Institute of Genetics and Cancer

Autophagy linked to enhanced oncogenic signalling and brain tumour development

A study shows that autophagy regulates oncogenic signalling of platelet-derived growth factor receptor alpha (PDGFRA) and that the absence of autophagy disrupts PDGFRA-driven brain tumour development: January 2024

Graphical abstract of the study by Simpson et al.
Graphical abstract of the study by Simpson et al. [Dev Cell. 2024 Jan 22;59(2):228-243]

Proteins known as receptor tyrosine kinases (RTKs) are cell surface receptors for a broad spectrum of growth factors, cytokines, and hormones. They play important roles in a variety of cellular processes including cell growth, differentiation, metabolism and motility. They have also been implicated in many forms of cancer and represent “target molecules” for several clinically approved anticancer therapeutics.

Autophagy is an intracellular process involved in degradation and removal of unnecessary or dysfunctional cellular components enabling the orderly degradation and recycling of those components. It is intricately linked to several other cellular processes (including endocytosis and lysosomal degradation) and has been also implicated in regulation of diverse intracellular signalling pathways (including signalling from cell surface receptors). There is accumulating evidence that autophagy can play important roles in carcinogenesis and in tumour resistance to some anticancer therapies. Unfortunately, our understanding of these roles is still very rudimentary.      

Edinburgh Cancer Researchers in the “Brain Cancer Survival Pathways” group led by Dr Noor Gammoh at the CRUK Scotland Centre in the Institute of Genetics and Cancer have longstanding interest in the functions of autophagy in regulation of RTKs, tumour formation and tumour therapy resistance. In their recent work they provided evidence that autophagy enhances the lysosomal degradation and oncogenic signalling of platelet-derived growth factor receptor alpha (PDGFRA), impacting receptor levels through posttranslational and transcriptional mechanisms. They found that PDGFRA can be targeted for autophagic degradation through the activity of the autophagy cargo receptor p62. As a result, short-term autophagy inhibition leads to elevated levels of PDGFRA but also an unexpected defect in PDGFRA-mediated signalling due to perturbed receptor trafficking. Defective PDGFRA signalling led to its reduced levels during prolonged autophagy inhibition, suggesting a mechanism of adaptation. Importantly, studies using mice models demonstrated that PDGFRA-driven gliomagenesis was disrupted and that this was dependent on the status of Pten gene (Pten is a type of gene called a "tumour suppressor” and changes in the PTEN gene are commonly found in many different types of cancer, including prostate cancer, uterine cancer, and some types of brain tumours), highlighting a genotype-specific role of autophagy during tumourigenesis.        

The study was performed by a team consisting of Joanne Simpson, Morwenna Muir, Martin Lee, Catherine Naughton, Nick Gilbert, Steven Pollard and Noor Gammoh. It has been published in the journal Developmental Cell in article titled “Autophagy supports PDGFRA-dependent brain tumor development by enhancing oncogenic signaling”, with Dr Gammoh serving as the corresponding author. The work was supported by funding from Cancer Research UK.

Our work provides a mechanism by which cells require autophagy to drive tumour formation. The results would help inform how autophagy could be targeted to provide new opportunities in treating some types of cancers.

Dr Joanne Simpson and Dr Noor GammohUniversity of Edinburgh

Related Links

Article in Developmental Cell:

Dr Noor Gammoh group website:

Information about brain tumours:

Information about gliomas:

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