some immune therapies are hindered by a persistent lack of immune-cell infiltration. Chemokines can promote T-cell migration into tumors; therefore, agents that induce T-cell attracting chemokines in the tumor microenvironment could potentially improve the clinical activity of current immune therapies for melanoma. CXCL10 has been implicated as a critical chemokine supporting T-cell infiltration into the tumor microenvironment. Here we report that combination treatment of human melanoma cell lines with Toll-like receptor (TLR) 2/6 agonists MALP-2 or FSL-1 +IFNlambda synergize to induce production of immune-cell attracting chemokines CCL3 and CXCL10 by melanoma cells. We find that TLR2 and TLR6 are widely expressed on human melanoma cells, and that stimulation of fresh patient melanoma specimens with TLR2/6 agonists+IFNlambda induces CXCL10 production from melanoma cells, endothelial and immune-cells. Furthermore, ex vivo migration assays demonstrate that stimulation of melanoma cells with TLR2/6 agonists+IFNlambda increases CD4+ and CD8+ T-cell migration toward melanoma. Collectively, these data identify a novel synergy of TLR2/6 agonists+IFNlambda for inducing CXCL10 production by melanoma cells and suggest that intralesional administration of TLR2/6 agonists+IFNlambda may improve immune signatures in melanoma metastases and have value in combination with other immune therapies, by supporting better T-cell migration to melanoma.
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Project description:The Zeb1 transcriptional repressor plays a key role in metastasis through the down-regulation of genes that are strong inducers of epithelial differentiation and inhibitors of stem-ness. Here we report that Zeb1 controls the expression of numerous oncogenic and tumor suppressive microRNAs (miRs). Zeb1 stimulated pro-migratory cytoskeletal processes by down-regulating miR-34a and activated Rho GTPases through Arhgap1, a Cdc42 GTPase activating protein and novel miR-34a target gene. Poor-prognosis human lung adenocarcinomas were highly enriched in a cytoskeletal gene signature activated by miR-34a down-regulation. These findings suggest that Zeb1 regulates a miR network and drives pro-migratory cytoskeletal processes through miR-34a. Microarray-based interrogation of global miR expression changes in a non-metastatic KP cell line (393P) that undergoes EMT and gains invasive and metastatic capabilities following forced Zeb1 expression (393P_Zeb1). two group comparison
2012-08-08 | E-GEOD-38386 | biostudies-arrayexpress
Project description:Both targeted inhibition of oncogenic driver mutations and immune-based therapies show efficacy in treatment of patients with metastatic cancer but responses are either short-lived or incompletely effective. Oncogene inhibition can augment the efficacy of immune-based therapy but mechanisms by which these two interventions might cooperate are incompletely resolved. Using a novel transplantable BRAFV600E-mutant murine melanoma model (SB-3123), we explore potential mechanisms of synergy between the selective BRAFV600E inhibitor vemurafenib and adoptive cell transfer (ACT)-based immunotherapy. We found that vemurafenib cooperated with ACT to delay melanoma progression but surprisingly did not enhance tumor infiltration or effector function of endogenous or adoptively transferred CD8+ T cells as previously observed. Instead, we found that the T cell cytokines IFN-gamma and TNF-alpha synergized with vemurafenib to induce cell cycle arrest of tumor cells in vitro. This was recapitulated in vivo as continuous vemurafenib administration was required to delay melanoma progression following ACT. The unexpected finding that immune cytokines synergize with oncogene inhibitors to induce growth arrest have major implications for understanding cancer biology at the intersection of oncogenic and immune signaling and provides a basis for design of combinatorial therapeutic approaches for patients with metastatic cancer. SB-3123p cells were treated in triplicate (biological replicates) under the following conditions for 96 hours: DMSO vehicle (control) (n=3); mouse IFNgamma (2.4 ng/ml) and mouse TNFalpha (0.24 ng/mL) (n=3); Vemurafenib (1uM) (n=3); and mouse IFNgamma (2.4 ng/ml), mouse TNFalpah (0.24 ng/mL) and Vemurafenib (1uM) (n=3).
2015-02-20 | E-GEOD-62249 | biostudies-arrayexpress
Project description:To have a mechanistic insight how the Zeb1 KD CD8+cDC1 perturbs the immune response globally. to identify the genes that are regulated by Zeb1 RNA was isolated and check for quality, then we used NEB RNA library preparation kit to prepare the library and send for sequencing on Illumina Hi-seq 2500 platform
2018-11-13 | E-MTAB-6916 | biostudies-arrayexpress
Project description:Adoptive immunotherapy using ex vivo expanded tumor reactive lymphocytes can mediate durable cancer regression in selected melanoma patients. Analyses of these trials have associated the in vivo engraftment ability of the transferred cells with their anti-tumor efficacy. Thus, there is significant clinical interest in the prospective isolation of tumor specific T cells that can reliably persist after transfer. Animal studies have suggested that central memory CD8+ T cells (TCM) have divergent capabilities including effector differentiation to target antigen and stem cell-like self renewal that enable long term survival after adoptive transfer. In this study, we sought to isolate human melanoma specific TCM to define their in vivo fate and function after autologous therapeutic transfer to metastatic patients. To facilitate the high throughput identification of these rare cells from patients, we report that TCM have a defined stoichiometric production of IL-2 and IFN-g mRNA after antigen stimulation. Melanoma specific T cells screened for high relative IL-2 production possessed a TCM phenotype and superior in vitro proliferative capacity compared to cells with low IL-2 production. To investigate in vivo effector function and self renewal capability, melanoma specific TCM underwent in vitro expansion and differentiation into lytic effector clones and then were adoptively transferred back into their hosts. These clones targeted skin melanocytes in all five patients and persisted long term and reacquired parental TCM attributes in four patients after transfer. These findings demonstrate the favorable engraftment fitness for human TCM-derived clones, but further efforts to improve their anti-tumor efficacy are still necessary. We used microarrays to compare the resting gene expression profile of melanoma specific CD8+ T cell clones that were derived from either High IL-2:IFN index precursors or Low IL-2:IFN index precursors. Three melanoma specific effector clones were derived from parental cells that possessed a high IL-2:IFN index from three independent patients with metastatic melanoma. Two melanoma specific effector clones were derived from parental cells that possessed a low IL-2:IFN index from two independent patients with metastatic melanoma. We used microarrays to compare the resting gene expression profile of the CD8+ T cell clones that were derived from either high IL-2:IFN index precursors or low IL-2:IFN index precursors.
2012-07-19 | E-GEOD-39508 | biostudies-arrayexpress
Project description:Both targeted inhibition of oncogenic driver mutations and immune-based therapies show efficacy in treatment of patients with metastatic cancer but responses are either short-lived or incompletely effective. Oncogene inhibition can augment the efficacy of immune-based therapy but mechanisms by which these two interventions might cooperate are incompletely resolved. Using a novel transplantable BRAFV600E-mutant murine melanoma model (SB-3123), we explore potential mechanisms of synergy between the selective BRAFV600E inhibitor vemurafenib and adoptive cell transfer (ACT)-based immunotherapy. We found that vemurafenib cooperated with ACT to delay melanoma progression but surprisingly did not enhance tumor infiltration or effector function of endogenous or adoptively transferred CD8+ T cells as previously observed. Instead, we found that the T cell cytokines IFN-gamma and TNF-alpha synergized with vemurafenib to induce cell cycle arrest of tumor cells in vitro. This was recapitulated in vivo as continuous vemurafenib administration was required to delay melanoma progression following ACT. The unexpected finding that immune cytokines synergize with oncogene inhibitors to induce growth arrest have major implications for understanding cancer biology at the intersection of oncogenic and immune signaling and provides a basis for design of combinatorial therapeutic approaches for patients with metastatic cancer.
2015-02-20 | GSE62249 | GEO
Project description:ZEB1 transcription factor promotes immune escape in melanoma
| PRJNA715643 | ENA
Project description:ZEB1 ChIP-seq Data from Control CD8+cDC1
| PRJEB27348 | ENA