LKB1 inactivation initiates a chromatin remodeling cascade to drive metastatic progression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA704434 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13774000_1.fastq.gz | Fastqsanger.gz | |||
| SRR13774000_2.fastq.gz | Fastqsanger.gz | |||
| SRR13774100_1.fastq.gz | Fastqsanger.gz | |||
| SRR13774100_2.fastq.gz | Fastqsanger.gz | |||
| SRR13774200_1.fastq.gz | Fastqsanger.gz |
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Project description:Metastasis is the leading cause of cancer-related deaths, enabling cancer cells to expand to secondary tumor sites and compromise systemic organ function1. Given that primary tumors and metastases often share the same constellation of functional driver mutations2–4, the mechanisms driving their distinct phenotypes are unclear. Here, we show that inactivation of a frequently mutated tumor suppressor gene, liver kinase B1 (LKB1), has evolving effects throughout lung cancer progression, differentially re-programming the epigenetic landscape of early-stage primary tumors compared to late-stage metastases. By integrating genome-scale CRISPR/Cas9 screening with bulk and single-cell multi-omic analyses, we unexpectedly identify LKB1 as a master regulator of chromatin state in lung adenocarcinoma primary tumors. Using an in vivo model of metastatic progression, we further reveal that loss of LKB1 activates the early endoderm transcription factor SOX17 in metastases and metastatic-like sub-populations of cancer cells within primary tumors. SOX17 expression is both necessary and sufficient to drive a second wave of epigenetic changes in LKB1-deficient cells that enhances metastatic ability. Overall, our study demonstrates how the downstream effects of an individual driver mutation can change throughout cancer development, with implications for stage-specific therapeutic resistance mechanisms and the gene regulatory underpinnings of metastatic evolution.
2021-04-30 | GSE167381 | GEO
Project description:Germline mutations in LKB1 (STK11) are associated with the Peutz–Jeghers syndrome (PJS), which includes aberrant mucocutaneous pigmentation, and somatic LKB1 mutations occur in 10% of cutaneous melanoma. By somatically inactivating Lkb1 with K-Ras activation (+/- p53 loss) in murine melanocytes, we observed variably pigmented and highly metastatic melanoma with 100% penetrance. LKB1 deficiency resulted in increased phosphorylation of the SRC-family kinase (SFK) YES and the subsequent expansion of a CD24+ cell population which showed increased metastatic behavior in vitro and in vivo relative to isogenic CD24- cells. These results suggest that LKB1 inactivation in the context of RAS activation facilitates metastasis by inducing a SFK-dependent expansion of a pro-metastatic, CD24+ tumor sub-population reference x sample
2012-06-24 | E-GEOD-34866 | biostudies-arrayexpress
Project description:Germline mutations in LKB1 (STK11) are associated with the Peutz–Jeghers syndrome (PJS), which includes aberrant mucocutaneous pigmentation, and somatic LKB1 mutations occur in 10% of cutaneous melanoma. By somatically inactivating Lkb1 with K-Ras activation (+/- p53 loss) in murine melanocytes, we observed variably pigmented and highly metastatic melanoma with 100% penetrance. LKB1 deficiency resulted in increased phosphorylation of the SRC-family kinase (SFK) YES and the subsequent expansion of a CD24+ cell population which showed increased metastatic behavior in vitro and in vivo relative to isogenic CD24- cells. These results suggest that LKB1 inactivation in the context of RAS activation facilitates metastasis by inducing a SFK-dependent expansion of a pro-metastatic, CD24+ tumor sub-population
2012-06-25 | GSE34866 | GEO
Project description:Metastasis is the leading cause of cancer-related deaths and enables cancer cells to compromise organ function by expanding in secondary sites. Since primary tumours and metastases often share the same constellation of driver mutations, the mechanisms that drive their distinct phenotypes are unclear. Here we show that inactivation of the frequently mutated tumour suppressor gene LKB1 (encoding liver kinase B1) has evolving effects throughout the progression of lung cancer, which leads to the differential epigenetic re-programming of early-stage primary tumours compared with late-stage metastases. By integrating genome-scale CRISPR-Cas9 screening with bulk and single-cell multi-omic analyses, we unexpectedly identify LKB1 as a master regulator of chromatin accessibility in lung adenocarcinoma primary tumours. Using an in vivo model of metastatic progression, we further show that loss of LKB1 activates the early endoderm transcription factor SOX17 in metastases and a metastatic-like sub-population of cancer cells within primary tumours. The expression of SOX17 is necessary and sufficient to drive a second wave of epigenetic changes in LKB1-deficient cells that enhances metastatic ability. Overall, our study demonstrates how the downstream effects of an individual driver mutation can change throughout cancer development, with implications for stage-specific therapeutic resistance mechanisms and the gene regulatory underpinnings of metastatic evolution.
| S-EPMC8355205 | biostudies-literature
Project description:Purpose: Mutations in STK11 (LKB1) occur in 17% of lung adenocarcinoma (LUAD) and drive a suppressive (cold) tumor immune microenvironment (TME) and resistance to immunotherapy. The mechanisms underpin the establishment and maintenance of a cold TME in LKB1 mutant LUAD remain poorly understood and the identification of downstream effectors is critical to inform therapeutic strategies to invigorate antitumor immunity. In this study, we investigated the association between inactivation of AMPK, one of the downstream substrates of LKB1, and immune evasion in human LUAD as well as the causal role of AMPK on TME in genetically engineered mouse model (GEMM) of LUAD. Experimental Design: We modeled AMPK inactivation in vivo using GEMM by deleting both AMPKα1 (Prkaa1) and AMPKα2 (Prkaa2) in KrasG12D-driven LUAD (KAA). Furthermore, we investigated the impact of AMPK inactivation on immune cell infiltration and global gene-expression programs of murine LUAD. Gene expression signature from AMPK-deficient murine LUAD was further compared to that of Lkb1 deficient murineLUAD as well as human LUAD with either LKB1 mutation or attenuated AMPK phosphorylation. Results: Inactivation of both AMPKα1 and AMPKα2 accelerates KrasG12D-driven LUAD. AMPK-deficient tumors are characterized with reduced infiltration of CD8+/CD4+ T cells and gene signatures associated with compromised immune microenvironment, which resembles LKB1-deficient murine and human LUAD (KL) as well as LKB1-wildtype LUAD with reduced AMPK phosphorylation. Attenuation of the MHC Class 1 component ß2 microglobulin (ß2M) was identified as a shared feature in KL and KAA murine LUAD as well as in human LUAD with either LKB1 mutations or reduced AMPK phosphorylation. Furthermore, reactivation of AMPK by expression of constitutive active form of AMPKα1 leads to restoration of ß2M level in LKB1 mutant LUAD cells. Conclusions: The results identify attenuation of the LKB1 substrate AMPK as an important mechanism for decreased MHC Class 1 expression and immune evasion in LKB1 mutant LUAD. Translational relevance: LKB1 loss-of-function mutations rank as the third most common genetic alterations found in lung adenocarcinoma and associated with immune evasion. In the current study, on the basis of GEMM of LUAD we established the causal relationship between inactivation of the LKB1 substrate AMPK and immune evasion. Furthermore we find that the status of AMPK phosphorylation is more sensitive than LKB1 mutation in predicting impaired tumor immune microenvironment and likely also for the resistance to immunotherapy. The results also suggest that restoration of AMPK activity could increase the number of patients benefiting from immunotherapy.
2022-01-26 | GSE175479 | GEO
Project description:We characterize the phenotype of mice in which the deletion of Lkb1 has been targeted in the liver. Lack of Lkb1 in the liver results in bile duct paucity leading to cholestasis. This phenotype is similar to that obtained upon inactivation of Notch signaling in the liver. We test the hypothesis of a functional overlap between the Lkb1 and Notch pathways by gene expression profiling of livers deficent in Lkb1 or in the Notch mediator RbpJκ. We used AlfpCre mice for liver-specific deletion of LKB1 that were crossed with a conditional knockout mouse model (LKB1 floxed mice). We used also AlfpCre mice for liver-specific inactivation of the Notch pathway. AlfpCre mice were crossed with the RbpJκ floxed mice. RNA was extracted from the liver of LKB1 KO mice (Lkb1Floxed, AlfpCre positive mice) and their wild-type counterpart (Lkb1Floxed, AlfpCre negative mice). RNA was also extracted from liver of RbpJK KO mice (RbpJK floxed, AlfpCre positive) and their wild type mice (RbpJK floxed, AlfpCe negative). 6 samples for the liver-specific deletion of LKB1 corresponding to 3 KO LKB1 (Cre positive) and 3 normal liver (Cre negative). 6 samples for the liver-specific inactivation of the Notch pathway corresponding to 3 KO RbpJk (Cre positive) and 3 normal liver (Cre negative).
2015-12-08 | E-GEOD-75564 | biostudies-arrayexpress
Project description:Inherited mutation in LKB1 results in the Peutz-Jeghers syndrome (PJS), characterized by intestinal hamartomas and a modestly increased frequency of gastrointestinal and breast cancer1. Somatic inactivation of LKB1 occurs in human lung adenocarcinoma2-4, but its tumor suppressor role in this tissue is unknown. Here we show that somatic Lkb1 deficiency strongly cooperates with somatic K-rasG12D activating mutation to accelerate the development of mouse lung tumorigenesis. Lkb1 deficiency in the setting of K-rasG12D mutation (K-ras Lkb1L/L) was associated with decreased tumor latency and increased tumor aggressiveness including metastasis. Furthermore, tumors from K-ras Lkb1L/L mice demonstrated histologies--squamous, adenosquamous and large cell--not seen with K-rasG12D mutation, Ink4a/Arf inactivation, or p53 inactivation alone or in combination. Experiments in vitro suggest that LKB1 suppresses lung tumorigenesis and progression through both p16INK4a-ARF-p53 dependent and independent mechanisms. These data indicate that LKB1 regulates lung tumor progression and differentiation. Keywords: cancer research To analyze the role of LKB1 in lung cancer progression and differentiation, we have dissected the lung tumors from mice with/without lkb1 loss and performed the microarray analyses to compare their gene expression pattern. In addition, we have also performed microarray analysis in both A549 and H2126 cell lines after reconsistitution of either wt-lkb1 or the kinase dead form of lkb1 (lkb1-KD) to confirm what we observed from in vivo studies.
2007-08-28 | E-GEOD-6135 | biostudies-arrayexpress
Project description:Inherited mutation in LKB1 results in the Peutz-Jeghers syndrome (PJS), characterized by intestinal hamartomas and a modestly increased frequency of gastrointestinal and breast cancer1. Somatic inactivation of LKB1 occurs in human lung adenocarcinoma2-4, but its tumor suppressor role in this tissue is unknown. Here we show that somatic Lkb1 deficiency strongly cooperates with somatic K-rasG12D activating mutation to accelerate the development of mouse lung tumorigenesis. Lkb1 deficiency in the setting of K-rasG12D mutation (K-ras Lkb1L/L) was associated with decreased tumor latency and increased tumor aggressiveness including metastasis. Furthermore, tumors from K-ras Lkb1L/L mice demonstrated histologies--squamous, adenosquamous and large cell--not seen with K-rasG12D mutation, Ink4a/Arf inactivation, or p53 inactivation alone or in combination. Experiments in vitro suggest that LKB1 suppresses lung tumorigenesis and progression through both p16INK4a-ARF-p53 dependent and independent mechanisms. These data indicate that LKB1 regulates lung tumor progression and differentiation. Keywords: cancer research
2007-08-28 | GSE6135 | GEO
Project description:We characterize the phenotype of mice in which the deletion of Lkb1 has been targeted in the liver. Lack of Lkb1 in the liver results in bile duct paucity leading to cholestasis. This phenotype is similar to that obtained upon inactivation of Notch signaling in the liver. We test the hypothesis of a functional overlap between the Lkb1 and Notch pathways by gene expression profiling of livers deficent in Lkb1 or in the Notch mediator RbpJκ. We used AlfpCre mice for liver-specific deletion of LKB1 that were crossed with a conditional knockout mouse model (LKB1 floxed mice). We used also AlfpCre mice for liver-specific inactivation of the Notch pathway. AlfpCre mice were crossed with the RbpJκ floxed mice. RNA was extracted from the liver of LKB1 KO mice (Lkb1Floxed, AlfpCre positive mice) and their wild-type counterpart (Lkb1Floxed, AlfpCre negative mice). RNA was also extracted from liver of RbpJK KO mice (RbpJK floxed, AlfpCre positive) and their wild type mice (RbpJK floxed, AlfpCe negative).
2015-12-08 | GSE75564 | GEO
Project description:Combinatorial tumor suppressor inactivation efficiently initiates lung adenocarcinoma with therapeutic vulnerabilities
| PRJNA729736 | ENA