Interrogating the precancerous evolution of pathway dysfunction in lung squamous cell carcinoma using XTABLE
- University of Manchester, United Kingdom
- Cancer Research UK Manchester Institute, United Kingdom
- The Christie Hospital, United Kingdom
- Boston University, United States
Abstract
Lung squamous cell carcinoma (LUSC) is a type of lung cancer with a dismal prognosis that lacks adequate therapies and actionable targets. This disease is characterized by a sequence of low and high-grade preinvasive stages with increasing probability of malignant progression. Increasing our knowledge about the biology of these premalignant lesions (PMLs) is necessary to design new methods of early detection and prevention, and to identify the molecular processes that are key for malignant progression. To facilitate this research, we have designed XTABLE, an open-source application that integrates the most extensive transcriptomic databases of PMLs published so far. With this tool, users can stratify samples using multiple parameters and interrogate PML biology in multiple manners, such as two and multiple group comparisons, interrogation of genes of interests and transcriptional signatures. Using XTABLE, we have carried out a comparative study of the potential role of chromosomal instability scores as biomarkers of PML progression and mapped the onset of the most relevant LUSC pathways to the sequence of LUSC developmental stages. XTABLE will critically facilitate new research for the identification of early detection biomarkers and acquire a better understanding of the LUSC precancerous stages.
Data availability
The current manuscript makes use of previously published databases, so no data have been generated for this manuscript. All analyses shown in the manuscript has been carried out using XTABLE and can be reproduced easily by any user.
Article and author information
Author details
Carlos Lopez-Garcia
Funding
Cancer Research UK (A25146)
- Julia Ogden
- A S Md Mukarram Hossain
- Anshuman Chaturvedi
- Alastair RW Kerr
- Caroline Dive
- Carlos Lopez-Garcia
Manchester Biomedical Research Centre
- Matthew Roberts
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Roberts et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Interrogating the precancerous evolution of pathway dysfunction in lung squamous cell carcinoma using XTABLE
eLife 12:e77507.
https://doi.org/10.7554/eLife.77507
Further reading
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TAK1 is a serine/threonine protein kinase that is a key regulator in a wide variety of cellular processes. However, the functions and mechanisms involved in cancer metastasis are still not well understood. Here, we found that TAK1 knockdown promoted esophageal squamous cancer carcinoma (ESCC) migration and invasion, whereas TAK1 overexpression resulted in the opposite outcome. These in vitro findings were recapitulated in vivo in a xenograft metastatic mouse model. Mechanistically, co-immunoprecipitation and mass spectrometry demonstrated that TAK1 interacted with phospholipase C epsilon 1 (PLCE1) and phosphorylated PLCE1 at serine 1060 (S1060). Functional studies revealed that phosphorylation at S1060 in PLCE1 resulted in decreased enzyme activity, leading to the repression of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. As a result, the degradation products of PIP2 including diacylglycerol (DAG) and inositol IP3 were reduced, which thereby suppressed signal transduction in the axis of PKC/GSK-3β/β-Catenin. Consequently, expression of cancer metastasis-related genes was impeded by TAK1. Overall, our data indicate that TAK1 plays a negative role in ESCC metastasis, which depends on the TAK1-induced phosphorylation of PLCE1 at S1060.
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