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TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma

ABSTRACT: Adenocarcinoma is the most common histologic subtype of lung cancer, which is the leading cause of cancer death. We and others previously identified TTF-1, a lineage-specific transcription factor required for branching morphogenesis and physiological lung functions, as a lineage-survival oncogene in lung adenocarcinoma. However, how TTF-1 mediates survival signals remains elusive. Here we show that TTF-1 induces receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn mediates TTF-1 survival signaling in lung adenocarcinoma. Inhibition of ROR1 impaired prosurvival signaling through the PI3K-AKT pathway and induced nuclear accumulation of FOXO1. These were found to be imposed, at least in part, through PTEN inactivation via c-Src, while ROR1 was shown to physically interact with and phosphorylate c-Src. ROR1 inhibition also elicited marked p38 activation, provoking ill-balance between prosurvival and proapoptotic signaling, and consequential “oncogenic shock.” In addition, we found that ROR1 is crucially involved in EGFR- and MET-mediated prosurvival signaling. ROR1 knockdown effectively induced apoptosis in lung adenocarcinoma cell lines with acquired EGFR TKI resistance conferred by a secondary T790M EGFR mutation, or HGF-elicited MET signaling and resultant switching of the addicted receptor tyrosine kinases (RTKs). Taken together, our findings indicate that ROR1 RTK is a very promising molecular target for development of a novel therapeutic means to treat this hard-to-cure cancer. Dye-swap experiment, vector control vs. stable TTF-1 transfectant of HPL1D, immortalized human peripheral lung epithelial cell line.

ORGANISM(S): Homo sapiens

SUBMITTER: Takahashi Takashi

PROVIDER: E-GEOD-25830 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma

Project description:Adenocarcinoma is the most common histologic subtype of lung cancer, which is the leading cause of cancer death. We and others previously identified TTF-1, a lineage-specific transcription factor required for branching morphogenesis and physiological lung functions, as a lineage-survival oncogene in lung adenocarcinoma. However, how TTF-1 mediates survival signals remains elusive. Here we show that TTF-1 induces receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn mediates TTF-1 survival signaling in lung adenocarcinoma. Inhibition of ROR1 impaired prosurvival signaling through the PI3K-AKT pathway and induced nuclear accumulation of FOXO1. These were found to be imposed, at least in part, through PTEN inactivation via c-Src, while ROR1 was shown to physically interact with and phosphorylate c-Src. ROR1 inhibition also elicited marked p38 activation, provoking ill-balance between prosurvival and proapoptotic signaling, and consequential “oncogenic shock.” In addition, we found that ROR1 is crucially involved in EGFR- and MET-mediated prosurvival signaling. ROR1 knockdown effectively induced apoptosis in lung adenocarcinoma cell lines with acquired EGFR TKI resistance conferred by a secondary T790M EGFR mutation, or HGF-elicited MET signaling and resultant switching of the addicted receptor tyrosine kinases (RTKs). Taken together, our findings indicate that ROR1 RTK is a very promising molecular target for development of a novel therapeutic means to treat this hard-to-cure cancer.

2011-12-31 | GSE25830 | GEO

MYBPH, a novel transcriptional target of NKX2-1/TTF-1, inhibits ROCK1 and actomyosin assembly, and reduces cell motility and tumor metastasis

Project description:Cell migration driven by actomyosin filament assembly is a critical step in tumour invasion and metastasis. Herein, we report identification of myosin binding protein H (MYBPH) as a transcriptional target of NKX2-1 (also known as TTF-1 and TITF1), a lineage-survival oncogene in lung adenocarcinoma. MYBPH inhibits assembly competence-conferring phosphorylation of the myosin regulatory light chain (RLC) as well as activating phosphorylation of LIM domain kinase (LIMK). These are unexpectedly implemented through direct physical interaction of MYBPH with Rho kinase 1 (ROCK1) rather than with RLC. In addition, MYBPH is shown to directly bind with non-muscle myosin heavy chain IIA (NMHC IIA), resulting in inhibition of NMHC IIA assembly. Thus, MYBPH plays multi-facetted roles in negative regulation of actomyosin organization, which in turn reduces cell motility, invasion, and metastasis. Finally, we also show that MYBPH is epigenetically inactivated by promoter DNA methylation in a fraction of lung adenocarcinomas abundantly expressing NKX2-1, which appears to be in accordance with its deleterious function for lung adenocarcinoma invasion and metastasis, as well as with the paradoxical association of NKX2-1 expression with favourable prognosis in lung adenocarcinoma patients. Dye-swap experiment, vector control vs. transiently transfectanted with TTF-1 in HPL1D, immortalized human peripheral lung epithelial cell line.

2011-12-22 | E-GEOD-26721 | biostudies-arrayexpress

Ito2019 - gefitnib resistance of lung adenocarcinoma caused by MET amplification

Project description:The model is based on publication: Mathematical analysis of gefitinib resistance of lung adenocarcinoma caused by MET amplification Abstract: Gefitinib, one of the tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR), is effective for treating lung adenocarcinoma harboring EGFR mutation; but later, most cases acquire a resistance to gefitinib. One of the mechanisms conferring gefitinib resistance to lung adenocarcinoma is the amplification of the MET gene, which is observed in 5–22% of gefitinib-resistant tumors. A previous study suggested that MET amplification could cause gefitinib resistance by driving ErbB3-dependent activation of the PI3K pathway. In this study, we built a mathematical model of gefitinib resistance caused by MET amplification using lung adenocarcinoma HCC827-GR (gefitinib resistant) cells. The molecular reactions involved in gefitinib resistance consisted of dimerization and phosphorylation of three molecules, EGFR, ErbB3, and MET were described by a series of ordinary differential equations. To perform a computer simulation, we quantified each molecule on the cell surface using flow cytometry and estimated unknown parameters by dimensional analysis. Our simulation showed that the number of active ErbB3 molecules is around a hundred-fold smaller than that of active MET molecules. Limited contribution of ErbB3 in gefitinib resistance by MET amplification is also demonstrated using HCC827-GR cells in culture experiments. Our mathematical model provides a quantitative understanding of the molecular reactions underlying drug resistance.

2024-09-02 | BIOMD0000000827 | BioModels

An EGFR-mutation signature reveals features of the EGFR-dependent phenotype and identifies MACC1 as an EGFR-associated regulator of MET.

Project description:EGFR-mutated non-small cell lung cancers bear hallmarks including sensitivity to EGFR inhibitors, and low proliferation, and increased MET. However, the biology of EGFR dependence is still poorly understood. Using a training cohort of chemo-naive lung adenocarcinomas, we have developed a 72-gene signature that predicts (i) EGFR mutation status in four independent datasets; (ii) sensitivity to erlotinib in vitro; and (iii) improved survival, even in the wild-type EGFR subgroup. The signature includes differences associated with enhanced receptor tyrosine kinase (RTK) signaling, such as increased expression of endocytosis-related genes, decreased phosphatase levels, decreased expression of proliferation-related genes, increased folate receptor-1 (FOLR1) (a determinant of pemetrexed response), and higher levels of MACC1 (which we identify as a regulator of MET in EGFR-mutant NSCLC). Those observations provide evidence that the EGFR-mutant phenotype is associated with alterations in the cellular machinery that links the EGFR and MET pathways and create a permissive environment for RTK signaling. We have developed a gene expression signature that predicts (i) EGFR mutation in chemo-naive and, to a lesser extent, in chemo-refractory NSCLC patients; (ii) EGFR TKI response in vitro; and (iii) survival in wild-type EGFR patients. The signature also identifies novel features of EGFR mutant NSCLC including increased levels of endocytosis-related genes and MACC1, which appears be an EGFR mutant associated regulator of MET. Gene expression profiles were measured in 124 core biopsies from patients with refractory non-small cell lung cancer in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We used the BATTLE dataset to test an EGFR-mutation gene expression signature trained in chemo-naive lung adenocarcinoma. The signature was computed as an index, called EGFR index.

2014-06-01 | E-GEOD-31852 | biostudies-arrayexpress

Homo sapiens

Project description:TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma

| PRJNA135741 | ENA

miR-205 mediates adaptive resistance to MET inhibition via ERRFI1 targeting and raised EGFR signaling

Project description:The onset of secondary resistance represents a major limitation to long term efficacy of target therapies in cancer patients. Thus, the identification of mechanisms mediating secondary resistance is key to the rational design of alternative therapeutic strategies for resistant patients. MiRNA profiling combined with RNA-seq in MET-addicted gastric and lung cancer cell lines led us to identify the miR-205/ERRFI1 (ERBB receptor feedback inhibitor-1) axis as a novel mediator of resistance to MET tyrosine kinase inhibitors (TKIs). In cells resistant to MET-TKIs, increased miR-205 expression determined the downregulation of the EGFR inhibitor ERRFI1, which, in turn, caused EGFR activation and MET-TKI resistance. MiR-205/ERRFI1 driven EGFR activation rendered MET-TKI resistant cells sensitive to combined MET/EGFR inhibition. As a proof of concept of the clinical relevance of this newly identified mechanism of adaptive resistance, we report that a patient with a MET amplified lung adenocarcinoma displayed deregulation of the miR-205/ERRFI1 axis in concomitance with the onset of clinical resistance to anti-MET therapy.

2018-07-16 | GSE114406 | GEO

PTPN23 ubiquitination by WDR4 suppresses EGFR and c-MET degradation to define a lung cancer therapeutic target

Project description:Aberrant overexpression or activation of EGFR drives the development of non-small cell lung cancer (NSCLC) and acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) by secondary EGFR mutations or c-MET amplification/activation remains as a major hurdle for NSCLC treatment. We previously identified WDR4 as a substrate adaptor of Cullin 4 ubiquitin ligase and an association of WDR4 high expression with poor prognosis of lung cancer. Here, using an unbiased ubiquitylome analysis, we uncover PTPN23, a component of the ESCRT complex, as a substrate of WDR4- based ubiquitin ligase. WDR4-mediated PTPN23 ubiquitination leads to its proteasomal degradation, thereby suppressing lysosome trafficking and degradation of wild type EGFR, EGFR mutant, and c-MET. Through this mechanism, WDR4 sustains EGFR and c-MET signaling to promote NSCLC proliferation, migration, invasion, stemness, and metastasis. Clinically, PTPN23 is downregulated in lung cancer and its low expression correlates with WDR4 high expression and poor prognosis. Targeting WDR4-mediated PTPN23 ubiquitination by a peptide that competes with PTPN23 for binding WDR4 promotes EGFR and c-MET degradation to block the growth and progression of EGFR TKI-resistant NSCLC. These findings identify a central role of WDR4/PTPN23 axis in EGFR and c-MET trafficking and a potential therapeutic target for treating EGFR TKI-resistant NSCLC.

2023-10-09 | PXD025361 | Pride

TTF-1-regulated miR-532-5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma [pts]

Project description:Thyroid transcription factor-1 (TTF-1), also known as NKX2-1, plays a role as a lineage-survival oncogene in lung adenocarcinoma with double-edged sword characteristics. Although previous studies steadily accumulated evidence for roles of TTF-1 in the transcriptional regulation of protein-coding genes, very little is known about its regulatory relationship with miRNAs. In this study, we have identified miR-532-5p as a novel transcriptional target of TTF-1 by an integrative approach, which was designed to extract maximal information from expression profiles of both patient tumors in vivo and TTF-1-inducible cell lines in vitro. Consequently, we have found that miR-532-5p is directly regulated by TTF-1 through its binding to a genomic region 8 kb upstream of miR-532-5p, which appeared to impose transcriptional regulation independent of that of CLCN5, a protein-coding gene harboring miR-532-5p in its intron 3. Further, we have also identified KRAS and MKL2 as novel direct targets of miR-532-5p. Introduction of miR-532-5p mimics markedly induced apoptosis in KRAS-mutant as well as KRAS wildtype lung adenocarcinoma cell lines. Interestingly, miR-532-5p affected the MEK-ERK pathway signaling specifically in cell lines sensitive to siKRAS treatment, while the miR-532-5p-mediated effects were clearly phenocopied by repressing expression or inhibiting function of MKL2 regardless of KRAS mutation status. In summary, our findings demonstrate that miR-532-5p is as novel transcriptional target of TTF-1 and plays a tumor suppressive role by targeting KRAS and MKL2 in lung adenocarcinoma. Novel therapeutic strategies using miR-532-5p or an MKL2 inhibitor may prove effective against this hard-to-cure cancer irrespective of the dependence on KRAS-mediated signaling.

2017-06-21 | GSE83836 | GEO

TTF-1-regulated miR-532-5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma [rt-pcr]

2017-06-21 | GSE83838 | GEO

TTF-1-regulated miR-532-5p targets KRAS and MKL2 oncogenes and induces apoptosis in lung adenocarcinoma [cell line]

2017-06-21 | GSE83837 | GEO