Littérature scientifique sur le sujet « LKB1/mTOR »

Liver kinase B1 (Lkb1) and mammalian target of rapamycin (mTOR) are key regulators of energy metabolism and cell growth. We have previously reported that adipocyte-specific KO of Lkb1 or mTOR in mice results in distinct developmental and metabolic phenotypes. Here, we aimed to assess how genetic KO of both Lkb1 and mTOR affects adipose tissue development and function in energy homeostasis. We used Adiponectin-Cre to drive adipocyte-specific double KO (DKO) of Lkb1 and mTOR in mice. We performed indirect calorimetry, glucose and insulin tolerance tests, and gene expression assays on the DKO and WT mice. We found that DKO of Lkb1 and mTOR results in reductions of brown adipose tissue and inguinal white adipose tissue mass, but in increases of liver mass. Notably, the DKO mice developed fatty liver and insulin resistance, but displayed improved glucose tolerance after high-fat diet (HFD)-feeding. Interestingly, the DKO mice were protected from HFD-induced obesity due to their higher energy expenditure and lower expression levels of adipogenic genes (CCAAT/enhancer binding protein α and PPARγ) compared with WT mice. These results together indicate that, compared with Lkb1 or mTOR single KOs, Lkb1/mTOR DKO in adipocytes results in overlapping and distinct metabolic phenotypes, and mTOR KO largely overrides the effect of Lkb1 KO.

Hepatic kinase B1 (LKB1) is a tumor suppressor and regulates cell proliferation and apoptosis. However, whether LKB1 affects bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation of during aging remains unclear. Two BMSCs derived from Zempster24−/− (aging) and Zempster24+/+ (normal) mice were cultured in vitro followed by measurement of LKB1 expression by real-time quantitative PCR and Western blot. LKB1 siRNA was transfected into Zempster24−/−BMSCs and LKB1 expression was measured. 14 days after osteogenic induction, mineralized nodule formation was evaluated by alizarin red staining, expression of Calcin, type I collagen, RUNX2 and OPN mRNA expression was measured, together with alkaline phosphatase (ALP) activity and the PI3K/mTOR pathway activity. Compared with normal BMSCs, LKB1 expression was significantly increased, calcified nodules were decreased, with reduced expression of osteocalcin, type I collagen, RUNX2 and OPN mRNA as well as decreased ALP activity and PI3K/mTOR signaling protein expression (P < 0.05). LKB1 siRNA transfection into senescent BMSCs down-regulated LKB1 expression, increased calcification nodule formation, expression of osteocalcin, type I collagen, RUNX2 and OPN mRNA, as well as increased ALP activity and PI3K/mTOR pathway protein expression (P < 0.05). Aging can promote the increase of LKB1 expression and inhibit the osteogenic differentiation of BMSCs. Down-regulation of LKB1 expression in BMSCs during senescence can promote osteogenic differentiation through regulating PI3K/mTOR pathway.

10612 Background: LKB1 is a serine/threonine kinase which is mutated in 20-30% of non-small cell lung cancers (NSCLC) and functions as a tumor suppressor by activating AMPK. Loss of LKB1 by point mutation or deletion suppresses AMPK, leading to increased mTOR signaling. We investigated the signaling pathways modulated by LKB1 mutations and by mTOR inhibition in NSCLC. Methods: Protein expression in cell lines was measured by reverse phase protein array. Differences in protein expression at baseline in LKB1 wild-type versus mutant cell lines and the effects of protein modulation by treatment were assessed by ANOVA. Results: LKB1 mutant cell lines had lower expression of phosphorylated AMPK and TSC (p<0.01 for both) consistent with prior observations. In addition, mutant cell lines expressed higher levels of proteins in the IGF1R pathway including IGFR1b (p<0.0001); AIB1, which is known to upregulate IGF1 (p<0.0001); and IGFBP2 (p=0.016). LKB1 mutant cell lines (n=11/25) were 1.5-fold more sensitive to the AMPK activator metformin, although this did not reach statistical significance (p=0.10). Expression levels of IGF1R pathway proteins increased significantly after 48h treatment with metformin, the mTOR inhibitor temsirolimus, and the dual PI3K/mTOR inhibitor PI103. For example, IGFBP2 and AIB1 were elevated after metformin treatment (p=0.02 and 0.005, respectively); IRS1 and IGFR1 were elevated after temsirolimus or PI103 (p<0.05 for both). Following treatment with metformin and temsirolimus, there was also increased pAkt, a downstream target of IGF1R and activator of mTOR (p<0.01 for both). Modulation of the IGF1R pathway by these drugs was independent of LKB1 mutation status. Conclusions: LKB1 mutant cell lines have increased IGFR activity with higher baseline IGFR1, IGFB2 and AIB1, suggesting that IGFR may be a potential therapeutic target in LKB1 mutant tumors. In addition, inhibition of the mTOR pathway upregulates the IGFR pathway possibly as a feedback mechanism. These results support the investigation of IGFR inhibitors in combination with drugs targeting the mTOR pathway, particularly for tumors bearing LKB1 mutations.

Abstract Scirrhous-type gastric carcinoma (SGC), which is characterized by the rapid proliferation of cancer cells accompanied by extensive fibrosis, shows extremely poor survival. A reason for the poor prognosis of SGC is that the driver gene responsible for SGC has not been identified. To identify the characteristic driver gene of SGC, we examined the genomic landscape of six human SGC cell lines of OCUM-1, OCUM-2M, OCUM-8, OCUM-9, OCUM-12 and OCUM-14, using multiplex gene panel testing by next-generation sequencing. In this study, the non-synonymous mutations of serine threonine kinase 11/liver kinase B1 (STK11/LKB1) gene were detected in OCUM-12, OCUM-2M and OCUM-14 among the six SGC cell lines. Capillary sequencing analysis confirmed the non-sense or missense mutation of STK11/LKB1 in the three cell lines. Western blot analysis showed that LKB1 expression was decreased in OCUM-12 cells and OCUM-14 cells harboring STK11/LKB1 mutation. The mammalian target of rapamycin (mTOR) inhibitor significantly inhibited the proliferation of OCUM-12 and OCUM-14 cells. The correlations between STK11/LKB1 expression and clinicopathologic features of gastric cancer were examined using 708 primary gastric carcinomas by immunochemical study. The low STK11/LKB1 expression group was significantly associated with SGC, high invasion depth and frequent nodal involvement, in compared with the high STK11/LKB1 expression group. Collectively, our study demonstrated that STK11/LKB1 mutation might be responsible for the progression of SGC, and suggested that mTOR signaling by STK11/LKB1 mutation might be one of therapeutic targets for patients with SGC.

AMP-activated protein kinase (AMPK) is an intracellular energy sensor that regulates metabolic and immune functions mainly through the inhibition of the mechanistic target of rapamycin (mTOR)-dependent anabolic pathways and the activation of catabolic processes such as autophagy. The AMPK/mTOR signaling pathway and autophagy markers were analyzed by immunoblotting in blood mononuclear cells of 20 healthy control subjects and 23 patients with an acute demyelinating form of Guillain–Barré syndrome (GBS). The activation of the liver kinase B1 (LKB1)/AMPK/Raptor signaling axis was significantly reduced in GBS compared to control subjects. In contrast, the phosphorylated forms of mTOR activator AKT and mTOR substrate 4EBP1, as well as the levels of autophagy markers LC3-II, beclin-1, ATG5, p62/sequestosome 1, and NBR1 were similar between the two groups. The downregulation of LKB1/AMPK signaling, but not the activation status of the AKT/mTOR/4EBP1 pathway or the levels of autophagy markers, correlated with higher clinical activity and worse outcomes of GBS. A retrospective study in a diabetic cohort of GBS patients demonstrated that treatment with AMPK activator metformin was associated with milder GBS compared to insulin/sulphonylurea therapy. In conclusion, the impairment of the LKB1/AMPK pathway might contribute to the development/progression of GBS, thus representing a potential therapeutic target in this immune-mediated peripheral polyneuropathy.

Abstract Macrophages play critical roles in maintaining tissue homeostasis and modulating immune responses. In response to microenvironmental cytokines, macrophages coordinate cellular signaling networks and diverse transcriptional programs to dictate their phenotypical and functional heterogeneity. For instance, LPS/IFNγ and IL-4 induce classically (M1) and alternatively (M2) activated macrophages, respectively. Remodeling cellular metabolism has been highlighted a key process underlying macrophage functional polarization. However, the precise mechanisms coordinating macrophage metabolism and polarization remain elusive. We report here that the kinase LKB1, a well-known negative regulator of mTOR signaling pathway, serves as a metabolic checkpoint that connects cellular metabolic reprogramming to functional polarization in macrophages. We found that genetic depletion of LKB1 in macrophages polarized their differentiation towards M2-like macrophages, characterized by enhanced expression of M2-associated markers, independently of mTOR and STAT6 signaling pathways. In contrast, loss of LKB1 had no substantial impact on M1-like macrophages. Moreover, LKB1-defienct macrophages orchestrated reprogramming of mitochondrial metabolism to facilitate M2 polarization and tumor immune evasion. Collectively, our studies establish a previously unappreciated role for LKB1 in connecting macrophage metabolism and functional polarization in modulating tumor immunity. This work was partially supported by the Herman B Wells Center and Riley Children’s Foundation.

The master kinase LKB1 is a key regulator of se veral cellular processes, including cell proliferation, cell polarity and cellular metabolism. It phosphorylates and activates several downstream kinases, including AMP-dependent kinase, AMPK. Activation of AMPK by low energy supply and phosphorylation of LKB1 results in an inhibition of mTOR, thus decreasing energy-consuming processes, in particular translation and, thus, cell growth. LKB1 itself is a constitutively active kinase, which is regulated by posttranslational modifications and direct binding to phospholipids of the plasma membrane. Here, we report that LKB1 binds to Phosphoinositide-dependent kinase (PDK1) by a conserved binding motif. Furthermore, a PDK1-consensus motif is located within the kinase domain of LKB1 and LKB1 gets phosphorylated by PDK1 in vitro. In Drosophila, knockin of phosphorylation-deficient LKB1 results in normal survival of the flies, but an increased activation of LKB1, whereas a phospho-mimetic LKB1 variant displays decreased AMPK activation. As a functional consequence, cell growth as well as organism size is decreased in phosphorylation-deficient LKB1. Molecular dynamics simulations of PDK1-mediated LKB1 phosphorylation revealed changes in the ATP binding pocket, suggesting a conformational change upon phosphorylation, which in turn can alter LKB1’s kinase activity. Thus, phosphorylation of LKB1 by PDK1 results in an inhibition of LKB1, decreased activation of AMPK and enhanced cell growth.

Metabolic processes underlying the development of the neural crest, an embryonic population of multipotent migratory cells, are poorly understood. Here, we report that conditional ablation of the Lkb1 tumor suppressor kinase in mouse neural crest stem cells led to intestinal pseudo-obstruction and hind limb paralysis. This phenotype originated from a postnatal degeneration of the enteric nervous ganglia and from a defective differentiation of Schwann cells. Metabolomic profiling revealed that pyruvate-alanine conversion is enhanced in the absence of Lkb1. Mechanistically, inhibition of alanine transaminases restored glial differentiation in an mTOR-dependent manner, while increased alanine level directly inhibited the glial commitment of neural crest cells. Treatment with the metabolic modulator AICAR suppressed mTOR signaling and prevented Schwann cell and enteric defects of Lkb1 mutant mice. These data uncover a link between pyruvate-alanine cycling and the specification of glial cell fate with potential implications in the understanding of the molecular pathogenesis of neural crest diseases.

Abstract The aim of this study was to investigate whether long non-coding RNA (lncRNA) DYNLRB2-2 can inhibit foam cell formation by activating autophagy. The location of DYNLRB2-2 in THP-1-derived macrophages was analyzed by fluorescence in situ hybridization (FISH). Oxidized-low-density lipoprotein (ox-LDL) was used to induce the formation of foam cells, Oil Red O (ORO) staining and high-performance liquid chromatography (HPLC) were performed to detect accumulation of lipid droplets and the level of cholesterol concentration, respectively. The mRNA and protein level of ATP-binding cassette transporter A1 (ABCA1) were examined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting. Relative protein levels of (p-) liver kinase B1 (LKB1), (p-) AMP-activated protein kinase (AMPK), (p-) the mammalian target of rapamycin (mTOR) and autophagy markers (LC3 II, Beclin-1 and p62) in THP-1 macrophage-derived foam cells were analyzed by Western blotting. The levels of inflammatory factors [tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β] in THP-1 macrophage-derived foam cells were detected by enzyme-linked immunosorbent assay (ELISA). 3-MA and compound C were used to block autophagy. Our data show that DYNLRB2-2 inhibited the formation of THP-1 macrophage-derived foam cells and promotes cholesterol efflux (CE) by activating autophagy. DYNLRB2-2 caused autophagy by activating the signaling pathway of LKB1/AMPK/mTOR in foam cells. DYNLRB2-2 activated the LKB1/AMPK/mTOR signaling pathway via the miR-298/Sirtuin 3 (SIRT3) axis. Our data indicated that DYNLRB2-2 enhanced CE by regulating the LKB1/AMPK/mTOR autophagy signaling pathway through the miR-298/SIRT3 axis, thereby blocking the formation of foam cells from THP-1 macrophages.

Le suppresseur de tumeur et sérine/thréonine kinase LKB1 est un régulateur clé de la polarité cellulaire et du métabolisme énergétique en partie grâce à l'activation de sa kinase substrat AMPK. Cette protéine est un senseur métabolique pour adapter les apports énergétiques aux besoins nutritionnels des cellules confrontées à un stress. Pour cela, AMPK phosphoryle divers substrats qui activent les réactions cataboliques et inhibent les processus anaboliques dont la kinase mTOR.Au cours de ma thèse, via l’utilisation de modèles murins d’inactivation conditionnelle, j'ai découvert que Lkb1 est crucial pour la formation des cellules de crête neurale (CCN). Ces cellules multipotentes, originaires du tube neural, donnent naissance à divers dérivés, comme les cellules des os et cartilage de la face, les cellules pigmentées de la peau et les cellules gliales et neurales des nerfs périphériques et du système nerveux entérique. J'ai démontré que Lkb1 est essentiel pour la formation de la tête des vertébrés et pour la différenciation et le maintien des dérivés des CCN dans le système nerveux périphérique. J'ai également mis en évidence l’acétylation de LKB1 sur la lysine 48 par l'acétyltransférase GCN5 et son rôle dans l'ontogenèse des CCN céphaliques et la formation de la tête. De plus, j'ai découvert que Lkb1 contrôle la différenciation des cellules gliales en réprimant un programme de biosynthèse d’acides aminés couplé à la transamination du pyruvate en alanine, en amont de la voie de signalisation mTOR.Les phénotypes dus à la perte de Lkb1 dans les CCN récapitulent les caractéristiques cliniques de maladies humaines appelées neurocristopathies. L’activation anormale du suppresseur de tumeur p53 est également associée à certaines neurocristopathies et l’ablation de p53 sauve le phénotype pathologique. Ainsi, j'ai montré que Lkb1 dans les cellules gliales contrôle p53 en limitant les dommages à l’ADN. Lkb1 est aussi essentiel pour maintenir l’homéostasie lysosomale et le recyclage des protéines et ainsi empêcher la formation de granules nommés lipofuscine, chargés en protéines et lipides oxydés. De façon intéressante, les voies mTOR et LKB1/AMPK sont activées à la surface des lysosomes de façon dépendante des niveaux d’acides aminés. Des données récentes de la littérature suggèrent que les lysosomes constitueraient une plateforme de signalisation pour contrôler la protéolyse et le devenir cellulaire. Ainsi, nos données proposent que les signalisations Lkb1 et p53 pourraient réguler l'homéostasie lysosomale et en conséquence le vieillissement cellulaire.De façon intéressante, les cellules de Sertoli, des cellules somatiques épithéliales, localisées dans les tubes séminifères des testicules, et qui régissent la maturation des cellules germinales et l'homéostasie testiculaire, partagent des fonctions métaboliques similaires avec les cellules gliales. En effet, ces cellules sécrètent le lactate et l'alanine qui alimentent les mitochondries des cellules voisines (cellules germinales ou neurones respectivement) contrôlant ainsi leur survie et leur maturation. Au cours de ma thèse, nous avons observé que Lkb1 est requis pour l'homéostasie testiculaire et la spermatogenèse en régulant la polarité des cellules de Sertoli et leur métabolisme énergétique par le cycle pyruvate-alanine. Ces résultats suggèrent une conservation des régulations métaboliques par Lkb1 dans divers tissus.Dans leur ensemble, mes travaux de thèse ont apporté une meilleure connaissance des mécanismes sous-jacents des régulations métaboliques lors du devenir cellulaire. Ces résultats fournissent de nouvelles perspectives sur le développement des CCN et élargissent notre compréhension du contrôle métabolique exercé par LKB1. Enfin, mes projets de doctorat ont mis en évidence l'existence d'une communication entre les voie de signalisation Lkb1 et p53 et suggèrent l’importance de cette communication dans les pathologies humaines dues à des défauts des CCN
The tumor suppressor LKB1 codes for a serine/threonine kinase. It acts as a key regulator of cell polarity and energy metabolism partly through the activation of the AMP-activated protein kinase (AMPK), a sensor that adapts energy supply to the nutrient demands of cells facing situations of metabolic stress. To achieve metabolic adaptations, AMPK phosphorylates numerous substrates which inhibit anabolic processes while activating catabolic reactions. In particular, AMPK inhibits the mammalian target of rapamycin (mTOR).During my PhD, based on genetically engineered mouse models, I uncovered that Lkb1 signaling is essential for neural crest cells (NCC) formation. NCC are multipotent cells that originate from the neural tube and give rise to various derivatives including bones and cartilage of the face, pigmented cells in the skin and glial and neural cells in peripheral nerves and the enteric nervous system. I demonstrated that Lkb1 is essential for vertebrate head formation and for the differentiation and maintenance of NCC-derivatives in the peripheral nervous system. I also emphasized that LKB1 is acetylated on lysine 48 by the acetyltransferase GCN5 and that this acetylation could regulates cranial NCC ontogeny and head formation. Furthermore, I discovered that Lkb1 controls NCC-derived glial differentiation through metabolic regulations involving amino acid biosynthesis coupled to pyruvate-alanine cycling upstream of mTOR signaling.Phenotypes due to Lkb1 loss in NCC recapitulate clinical features of human disorders called neurocristopathies and therefore suggest that aberrant Lkb1 metabolic signaling underlies the etiology of these pathologies. Abnormal activation of the tumor suppressor p53 has been described in some NCC disorders and p53 inactivation in neurocristopathy mouse models rescues the pathological phenotype. By using a NCC line that can be cultivated as progenitors or differentiated in glial cells in vitro, I demonstrated that Lkb1 expression in NCC-derivatives controls p53 activation by limiting oxidative DNA damage and prevents the formation of lysosomes filled with oxidized proteins and lipids called lipofuscin granules. Interestingly, activation of mTOR and LKB1/AMPK pathways is governed by amino acid sensors and takes place at the lysosome surface. Lysosomes have been proposed as a signaling hub controlling proteolysis and aging. Thus Lkb1 and p53 signaling could converge especially through lysosome homeostasis thereby potentially impacting cellular aging.Strikingly, Sertoli cells, that are epithelial somatic cells, located in seminiferous tubules in testes, and which govern germ cells maturation and whole testis homeostasis, share similar metabolic functions with glial cells. For example, they secrete lactate and alanine to fuel mitochondria of neighboring cells (germ cells or neurons respectively) to control their survival and maturation. During my PhD, we highlighted that Lkb1 is essential for testis homeostasis and spermatogenesis by regulating Sertoli cell polarity and, as observed in glial cells, energy metabolism through pyruvate-alanine cycling. These data suggest that this particular Lkb1 metabolic regulation is conserved in tissues with similar function.Taken together, these studies reveal the underlying molecular mechanisms that coordinately regulate energy metabolism and cell fate. They provide new insights into NCC development and expand our understanding of the role of LKB1 as an energy metabolic regulator. Finally, my PhD projects uncover the existence of a crosstalk between Lkb1 and p53 and underline its importance in NCC disorders

Les adénocarcinomes pulmonaires font partie des cancers bronchiques non à petites cellules qui représentent 85% des diagnostics de cancers pulmonaires. En fonction du stade du cancer déterminé, l’espérance de vie à 5 ans est autour de 68% pour les stades précoces et proche de 0% pour les stades les plus avancés. Ces cancers présentent diverses caractéristiques mutationnelles qui peuvent expliquer les différents degrés de gravité. La Liver Kinase B, connue sous l’acronyme LKB1, est mutée dans 8 à 21% des adénocarcinomes pulmonaires. Bien que n’étant pas initiatrice de la tumorigenèse pulmonaire, la perte de cette protéine entraine une aggravation notable du pronostic des patients.LKB1 est une sérine thréonine kinase codée par le gène STK11 qui joue un rôle clé au cours du développement et du maintien de nombreux organes. Notre équipe a mis en évidence des régulations métaboliques par LKB1 essentielles pour divers lignages d’une population particulière de cellules souches embryonnaires, les cellules de crêtes neurales (CCNs). Au cours de ma thèse, j’ai participé à l’exploration des contributions de LKB1 lors de la mise en place du système nerveux entérique, un réseau de ganglions qui contrôle la motricité digestive et dérive intégralement des CCNs. Nous avons montré le rôle crucial de LKB1 pour la différenciation des neurones entériques et le maintien des cellules gliales entériques via la limitation du stress oxydant et l’activité du facteur de transcription p53.Dans ce contexte, mes travaux de thèse ont également exploré si les régulations métaboliques exercées par LKB1 lors de la formation des CCNs contribueraient également à l’activité suppresseur de tumeur de LKB1. Par l’analyse in silico de données transcriptomiques de patients mutés pour LKB1 (en association avec les mutations oncogéniques KRAS) et porteurs d’adénocarcinomes pulmonaires, j’ai montré que la perte de fonction de LKB1 est associée à une modulation importante du métabolisme des acides aminés. En particulier, l’expression de nombreuses enzymes du métabolisme de l’alanine est augmentée en absence de LKB1 dans les adénocarcinomes pulmonaires. Cette augmentation est corrélée à des données obtenues en culture de cellules tumorales pulmonaires qui montrent des taux d’alanine plus importants en absence de Lkb1. De plus, les mutations de LKB1 s’associent avec une dérégulation de métabolites et enzymes de l’homéostasie rédox, ainsi qu’une stabilisation de p53 et des modifications d’expression de ces gènes cibles.Ainsi, mes résultats mettent en lumière des régulations communes entre l’activité développementale de LKB1 dans les CCNs et son activité suppresseur de tumeur dans les adénocarcinomes pulmonaires. Ces analyses obtenues chez les patients LUAD renforcent la contribution potentielle de la signalisation LKB1 dans des syndromes développementaux chez l’homme bien que des mutations de cette voie ne soient pas connues dans les neurocristopathies, les pathologies dues à une malformation des CCNs. Enfin, l’identification d’autres dérégulations dans les LUAD (régulation du stress oxydant par la voie NRF2-KEAP1, dérégulation du facteur de transcription et régulateur de la chromatine BRG1 par exemple) constituent une source d’inspiration réciproque pour mieux comprendre les fonctions de LKB1 développementales. Dans leur ensemble, ces données ouvrent un nouveau regard sur la recherche de pistes thérapeutiques des pathologies liées à une réduction de la signalisation LKB1
Lung adenocarcinomas (LUAD) are a subset of non-small-cell lung cancers, comprising approximately 85% of diagnosed lung cancer cases. The 5-year survival rate varies depending on the tumor stage, with approximately 68% survival for early-stage cases and nearly 0% survival for the most advanced stages. These cancers exhibit a range of mutational characteristics that may account for the varying degrees of severity. Liver Kinase B, abbreviated as LKB1, is found to be mutated in 8 to 21% of LUAD cases. While it is not the initiating factor in lung tumorigenesis, the loss of this protein significantly worsens the prognosis for affected patients.LKB1 is a serine-threonine kinase encoded by the STK11 gene, and it plays a pivotal role in the development and maintenance of various organs. Our team has uncovered essential metabolic regulations governed by LKB1 in distinct lineages of a specific embryonic stem cell population known as neural crest cells (NCCs). During my PhD, I contributed to investigating the significance of LKB1 in the establishment of the enteric nervous system—a complex network of ganglia responsible for regulating digestive motility and entirely derived from NCCs. Our research demonstrated the critical role of LKB1 in the differentiation of enteric neurons and the maintenance of enteric glial cells by limiting oxidative stress and modulating the activity of the p53 transcription factor.In this context, my doctoral research also delved into whether the metabolic regulations governed by LKB1 during NCC formation could also contribute to LKB1's tumor-suppressive activity. By conducting in silico analysis of transcriptomic data from LUAD patients with LKB1 mutations (in conjunction with oncogenic KRAS mutations), I have demonstrated that the loss of LKB1 function is linked to significant alterations in amino acid metabolism. Specifically, the expression of numerous enzymes involved in alanine metabolism is increased in the absence of LKB1 in lung adenocarcinomas. This increase aligns with data obtained from lung tumor cell cultures, which indicate higher levels of alanine in the absence of LKB1. Furthermore, LKB1 mutations are associated with dysregulation of metabolites and enzymes related to redox homeostasis, global epigenetic changes, as well as the stabilization of p53 and alterations in the expression of its target genes.Hence, my findings underscore the shared regulatory mechanisms between LKB1's developmental role in NCCs and its tumor-suppressive function in lung adenocarcinomas. These analyses, conducted in LUAD patients, further underscore the potential significance of LKB1 signaling in human developmental syndromes, even though mutations in this pathway are not currently associated with neurocristopathies—pathologies stemming from NCC malformations. Additionally, the identification of other dysregulations in LUADs, such as the regulation of oxidative stress via the NRF2-KEAP1 pathway and the deregulation of the transcription factor and chromatin regulator BRG1, reciprocally inspire a deeper understanding of LKB1's developmental functions. Collectively, these findings pave the way for exploring novel therapeutic strategies for conditions linked to diminished LKB1 signaling

Abstract Rrowth control in all metazoans is regulated by a number of conserved signal transduction pathways. These pathways govern the timing and developmental speci&gt;city of cell growth and differentiation in response to external cues including presence and location of growth factors, morphogens, nutrients, and neighboring cells. The phosphoinositol 3-kinase (PI3K) pathway is one of the central signaling pathways governing cell growth, cell survival, and cell migration. Studies in the past few years have revealed that activation of PI3K underlies the development of a large number of human cancers. One of the main downstream targets of PI3K activity is the protein serine/ threonine kinase mTOR (mammalian target of rapamycin). Recent studies have revealed that hyperactivation of mTOR signaling is a common biochemical thread underlying a handful of inherited familial cancer syndromes including those with phosphatase and tensin homolog deleted on chromosome ten (PTEN), TSC1, TSC2, NF1, and LKB1 (STK11) mutations. Here we illuminate what is known about the detailed circuitry of these signaling pathways, and discuss potential points for therapeutic intervention (Fig. 57–1).