STK11 (LKB1) missense somatic mutant isoforms promote tumor growth, motility and inflammation

Granado-Martínez, Paula; García-Ortega, Sara; González‐Sánchez, Elena; McGrail, Kimberley; Selgas, Rafael; Grueso, Judit; Gil, R. Sánchez; Naldaiz-Gastesi, Neia; Rhodes, Ana Carolina; Hernández‐Losa, Javier; Ferrer, Berta; Canals, Françesc; Villanueva, Josep; Méndez, Olga; Espinosa-Gil, Sergio; Lizcano, José M.; Muñoz‐Couselo, Eva; García-Patos, Vicenç; Recio, Juán A.

doi:10.1038/s42003-020-1092-0

Cited by 24 publications

(20 citation statements)

References 47 publications

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“…The following oligonucleotide sequences were used to assess target genes expression (5' to 3'; f, fly; m, mouse; h, human). The following primer pairs were obtained from previous reports: fly AMPKγ [41], mouse proteasomal and mitophagy genes [13], mouse and human AMPK subunits [42], mouse Lkb1 [43], and human LKB1 [44].…”

Section: Qrt-pcr Assaysmentioning

confidence: 99%

A conserved role for AMP-activated protein kinase in NGLY1 deficiency

et al. 2020

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Mutations in human N-glycanase 1 (NGLY1) cause the first known congenital disorder of deglycosylation (CDDG). Patients with this rare disease, which is also known as NGLY1 deficiency, exhibit global developmental delay and other phenotypes including neuropathy, movement disorder, and constipation. NGLY1 is known to regulate proteasomal and mitophagy gene expression through activation of a transcription factor called "nuclear factor erythroid 2-like 1" (NFE2L1). Loss of NGLY1 has also been shown to impair energy metabolism, but the molecular basis for this phenotype and its in vivo consequences are not well understood. Using a combination of genetic studies, imaging, and biochemical assays, here we report that loss of NGLY1 in the visceral muscle of the Drosophila larval intestine results in a severe reduction in the level of AMP-activated protein kinase α (AMPKα), leading to energy metabolism defects, impaired gut peristalsis, failure to empty the gut, and animal lethality. Ngly1–/– mouse embryonic fibroblasts and NGLY1 deficiency patient fibroblasts also show reduced AMPKα levels. Moreover, pharmacological activation of AMPK signaling significantly suppressed the energy metabolism defects in these cells. Importantly, the reduced AMPKα level and impaired energy metabolism observed in NGLY1 deficiency models are not caused by the loss of NFE2L1 activity. Taken together, these observations identify reduced AMPK signaling as a conserved mediator of energy metabolism defects in NGLY1 deficiency and suggest AMPK signaling as a therapeutic target in this disease.

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Section: Qrt-pcr Assaysmentioning

confidence: 99%

A conserved role for AMP-activated protein kinase in NGLY1 deficiency

et al. 2020

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“…Additionally, while tissue assessment by next-generation sequencing (NGS) using the FoundationOne CDx™ panel captures both homozygosity and heterozygosity, plasma assessment by targeted NGS of circulating tumor DNA (ctDNA) using the Guardant360® CDx panel is not able to capture homozygous deletions. However, as previously described (28,29), heterozygosity is sufficient to demonstrate loss of function.…”

Section: Discussionmentioning

confidence: 50%

Resistance to Durvalumab and Durvalumab plus Tremelimumab Is Associated with Functional STK11 Mutations in Patients with Non–Small Cell Lung Cancer and Is Reversed by STAT3 Knockdown

Pore

Standifer

et al. 2021

Cancer Discovery

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Mutations in the STK11 (LKB1) gene regulate resistance to PD-1/PD-L1 blockade. This study evaluated this association in patients with nonsquamous non-small-cell lung cancer enrolled in three Phase 1/2 trials. STK11 mutations were associated with resistance to the anti-PD-L1 antibody durvalumab (alone/with the anti-CTLA-4 antibody tremelimumab) independently of KRAS mutational status, highlighting STK11 as a potential driver of resistance to checkpoint blockade. Retrospective assessments of tumor tissue, whole blood and serum revealed a unique immune phenotype in patients with STK11 mutations, with increased expression of markers associated with neutrophils (i.e. CXCL2, IL6), Th17 contexture (i.e. IL17A) and immune checkpoints. Associated changes were observed in the periphery. Reduction of STAT3 in the tumor microenvironment using an antisense oligonucleotide reversed immunotherapy resistance in preclinical STK11 knockout models. These results suggest that STK11 mutations may hinder response to checkpoint blockade through mechanisms including suppressive myeloid cell biology, which could be reversed by STAT3-targeted therapy. SIGNIFICANCEPatients with nonsquamous STK11mut NSCLC are less likely than STK11wt patients to respond to anti-PD-L1 ± anti-CTLA-4 immunotherapies, and their tumors show increased expression of genes and cytokines that activate STAT3 signaling. Preclinically, STAT3 modulation reverses this resistance, suggesting STAT3-targeted agents as potential combination partners for immunotherapies in STK11mut NSCLC.

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“…To further explore the possible mechanism in PTC, we analyzed the kinase, miRNA or transcription factor of ADORA1 using the LinkedOmics database. STK11, a kinase involved in the regulation of ADORA1, was aberrantly expressed in various tumors and played a role in promoting cancer cell adhesion and angiogenesis [40]. Besides, LKB1 has been used for immunotherapy [41].…”

Section: Discussionmentioning

confidence: 99%

ADORA1 is a diagnostic-related biomarker and correlated with immune infiltrates in papillary thyroid carcinoma

Lin¹,

Wang²,

Xue³

et al. 2021

J. Cancer

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Background: Adenosine A1 Receptor (ADORA1) is an adenosine receptor particularly relevant to the immunomodulatory process of malignant tumors. There are growing evidences that dysregulated overexpression of ADORA1 can promote many types of tumorigenesis. However, the expression and prognostic value and mechanism of ADORA1 in thyroid papillary carcinoma have not been reported. Methods: TCGA, ONCOMINE, UALCAN, cBioPortal, GeneMANIA, LinkedOmics, TIMER, GSCALite, TISIDB and EPIC tools were used in this study. Results: ADORA1 was overexpressed in papillary thyroid carcinoma compared to paracancerous tissue. And ADORA1 was positively correlated with lymph node metastasis as well as pathological stage in PTC. ADORA1 had diagnostic and prognostic value for PTC. The functions of ADORA1 co-expressed genes were mainly enriched in immune response, immune response-regulation signaling pathway, regulation of leukocyte activation and cancer-related pathways. Besides, ADORA1 expression was significantly correlated with tumor-infiltrating cells and immune biomarkers in PTC. Finally, the high expression of ADORA1 was sensitive to JW-55 drug. Conclusion: ADORA1 is a diagnostic and a prognostic biomarker for PTC. The expression of ADORA1 is positively correlated with many immunoregulatory factors in PTC.

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STK11 (LKB1) missense somatic mutant isoforms promote tumor growth, motility and inflammation

Cited by 24 publications

References 47 publications

A conserved role for AMP-activated protein kinase in NGLY1 deficiency

A conserved role for AMP-activated protein kinase in NGLY1 deficiency

Resistance to Durvalumab and Durvalumab plus Tremelimumab Is Associated with Functional STK11 Mutations in Patients with Non–Small Cell Lung Cancer and Is Reversed by STAT3 Knockdown

ADORA1 is a diagnostic-related biomarker and correlated with immune infiltrates in papillary thyroid carcinoma

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