An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA606214 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11071700.fastq.gz | Fastqsanger.gz | |||
| SRR11071701.fastq.gz | Fastqsanger.gz | |||
| SRR11071702.fastq.gz | Fastqsanger.gz | |||
| SRR11071703.fastq.gz | Fastqsanger.gz | |||
| SRR11071704.fastq.gz | Fastqsanger.gz |
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Project description:Cancer cells often undergo lineage switching during their natural progression and in response to therapy. Lung adenocarcinomas (LUADs) exhibit a variety of differentiation states accompanied by dysregulation of lineage-specific transcription factors such as NKX2-1. Loss of NKX2-1 in human and murine LUAD leads to invasive mucinous adenocarcinoma (IMA), a subtype of lung cancer that exhibits pulmonary to gastric transdifferentiation. Human IMAs harbor a distinct spectrum of mutationally activated driver oncogenes compare to LUAD overall, suggesting that the pulmonary to gastric transdifferentiation induced by NKX2-1 loss plays a context-dependent role in LUAD progression. Using genetically engineered mouse models, we find that NKX2-1 is required for optimal BRAFV600E driven lung tumor initiation but is dispensable for growth of established lung tumors. NKX2-1-deficient, BRAFV600E driven tumors morphologically resemble human IMA, have high levels of ERK phosphorylation and exhibit a distinct response to treatment with combined BRAF/MEK inhibitors. Whereas NKX2-1-positive tumor cells enter quiescence when treated with BRAF/MEK inhibitors, residual NKX2-1-negative cells fail to exit the cell cycle in response to the same therapy. Additionally, BRAF/MEK inhibitors induce canonical WNT signaling in NKX2-1-negative lung tumor cells, which is accompanied by cell identity switching within the gastric lineage. Co-inhibition of MAPK and WNT pathways blocked elements of this lineage switch in vitro and interfered with cell cycle changes imposed by MAPK inhibition in vivo. Our data show that there is a complex and reciprocal relationship between lineage specifiers and oncogenic signaling pathways in the regulation of LUAD identity and suggest that lineage switching induced by targeted therapies may confer new therapeutic vulnerabilities.
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Project description:Cancer cells undergo lineage switching during natural progression and in response to therapy. NKX2-1 loss in human and murine lung adenocarcinoma leads to invasive mucinous adenocarcinoma (IMA), a lung cancer subtype that exhibits gastric differentiation and harbors a distinct spectrum of driver oncogenes. In murine BRAFV600E-driven lung adenocarcinoma, NKX2-1 is required for early tumorigenesis, but dispensable for established tumor growth. NKX2-1-deficient, BRAFV600E-driven tumors resemble human IMA and exhibit a distinct response to BRAF/MEK inhibitors. Whereas BRAF/MEK inhibitors drive NKX2-1-positive tumor cells into quiescence, NKX2-1-negative cells fail to exit the cell cycle after the same therapy. BRAF/MEK inhibitors induce cell identity switching in NKX2-1-negative lung tumors within the gastric lineage, which is driven in part by WNT signaling and FoxA1/2. These data elucidate a complex, reciprocal relationship between lineage specifiers and oncogenic signaling pathways in the regulation of lung adenocarcinoma identity that is likely to impact lineage-specific therapeutic strategies.
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Project description:PRH/HHEX-Notch3 feedback loop drives cholangiocarcinoma
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Project description:Kim2007 - Crosstalk between Wnt and ERK pathways
Experimental studies have shown that both Wnt and the MAPK pathways are involved in the pathogenesis of various kinds of cancers (eg. colorectal cancer). The crosstalk between the two pathways have also been identified. Here, Kim et al., (2007) have integrated the experimental evidences on crosstalk mechanisms between the two pathways into a pathway model, and have identified the existence of a hidden positive feedback loop and suggest that this positive feedback loop might participate in the pathogenesis of colorectal cancer.
This model is described in the article:
A hidden oncogenic positive feedback loop caused by crosstalk between Wnt and ERK pathways.
Kim D, Rath O, Kolch W, Cho KH.
Oncogene 2007 Jul; 26(31): 4571-4579
Abstract:
The Wnt and the extracellular signal regulated-kinase (ERK) pathways are both involved in the pathogenesis of various kinds of cancers. Recently, the existence of crosstalk between Wnt and ERK pathways was reported. Gathering all reported results, we have discovered a positive feedback loop embedded in the crosstalk between the Wnt and ERK pathways. We have developed a plausible model that represents the role of this hidden positive feedback loop in the Wnt/ERK pathway crosstalk based on the integration of experimental reports and employing established basic mathematical models of each pathway. Our analysis shows that the positive feedback loop can generate bistability in both the Wnt and ERK signaling pathways, and this prediction was further validated by experiments. In particular, using the commonly accepted assumption that mutations in signaling proteins contribute to cancerogenesis, we have found two conditions through which mutations could evoke an irreversible response leading to a sustained activation of both pathways. One condition is enhanced production of beta-catenin, the other is a reduction of the velocity of MAP kinase phosphatase(s). This enables that high activities of Wnt and ERK pathways are maintained even without a persistent extracellular signal. Thus, our study adds a novel aspect to the molecular mechanisms of carcinogenesis by showing that mutational changes in individual proteins can cause fundamental functional changes well beyond the pathway they function in by a positive feedback loop embedded in crosstalk. Thus, crosstalk between signaling pathways provides a vehicle through which mutations of individual components can affect properties of the system at a larger scale.
Figure 6 of the reference publication has been reproduced. The model as such reproduces the plots corresponding to the normal conditions. To obtain simulations under 1) beta-cataenin mutation; set V12=0.846 (two-fold of the beta-catenin synthetic rate than the normal system. i.e. 2*0.426), 2) PP2A mutation; set Vmax4=Vmax5=33.75 (three-fourths of the PP2A activity that the normal system. i.e. (3/4)*45). The simulation was performed using Copasi 4.10 (Build 55).
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2024-09-02 | BIOMD0000000149 | BioModels
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