Single cell transcriptional profiling of distal epithelial cells during early-stage KRAS-driven lung adenocarcinoma in mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA630215 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11684865.fastq.gz | Fastqsanger.gz | |||
| SRR11684866.fastq.gz | Fastqsanger.gz | |||
| SRR11684867.fastq.gz | Fastqsanger.gz | |||
| SRR11684868.fastq.gz | Fastqsanger.gz | |||
| SRR11684869.fastq.gz | Fastqsanger.gz |
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Project description:The purpose of this study was to understand the transcriptional changes that occur during early stage lung adenocarcinoma in mouse models using single cell RNA Seq
2020-09-04 | GSE149813 | GEO
Project description:Cancers with activating mutations of KRAS show a high prevalence and poor prognosis but remain intractable, requiring innovative strategies to overcome the poor targetability of KRAS. Here, we report that KRAS expression was post-translationally up-regulated through the deubiquitination of KRAS protein when the scaffolding function of NDRG3 (N-Myc downstream regulated gene 3) promoted specific interaction between KRAS and a deubiquitinating enzyme, USP9X. In KRAS-mutant pancreatic or lung cancer cells KRAS protein expression, downstream signaling, and cell growth were highly dependent on NDRG3. In conditional KrasG12D knock-in mouse models of pancreatic ductal adenocarcinoma (PDAC), Ndrg3 depletion abolished Kras protein expression in pancreas, and suppressed pancreatic intraepithelial neoplasia (PanIN) formation. Mechanistically, KRAS protein bound to the C-terminal serine/threonine-rich region of NDRG3, subsequently going through the deubiquitination by USP9X recruited to the complex. This interaction could be disrupted in a dominant-negative manner by a C-terminal NDRG3 fragment that can bind KRAS but is defective in USP9X binding, highly suppressing the KRAS protein expression and KRAS-driven cell growth. In summary, KRAS-driven cancer development critically depends on the deubiquitination of KRAS protein mediated by USP9X/NDRG3, and KRAS-addicted cancers could be effectively targeted by inhibiting the KRAS-NDRG3 interaction.
2025-05-07 | PXD052379 | Pride
Project description:Cancers with activating mutations of KRAS show a high prevalence and poor prognosis but remain intractable, requiring innovative strategies to overcome the poor targetability of KRAS. Here, we report that KRAS expression was post-translationally up-regulated through the deubiquitination of KRAS protein when the scaffolding function of NDRG3 (N-Myc downstream regulated gene 3) promoted specific interaction between KRAS and a deubiquitinating enzyme, USP9X. In KRAS-mutant pancreatic or lung cancer cells KRAS protein expression, downstream signaling, and cell growth were highly dependent on NDRG3. In conditional KrasG12D knock-in mouse models of pancreatic ductal adenocarcinoma (PDAC), Ndrg3 depletion abolished Kras protein expression in pancreas, and suppressed pancreatic intraepithelial neoplasia (PanIN) formation. Mechanistically, KRAS protein bound to the C-terminal serine/threonine-rich region of NDRG3, subsequently going through the deubiquitination by USP9X recruited to the complex. This interaction could be disrupted in a dominant-negative manner by a C-terminal NDRG3 fragment that can bind KRAS but is defective in USP9X binding, highly suppressing the KRAS protein expression and KRAS-driven cell growth. In summary, KRAS-driven cancer development critically depends on the deubiquitination of KRAS protein mediated by USP9X/NDRG3, and KRAS-addicted cancers could be effectively targeted by inhibiting the KRAS-NDRG3 interaction.
2025-05-06 | PXD051954 | Pride
Project description:UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma
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Project description:NSD2, through generation of the epigenetic modification histone H3 di-methylated at lysine 36 (H3K36me2), is a candidate convergent downstream effector of oncogenic KRAS-signaling. However, whether NSD2 targeting represents a therapeutic vulnerability of KRAS-driven cancers is unknown. Here, we characterize a first-in-class, clinical grade small molecule catalytic NSD2 inhibitor (NSD2i) series and find pharmacological targeting of NSD2 constitutes an epigenetic dependency with broad therapeutic efficacy in KRAS-driven pre-clinical cancer models. NSD2i inhibits NSD2 potently, with single digit nM IC50 values, and shows high selectively for NSD2 versus NSD1, NSD3, and other similar enzymes. Structural analyses reveal the molecular basis of NSD2i specificity for NSD2, which includes S-adenosylmethionine (SAM)-competitive binding and catalytic disruption via a dual-channel obstruction mechanism. Proteo-epigenomic and single cell strategies in pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LUAD) samples support a model in which durable NSD2i exposure reverses H3K36me2-driven pathologic chromatin plasticity, re-establishing silencing at H3K27me3-legacy loci to curtail KRAS-regulated and oncogenic-associated gene expression programs. Accordingly, NSD2i treatment inhibits PDAC and LUAD cell viability and patient-derived xenograft tumor growth. Further, NSD2 inhibition, which is well tolerated in vivo, is equally effective as KRAS inhibition (sotorasib) treatment in prolonging survival in advanced stage autochthonous KRASG12C-driven PDAC and LUAD mouse tumor models. Moreover, in these models, NSD2 inhibition and sotorasib co-treatment synergize to confer sustained survival with extensive tumor nodule regression and elimination. Together, our work uncovers targeting of the NSD2-H3K36me2 axis as an actionable vulnerability in KRAS-driven cancers and provides a mechanistic rationale for testing NSD2i-KRAS inhibition combination therapies in the clinic.
2025-04-16 | GSE273502 | GEO
Project description:Non-small cell lung cancer (NSCLC), the most frequent subtype of lung cancer, remains a highly lethal malignancy and one of the leading causes of cancer deaths worldwide. Mutant KRAS is the prevailing oncogenic driver of lung adenocarcinoma, the most common histological form of NSCLC. In this study, we examined the role of PKCe, an oncogenic kinase highly expressed in NSCLC and other cancers, in KRAS-driven tumorigenesis. Notably, database analysis revealed an association between PKCe expression and poor outcome in lung adenocarcinoma patients specifically having KRAS mutation. By generating a PKCe-deficient, conditionally activatable allele of oncogenic Kras (LSL-Kras G12D ;PKCe -/- mice) we were able to demonstrate the requirement of PKCe for Kras-driven lung tumorigenesis in vivo, which is consistent with the impaired transformed growth observed in PKCe-deficient KRAS-dependent NSCLC cells. Moreover, PKCe-knockout mice were found to be less susceptible to lung tumorigenesis induced by benzo[a]pyrene, a carcinogen that induces mutations in Kras. Mechanistic analysis using RNA-Seq revealed little overlapping for PKCe and KRAS in the control of genes/biological pathways relevant in NSCLC, suggesting that a permissive role of PKCe in KRAS-driven lung tumorigenesis may involve non-redundant mechanisms. Our results thus highlight the relevance and potential of targeting PKCe for lung cancer therapeutics.
2020-07-31 | GSE149205 | GEO
Project description:NSD2, through generation of the epigenetic modification histone H3 di-methylated at lysine 36 (H3K36me2), is a candidate convergent downstream effector of oncogenic KRAS-signaling. However, whether NSD2 targeting represents a therapeutic vulnerability of KRAS-driven cancers is unknown. Here, we characterize a first-in-class, clinical grade small molecule catalyticNSD2inhibitor (NSD2i) series and find pharmacological targeting of NSD2 constitutes an epigenetic dependency with broad therapeutic efficacy in KRAS-driven pre-clinical cancer models. NSD2i inhibits NSD2 potently, with single digit nM IC50values, and shows high selectively for NSD2 versus NSD1, NSD3, and other similar enzymes. Structural analyses reveal the molecular basis of NSD2i specificity for NSD2, which includesS-adenosylmethionine (SAM)-competitive binding and catalytic disruption via a dual-channel obstruction mechanism. Proteo-epigenomic and single cell strategies in pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LUAD) samples support a model in which durable NSD2i exposure reverses H3K36me2-driven pathologic chromatin plasticity, re-establishing silencing at H3K27me3-legacy loci to curtail KRAS-regulated and oncogenic-associated gene expression programs. Accordingly, NSD2i treatment inhibits PDAC and LUAD cell viability and patient-derived xenograft tumor growth. Further, NSD2 inhibition, which is well toleratedin vivo, is equally effective as KRAS inhibition (sotorasib) treatment in prolonging survival in advanced stage autochthonous KRASG12C-driven PDAC and LUAD mouse tumor models. Moreover, in these models, NSD2 inhibition and sotorasib co-treatment synergize to confer sustained survival with extensive tumor nodule regression and elimination.Together, our work uncovers targeting of the NSD2-H3K36me2 axis as an actionable vulnerability in KRAS-driven cancers and provides a mechanistic rationale for testing NSD2i-KRAS inhibition combination therapies in the clinic.
2025-04-12 | GSE273491 | GEO
Project description:NSD2, through generation of the epigenetic modification histone H3 di-methylated at lysine 36 (H3K36me2), is a candidate convergent downstream effector of oncogenic KRAS-signaling. However, whether NSD2 targeting represents a therapeutic vulnerability of KRAS-driven cancers is unknown. Here, we characterize a first-in-class, clinical grade small molecule catalyticNSD2inhibitor (NSD2i) series and find pharmacological targeting of NSD2 constitutes an epigenetic dependency with broad therapeutic efficacy in KRAS-driven pre-clinical cancer models. NSD2i inhibits NSD2 potently, with single digit nM IC50values, and shows high selectively for NSD2 versus NSD1, NSD3, and other similar enzymes. Structural analyses reveal the molecular basis of NSD2i specificity for NSD2, which includesS-adenosylmethionine (SAM)-competitive binding and catalytic disruption via a dual-channel obstruction mechanism. Proteo-epigenomic and single cell strategies in pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LUAD) samples support a model in which durable NSD2i exposure reverses H3K36me2-driven pathologic chromatin plasticity, re-establishing silencing at H3K27me3-legacy loci to curtail KRAS-regulated and oncogenic-associated gene expression programs. Accordingly, NSD2i treatment inhibits PDAC and LUAD cell viability and patient-derived xenograft tumor growth. Further, NSD2 inhibition, which is well toleratedin vivo, is equally effective as KRAS inhibition (sotorasib) treatment in prolonging survival in advanced stage autochthonous KRASG12C-driven PDAC and LUAD mouse tumor models. Moreover, in these models, NSD2 inhibition and sotorasib co-treatment synergize to confer sustained survival with extensive tumor nodule regression and elimination.Together, our work uncovers targeting of the NSD2-H3K36me2 axis as an actionable vulnerability in KRAS-driven cancers and provides a mechanistic rationale for testing NSD2i-KRAS inhibition combination therapies in the clinic.
2025-04-12 | GSE273490 | GEO
Project description:UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma [CRISPR_screen]
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Project description:UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma [epic_methyl]
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