Identifying and understanding drivers of chemoresistance in small cell lung cancer
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PROVIDER: PRJNA1272154 | ENA |
REPOSITORIES: ENA
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Project description:Identifying and understanding drivers of chemoresistance in small cell lung cancer
| PRJNA1272153 | ENA
Project description:Small cell lung cancer (SCLC) is the most lethal type of lung cancer, characterized by limited treatment options and rapid evolution from chemosensitivity to chemoresistance. However, the mechanisms underlying this evolution remain poorly understood. Identifying the druggable drivers and developing pharmacological strategies to overcome chemoresistance are imperative. Here, we show that Retinoid X receptor γ (RXRγ) is uniquely overexpressed in chemo-resistant SCLC tumors, and that RXRγ serves as an essential factor driving chemoresistance in SCLC. RXRγ forms phase-separated droplets with LSD1 in the nucleus, which enhances RXRγ-mediated gene transcription activity and reprograms gene expression, promoting tumor stemness and metastasis, and eventually driving SCLC chemoresistance. In turn, RXRγ antagonist disrupts RXRγ-LSD1 interaction, reducing their binding to the target gene locus, markedly suppressing the expression of the RXRγ target gene network. Finally, RXRγ antagonists strongly suppress tumor growth and metastasis and restore SCLC vulnerability to chemotherapy in multiple preclinical SCLC models, without overt toxicity, in mice. Thus, these results establish RXRγ as a key player in SCLC by phase separation and as a potential therapeutic target for this deadly disease.
2024-12-31 | GSE277738 | GEO
Project description:Small cell lung cancer (SCLC) is the most lethal type of lung cancer, characterized by limited treatment options and rapid evolution from chemosensitivity to chemoresistance. However, the mechanisms underlying this evolution remain poorly understood. Identifying the druggable drivers and developing pharmacological strategies to overcome chemoresistance are imperative. Here, we show that Retinoid X receptor γ (RXRγ) is uniquely overexpressed in chemo-resistant SCLC tumors, and that RXRγ serves as an essential factor driving chemoresistance in SCLC. RXRγ forms phase-separated droplets with LSD1 in the nucleus, which enhances RXRγ-mediated gene transcription activity and reprograms gene expression, promoting tumor stemness and metastasis, and eventually driving SCLC chemoresistance. In turn, RXRγ antagonist disrupts RXRγ-LSD1 interaction, reducing their binding to the target gene locus, markedly suppressing the expression of the RXRγ target gene network. Finally, RXRγ antagonists strongly suppress tumor growth and metastasis and restore SCLC vulnerability to chemotherapy in multiple preclinical SCLC models, without overt toxicity, in mice. Thus, these results establish RXRγ as a key player in SCLC by phase separation and as a potential therapeutic target for this deadly disease.
2024-12-31 | GSE269090 | GEO
Project description:Small cell lung cancer (SCLC) is the most lethal type of lung cancer, characterized by limited treatment options and rapid evolution from chemosensitivity to chemoresistance. However, the mechanisms underlying this evolution remain poorly understood. Identifying the druggable drivers and developing pharmacological strategies to overcome chemoresistance are imperative. Here, we show that Retinoid X receptor γ (RXRγ) is uniquely overexpressed in chemo-resistant SCLC tumors, and that RXRγ serves as an essential factor driving chemoresistance in SCLC. RXRγ forms phase-separated droplets with LSD1 in the nucleus, which enhances RXRγ-mediated gene transcription activity and reprograms gene expression, promoting tumor stemness and metastasis, and eventually driving SCLC chemoresistance. In turn, RXRγ antagonist disrupts RXRγ-LSD1 interaction, reducing their binding to the target gene locus, markedly suppressing the expression of the RXRγ target gene network. Finally, RXRγ antagonists strongly suppress tumor growth and metastasis and restore SCLC vulnerability to chemotherapy in multiple preclinical SCLC models, without overt toxicity, in mice. Thus, these results establish RXRγ as a key player in SCLC by phase separation and as a potential therapeutic target for this deadly disease.
2024-12-31 | GSE268220 | GEO
Project description:Small cell lung cancer (SCLC) is the most lethal type of lung cancer, characterized by limited treatment options and rapid evolution from chemosensitivity to chemoresistance. However, the mechanisms underlying this evolution remain poorly understood. Identifying the druggable drivers and developing pharmacological strategies to overcome chemoresistance are imperative. Here, we show that Retinoid X receptor γ (RXRγ) is uniquely overexpressed in chemo-resistant SCLC tumors, and that RXRγ serves as an essential factor driving chemoresistance in SCLC. RXRγ forms phase-separated droplets with LSD1 in the nucleus, which enhances RXRγ-mediated gene transcription activity and reprograms gene expression, promoting tumor stemness and metastasis, and eventually driving SCLC chemoresistance. In turn, RXRγ antagonist disrupts RXRγ-LSD1 interaction, reducing their binding to the target gene locus, markedly suppressing the expression of the RXRγ target gene network. Finally, RXRγ antagonists strongly suppress tumor growth and metastasis and restore SCLC vulnerability to chemotherapy in multiple preclinical SCLC models, without overt toxicity, in mice. Thus, these results establish RXRγ as a key player in SCLC by phase separation and as a potential therapeutic target for this deadly disease.
2024-12-31 | GSE268219 | GEO
Project description:Small cell lung cancer (SCLC) is characterized by exquisite chemosensitivity followed by rapid emergence of chemoresistance. To identify genetic events that drive resistance to cisplatin-etoposide chemotherapy, we conducted cDNA overexpression and CRISPR knockout screens in an in vivo platform centered on chemosensitive patient derived xenograft (PDX) models of SCLC. cDNA overexpression screens revealed MYC, MYCN and MYCL as drivers of tumor cell growth through chemotherapy. CRISPR knockout screens identified the KEAP1/NRF2 pathway and members of the SAGA (Spt-Ada-Gcn5 acetyltransferase) complex, including the deubiquitylase USP22. We demonstrated that knockout of either KEAP1 or USP22 switches chemosensitive PDX models to become chemoresistant, with our data supporting distinct molecular consequences of each, including suppression of DNA damage signaling upon USP22 deletion. Data from the IMpower133 clinical trial revealed that a substantial proportion of SCLC patients exhibit KEAP1/NFE2L2 genetic alterations, with activation of an NRF2 transcriptional signature associated with reduced SCLC patient survival with chemotherapy.
2025-03-11 | GSE255095 | GEO
Project description:This experiment is designed to screen miRNAs that are deregulated during chemoresistance-associated metastasis of lung cancer cells. Chemoresistant metastatic in vivo tumor model of A549-luc-Vector cells was established after four rounds of cisplatin (CDDP) treatments compared to corresponding control solvent treatments. Upon examining profiles of miRNA expression differential between tumor-derived cultured cells from the Ctrl-4th and CDDP-4th treatments, most markedly upregulated and downregulated miRNAs in chemoresistant, metastatic A549-luc-CDDP-4th cells were identified. In order to establish a chemoresistant in vivo tumor model, after inoculation of A549-luc-Vector cells, cisplatin (CDDP) or control solvent was intraperitoneally (i.p.) injected six rounds in a two-week period and cells were isolated from corresponding resultant tumors, cultured and re-transplanted into syngeneic mice to receive the next round of treatment. In our experimental model, human lung cancer xenografts developed chemoresistance in the third round of CDDP treatment (CDDP-3rd) and chemoresistance-associated metastases following the fourth round of treatment. Tumor-derived cultured cells from Ctrl-4th and CDDP (cisplatin)-4th treatment were subjected to miRNA array (Agilent-031181 human miRNA (8*60k) V16.0) analysis, with two biological replications for each treatment.
2015-04-10 | E-GEOD-67727 | biostudies-arrayexpress
Project description:An in vivo screening platform using PDX models reveals KEAP1, USP22 and other drivers of chemoresistance in small cell lung cancer
| PRJNA1073511 | ENA
Project description:Small Cell Lung Cancer (SCLC) is often a heterogeneous tumor, where dynamic regulation of key transcription factors can drive multiple populations of phenotypically different cells which contribute differentially to tumor dynamics. This tumor is characterized by a very low 2-year survival rate, high rates of metastasis, and rapid acquisition of chemoresistance. The heterogeneous nature of this tumor makes it difficult to study and to treat, as it is not clear how or when this heterogeneity arises. Here we describe temporal, single-cell analysis of SCLC to investigate tumor initiation and chemoresistance in both SCLC xenografts and in situ SCLC mouse models. We identify an early population of tumor cells with high expression of AP-1 network genes that are critical for tumor growth. Furthermore, we have identified and validated the cancer testis antigens (CTAs) PAGE5 and GAGE2A as mediators of chemoresistance in human SCLC. CTAs have successfully been targeted in other tumor types and may be a promising avenue for targeted therapy in SCLC.
2023-06-22 | GSE216182 | GEO
Project description:Almost half of the patients with advanced colorectal cancer (CRC) are resistant to oxaliplatin based therapy, the first line treatment for CRC. Therefore, predicting and understanding oxaliplatin resistance is important to improve CRC patient survival. Investigated here is the use of proteomic folding stability measurements to differentiate oxaliplatin resistant and sensitive CRCs using patient-derived CRC cell lines and patient-derived xenografts (PDXs). Three protein stability profiling techniques (including the Stability of Proteins from Rates of Oxidation (SPROX), the Thermal Protein Profiling (TPP), and Limited Proteolysis (LiP) approaches) were employed to identify differentially stabilized proteins in 6 patient-derived CRC cell lines with different oxaliplatin sensitivities and 8 CRC PDXs derived from 2 of the patient derived cell lines with different oxaliplatin sensitivity. A total of 23 proteins were found in at least 2 techniques to be differentially stabilized in both the cell line and PDX studies of oxaliplatin resistance. These 23 differentially stabilized proteins included 9 proteins that have been previously connected to cancer chemoresistance. Over-representation analysis (ORA) of all the differentially stabilized proteins identified here, revealed novel pathways related to oxaliplatin resistance. Compared to conventional protein expression level analyses, which were also performed on the cell lines and PDXs, the stability profiling techniques identified novel proteins and pathways and provided new insight on the molecular basis of oxaliplatin resistance. Our results suggest that protein stability profiling techniques are complementary to expression level analyses for identifying biomarkers and understanding molecular mechanisms associated with oxaliplatin chemoresistance in CRC and disease phenotypes in general.
2023-04-28 | PXD036298 | Pride