RNA-seq of live cell 3-D models with engineered genetic sub-types of lung cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE271368 | GEO | 2024/07/25
REPOSITORIES: GEO
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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: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:To illuminate the evolutionary trajectory of LUAD from AIS to IAC, high-throughput scRNA-seq and ST data were generated and integrated to create a large-scale, single-cell spatiotemporal atlas of LUAD. We compiled a multi-omics atlas of the early-stage LUAD invasion process that reflects the heterogeneity of cancer cells, the competitive polyclonal origin of LUAD, signalling interactions between cancer cells and the TME, and the pseudo-chronological nature of LUAD invasion. The spatial distribution characteristics of LUAD cells revealed the spatial heterogeneity of LUAD and the mechanism of spatial immune escape in LUAD, which provides strong evidence supporting clinical diagnosis and surgical intervention at the single-cell level.
2021-11-30 | GSE189357 | GEO
Project description:LKB1 deficiency in lung adenocarcinoma (LUAD) leads to primary resistance to immune checkpoint inhibitors. However, the underlying molecular mechanism remains unclear. Here, we showed that LKB1 deficiency significantly affected the tumor immune landscape by decreasing the infiltration of most immunocyte populations and downregulating the expression of intercellular adhesion molecule-1 (ICAM1). LKB1 deficiency promoted cancer evasion due to loss of ICAM1-mediated antitumor immunity, including immune-competent cell cytotoxicity and tumor infiltration. CDK4/6 inhibitors reversed this process in a targeted manner. A tailored combination strategy using CDK4/6 inhibitors and anti-PD-1 antibodies slowed tumor growth and increased survival in syngeneic mouse models of LKB1-deficient lung adenocarcinoma. Combining a CDK4/6 inhibitor, which is clinically approved, with PD-1 blockade therapy is thus a promising option for lung adenocarcinoma patients harboring LKB1 mutations.
2022-12-16 | GSE182228 | GEO
Project description:To illuminate the evolutionary trajectory of LUAD from AIS to IAC, high-throughput scRNA-seq and ST data were generated and integrated to create a large-scale, single-cell spatiotemporal atlas of LUAD. We compiled a multi-omics atlas of the early-stage LUAD invasion process that reflects the heterogeneity of cancer cells, the competitive polyclonal origin of LUAD, signalling interactions between cancer cells and the TME, and the pseudo-chronological nature of LUAD invasion. The spatial distribution characteristics of LUAD cells revealed the spatial heterogeneity of LUAD and the mechanism of spatial immune escape in LUAD, which provides strong evidence supporting clinical diagnosis and surgical intervention at the single-cell level. The seurat object of ST data are available on https://drive.google.com/drive/folders/1dkGF4kKMbHSm04DKHg6P_y_iTD1pXCH8?usp=sharing.
2021-11-30 | GSE189487 | GEO
Project description:Glioblastomas (GBMs) are highly invasive brain tumors replete with brain- and blood-derived macrophages, collectively known as tumor-associated macrophages (TAMs). Targeting TAMs has been proposed as a therapeutic strategy but has thus far yielded limited clinical success in slowing GBM progression, due in part to an incomplete understanding of TAM function in GBM. Here, by using an engineered hyaluronic acid-based 3D invasion platform, patient-derived GBM cells, and multi-omics analysis of GBM tumor microenvironments, we show that M2-polarized macrophages stimulate GBM stem cell (GSC) mesenchymal transition and invasion. We identify TAM-derived transforming growth factor beta induced (TGFβI/BIGH3) as a pro-tumorigenic factor in the GBM microenvironment. In GBM patients, BIGH3 mRNA expression correlates with poor patient prognosis and is highest in the most aggressive GBM molecular subtype. Inhibiting TAM-derived BIGH3 signaling with a blocking antibody or small molecule inhibitor suppresses GSC invasion. Our work highlights the utility of 3D in vitro tumor microenvironment platforms to investigate TAM-cancer cell crosstalk and offers new insights into TAM function to guide novel TAM-targeting therapies.
2023-12-21 | GSE251777 | GEO
Project description:Mutations in STK11/LKB1 in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB) and introduction of a Stk11/Lkb1 (L) mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss (KP) resulted in an ICB refractory syngeneic KPL tumor. Mechanistically this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1 mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+ PD-1+ CD8 T cells, restoring therapeutic response to PD-1 ICB for KPL tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. NSCLC patients with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.
2022-01-24 | GSE194166 | GEO
Project description:We found lncRNA RP3-340N1.2 is highly expressed in LUAD and relatived with the progression of LUAD through high-throughput sequencing. Our results showed that the expression level of RP3-340N1.2 was upregulated significantly in three LUAD cell lines (A549, NCI_x001E_H1299, and NCI-H1975) and lentivirus-mediated knockdown of RP3-340N1.2 inhibited the differentiation, proliferation, migration, invasion, cell cycle, and other biological processes of tumor cells significantly. Bioinformatic software predicted the downstream target of RP3-340N1.2, which was verified using dual luciferase assays and other methods. We found that RP3-340N1.2 can competitively bind miR-134-5p in LUAD, and this microRNA has a significant regulatory effect on the expression of epidermal growth factor receptor (EGFR), which leads to increased migration and invasion of LUAD cells. This discovery provided a possible mechanism by which RP3-340N1.2 participates in the development of LUAD. In conclusion, our results showed that lncRNA RP3_x001E_340N1.2 regulates the expression of EGFR indirectly by targeting miR-134-5p and promotes the progression of LUAD. Therefore, RP3-340N1.2 may become a valuable biomarker and therapeutic target in LUAD.
2023-12-01 | GSE190461 | GEO
Project description:RNA-seq of live cell 3-D models with engineered genetic sub-types of lung cancer
| PRJNA1131001 | ENA