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LKB1 modulates lung cancer differentiation and metastasis

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Ji H

PROVIDER: S-ECPF-GEOD-6135 | biostudies-other | 2007 Aug

REPOSITORIES: biostudies-other

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LKB1 modulates lung cancer differentiation and metastasis

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

LKB1 modulates lung cancer differentiation and metastasis

2007-08-28 | GSE6135 | GEO

LKB1 modulates lung cancer differentiation and metastasis

Project description:LKB1 modulates lung cancer differentiation and metastasis

| PRJNA97709 | ENA

LKB1 prevents ILC2 exhaustion and lung cancer metastasis

Project description:Group 2 innate lymphoid cells (ILC2s) mediate type 2 immune responses involved in anti-helminth immunity, allergic inflammation, and metabolic homeostasis. Recently, they have emerged as key players in regulating tumor immunity. The tumor suppressor liver kinase B1 (LKB1) inactivating mutations is associated with a variety of human cancers, but the role of LKB1 in ILC2 function and ILC2-mediated tumor immunity remains unknown. Here, we show that LKB1 is required for mature ILC2 survival. Ablation of LKB1 in ILC2s results in impaired proliferation and a marked decrease in type 2 cytokine production upon activation, accompanied with the expression of exhaustion signature genes and reduced cellular metabolism, which promote the development of lung melanoma metastasis. In addition, LKB1 deficiency leads to a marked increase of programmed cell death protein-1 (PD-1) expression in ILC2s through activation of nuclear factor of activated T cells (NFAT) pathway. Blockade of PD-1 can restore type 2 cytokine production in LKB1-deficient ILC2 and reverse its exhaustion state, leading to enhanced antitumor immune responses in vivo. Together, our results reveal that LKB1 retrains ILC2 exhaustion state to maintain immune homeostasis and their antitumor immunity.

2024-05-21 | GSE209588 | GEO

An LKB1-SIK Axis Suppresses Lung Tumor Growth and Controls Differentiation.

Project description:The kinase LKB1 is a critical tumor suppressor in sporadic and familial human cancers, yet the mechanisms by which it suppresses tumor growth remain poorly understood. To investigate the tumor-suppressive capacity of four canonical families of LKB1 substrates in vivo, we used CRISPR/Cas9-mediated combinatorial genome editing in a mouse model of oncogenic KRAS-driven lung adenocarcinoma. We demonstrate that members of the SIK family are critical for constraining tumor development. Histologic and gene-expression similarities between LKB1- and SIK-deficient tumors suggest that SIKs and LKB1 operate within the same axis. Furthermore, a gene-expression signature reflecting SIK deficiency is enriched in LKB1-mutant human lung adenocarcinomas and is regulated by LKB1 in human cancer cell lines. Together, these findings reveal a key LKB1-SIK tumor-suppressive axis and underscore the need to redirect efforts to elucidate the mechanisms through which LKB1 mediates tumor suppression. SIGNIFICANCE: Uncovering the effectors of frequently altered tumor suppressor genes is critical for understanding the fundamental driving forces of cancer growth. Our identification of the SIK family of kinases as effectors of LKB1-mediated tumor suppression will refocus future mechanistic studies and may lead to new avenues for genotype-specific therapeutic interventions.This article is highlighted in the In This Issue feature, p. 1469.

| S-EPMC6825558 | biostudies-literature

Cul4A Modulates Invasion and Metastasis of Lung Cancer Through Regulation of ANXA10.

Project description:: Cullin 4A (Cul4A) is overexpressed in a number of cancers and has been established as an oncogene. This study aimed to elucidate the role of Cul4A in lung cancer invasion and metastasis. We observed that Cul4A was overexpressed in non-small cell lung cancer (NSCLC) tissues and the overexpression of Cul4A was associated with poor prognosis after surgical resection and it also decreased the expression of the tumor suppressor protein annexin A10 (ANXA10). The knockdown of Cul4A was associated with the upregulation of ANXA10, and the forced expression of Cul4A was associated with the downregulation of ANXA10 in lung cancer cells. Further studies showed that the knockdown of Cul4A inhibited the invasion and metastasis of lung cancer cells, which was reversed by the further knockdown of ANXA10. In addition, the knockdown of Cul4A inhibited lung tumor metastasis in mouse tail vein injection xenograft models. Notably, Cul4A regulated the degradation of ANXA10 through its interaction with ANXA10 and ubiquitination in lung cancer cells. Our findings suggest that Cul4A is a prognostic marker in NSCLC patients, and Cul4A plays important roles in lung cancer invasion and metastasis through the regulation of the ANXA10 tumor suppressor.

| S-EPMC6562482 | biostudies-literature

RARRES3 suppresses breast cancer lung metastasis by regulating adhesion and differentiation.

Project description:In estrogen receptor-negative breast cancer patients, metastatic relapse usually occurs in the lung and is responsible for the fatal outcome of the disease. Thus, a better understanding of the biology of metastasis is needed. In particular, biomarkers to identify patients that are at risk of lung metastasis could open the avenue for new therapeutic opportunities. Here we characterize the biological activity of RARRES3, a new metastasis suppressor gene whose reduced expression in the primary breast tumors identifies a subgroup of patients more likely to develop lung metastasis. We show that RARRES3 downregulation engages metastasis-initiating capabilities by facilitating adhesion of the tumor cells to the lung parenchyma. In addition, impaired tumor cell differentiation due to the loss of RARRES3 phospholipase A1/A2 activity also contributes to lung metastasis. Our results establish RARRES3 downregulation as a potential biomarker to identify patients at high risk of lung metastasis who might benefit from a differentiation treatment in the adjuvant programme.

| S-EPMC4119352 | biostudies-literature

Nanog maintains stemness of Lkb1-deficient lung adenocarcinoma and prevents gastric differentiation.

Project description:Growing evidence supports that LKB1-deficient KRAS-driven lung tumors represent a unique therapeutic challenge, displaying strong cancer plasticity that promotes lineage conversion and drug resistance. Here we find that murine lung tumors from the KrasLSL-G12D/+ ; Lkb1flox/flox (KL) model show strong plasticity, which associates with up-regulation of stem cell pluripotency genes such as Nanog. Deletion of Nanog in KL model initiates a gastric differentiation program and promotes mucinous lung tumor growth. We find that NANOG is not expressed at a meaningful level in human lung adenocarcinoma (ADC), as well as in human lung invasive mucinous adenocarcinoma (IMA). Gastric differentiation involves activation of Notch signaling, and perturbation of Notch pathway by the γ-secretase inhibitor LY-411575 remarkably impairs mucinous tumor formation. In contrast to non-mucinous tumors, mucinous tumors are resistant to phenformin treatment. Such therapeutic resistance could be overcome through combined treatments with LY-411575 and phenformin. Overall, we uncover a previously unappreciated plasticity of LKB1-deficient tumors and identify the Nanog-Notch axis in regulating gastric differentiation, which holds important therapeutic implication for the treatment of mucinous lung cancer.

| S-EPMC7933951 | biostudies-literature

Nanog maintains stemness of Lkb1-deficient lung adenocarcinoma and prevents gastric differentiation.

Project description: Not available

| S-EPMC8422069 | biostudies-literature

The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer.

Project description:Loss of LKB1 is associated with increased metastasis and poor prognosis in lung cancer, but the development of targeted agents is in its infancy. Here we report that a glutaminolytic enzyme, glutamate dehydrogenase 1 (GDH1), upregulated upon detachment via pleomorphic adenoma gene 1 (PLAG1), provides anti-anoikis and pro-metastatic signals in LKB1-deficient lung cancer. Mechanistically, the GDH1 product α-KG activates CamKK2 by enhancing its substrate AMPK binding, which contributes to energy production that confers anoikis resistance. The effect of GDH1 on AMPK is evident in LKB1-deficient lung cancer, where AMPK activation predominantly depends on CamKK2. Targeting GDH1 with R162 attenuated tumor metastasis in patient-derived xenograft model and correlation studies in lung cancer patients further validated the clinical relevance of our finding. Our study provides insight into the molecular mechanism by which GDH1-mediated metabolic reprogramming of glutaminolysis mediates lung cancer metastasis and offers a therapeutic strategy for patients with LKB1-deficient lung cancer.

| S-EPMC5777230 | biostudies-literature

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