Uncovering the rewired IAP-JAK regulatory axis as an immune-dependent vulnerability of LKB1-mutant lung cancer
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PROVIDER: PRJNA1141560 | ENA |
REPOSITORIES: ENA
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Project description:Harnessing the power of immune system to treat cancer has become a core clinical approach. However, rewiring of intrinsic circuitry by genomic alterations enables tumor cells to escape immune surveillance, leading to therapeutic failure. Uncovering the molecular basis of how tumor mutations induce therapeutic resistance may guide the development of intervention approaches to advance precision immunotherapy. Here we report the identification of the LKB1-IAP-JAK dynamic complex as a molecular determinant for immune response of LKB1-mut lung cancer cells. LKB1 alteration exposes a critical dependency of lung cancer cells on IAP for their immune resistance. Indeed, pharmacological inhibition of IAP re-established JAK-regulated STING expression and DNA sensing signaling, enhanced cytotoxic immune cell infiltration, and augmented immune-dependent anti-tumor activity in an LKB1-mutant immune-competent mouse model. Thus, IAP-JAK-targeted strategies, like IAP inhibitors, may offer a promising therapeutic approach to restore the responsiveness of “immunologically-cold” LKB1-mutant tumors to immune checkpoint inhibitors or STING-directed therapies.
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Project description:Cellular inhibitor of apoptosis proteins 1 and 2 (c-IAP1/2) play central roles in signal transduction mediated by numerous receptors that participate in inflammatory and immune responses. In certain pathways, such as activation of NF-kB, their degradation is a major regulatory event and is physiologically induced by activation of receptors. Additionally, a number of synthetic compounds have been developed that also target the c-IAPs and induce their degradation. However, the extent of a synthetic IAP antagonist’s ability to mirror the transcriptional program by a physiological signal remains unclear. Here we take a systems approach to compare the transcriptional programs triggered by activation of CD30, a well-characterized receptor previously shown to induce the degradation of the c-IAPs, to SM-164, a synthetic IAP antagonist that specifically triggers c-IAP degradation. Employing a technique that allows the specific analysis of newly transcribed RNA, we have generated comparative transcriptome profiles for CD30 activation and SM-164 treatment. Analysis of these profiles revealed that the genes regulated by each stimulus were not completely shared, indicating novel functions of IAP antagonists and consequences of c-IAP1/2 degradation. The data identified a role for c-IAP1/2 in the regulation of the ribosome and protein synthesis, which was subsequently confirmed by biological assays. These findings expand our knowledge of the roles of c-IAP1/2 in signaling and provide insight into the mechanism of synthetic IAP antagonists, furthering our understanding of their therapeutic potential. This submission contains two different experiments. In experiment 1, cells were exposed to drug treament (DMSO or SM-164) for 3 hours. In experiment 2, cells were exposed to an adherent layer of CHO cells either expressing or not CD30L. Each treatment in each experiment was conducted once, leading to a total of 4 samples.
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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.
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Project description:Cellular inhibitor of apoptosis proteins 1 and 2 (c-IAP1/2) play central roles in signal transduction mediated by numerous receptors that participate in inflammatory and immune responses. In certain pathways, such as activation of NF-kB, their degradation is a major regulatory event and is physiologically induced by activation of receptors. Additionally, a number of synthetic compounds have been developed that also target the c-IAPs and induce their degradation. However, the extent of a synthetic IAP antagonist’s ability to mirror the transcriptional program by a physiological signal remains unclear. Here we take a systems approach to compare the transcriptional programs triggered by activation of CD30, a well-characterized receptor previously shown to induce the degradation of the c-IAPs, to SM-164, a synthetic IAP antagonist that specifically triggers c-IAP degradation. Employing a technique that allows the specific analysis of newly transcribed RNA, we have generated comparative transcriptome profiles for CD30 activation and SM-164 treatment. Analysis of these profiles revealed that the genes regulated by each stimulus were not completely shared, indicating novel functions of IAP antagonists and consequences of c-IAP1/2 degradation. The data identified a role for c-IAP1/2 in the regulation of the ribosome and protein synthesis, which was subsequently confirmed by biological assays. These findings expand our knowledge of the roles of c-IAP1/2 in signaling and provide insight into the mechanism of synthetic IAP antagonists, furthering our understanding of their therapeutic potential.
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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).
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Project description:LKB1 encodes a Ser/Thr kinase and acts as an evolutionarily conserved sensor of cellular energy status in eukaryotic cells. LKB1 functions as the major upstream kinase to phosphorylate AMPK and 12 other AMPK-related kinases, which is required for their activation in many cellular contexts. Once activated, AMPK and AMPK-related kinases phosphorylate a diverse array of downstream effectors to switch on ATP-generating catabolic processes and switch off ATP-consuming anabolic processes, thus restoring energy balance during periods of energetic stress. To study the role and mechanisms of Lkb1 in the regulation of hematopoietic stem cell (HSC) biology, we performed transcriptome analysis of sorted LSK (Lin-, Sca-1+, c-Kit+) cells from Lkb1 WT and KO bone marrows at 1 day post-completing tamoxifen injection (DPI). To identify more proximal molecular effects, we chose 1 DPI due to the modest phenotypes in Lkb1 KO mice, yet documentation of efficient Lkb1 deletion in LSK cells at this very early time point. We treated Lkb1 L/L rosa26CreERT2 and Lkb1 L/L mice (C57BL/Ka-CD45.2:Thy-1.1 background) with Tamoxifen for 5 days to somatically delete Lkb1 in adult mice, and generated Lkb1 WT and KO mice. At 1 DPI, we prepared single-cell suspensions from bone marrow (from femoral and tibial bones), and stained and sorted LSK populations using FACSAria (Becton Dickinson, Mountain View, CA). The RNA was extracted from sorted LSK cells, amplified and subjected to gene profiling. The samples include 3 Lkb1 WT (Lkb1 WT 5-7) and 4 Lkb1 KO (Lkb1 KO 4-7) replicates.
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Project description:LKB1 is a tumor suppressor lost in approximately 30% of lung adenocarcinomas. It is a serine-threonine kinase involved in regulating metabolism, proliferation, and cell polarity. We have characterized its association with mRNA expression profiles in resected tumors and in cell lines, but little is known about the direct effects of LKB1 on the regulation of these genes. This study investigates the effects of LKB1 activity on mRNA expression in two LKB1-mutant lung adenocarcinoma cell lines, H2122 and A549. Wild-type LKB1 has been stably expressed in these cell lines using a pBABE retrovirus as well as an empty pBABE control and a kinase-dead mutant of LKB1 (K78I) control (Addgene). Samples submitted are two cell lines, three experimental conditions, and three replicates, for a total of 17 samples (one sample was excluded for poor RNA quality). Gene expression of these samples are analyzed to determine transcriptional regulatory effects of LKB1 expression. Results of this analysis are compared to our analysis of resected human tumors to determine gene patterns that are differentially expressed between LKB1-deficient and LKB1-wild-type tumors whose expression is also affected by restoration of LKB1 in vitro. RMA gene expression was taken from two cell lines stably expressing LKB1 or controls of K78I mutant LKB1 or empty pBABE vector. Log2 average expression differences are calculated and compared to results from analysis of gene expression associated with LKB1 loss in resected human tumors.
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