Background.
The tumour microenvironment (TME) has a key role in promoting tumour formation and progression. In breast and pancreatic cancers, this accompanied by the accumulation of extracellular matrix (ECM) in the TME. Due to the elevated cancer cell growth rate and the limited blood supply, the TME is often nutrient deprived. This pushes cancer cells to develop alternative strategies to obtain metabolic fuels. We have recently demonstrated that the ECM supports breast cancer cell growth under amino acid depleted conditions (Nazemi et al., 2021, bioRxiv, https://www.biorxiv.org/content/10.1101/2021.06.09.447520v2). This requires ECM internalisation and lysosomal degradation, resulting in the activation of amino acid catabolism and energy production. Therefore, understanding how ECM components are targeted for lysosomal degradation might lead to the identification of new therapeutic targets to limit the growth on highly fibrotic tumours. Our preliminary studies suggest that an endocytic adaptor complex, AP-3, is required for the delivery of internalised ECM to the lysosome and for ECM-dependent cell growth under amino acid starvation.
Hypothesis and aims.
Here we hypothesise that ECM components are internalised by binding to 21 and are delivered to early endosomes. Integrin/AP-3 interaction promotes the delivery of ECM-bound integrins to the lysosomes, where ECM components are degraded. This results in the generation of amino acids to sustain cancer cell growth under starvation. To investigate this, we will:
1. Characterise the role of AP-3 in controlling integrin/ECM trafficking, by using high-resolution and super-resolution microscopy
2. Further investigate the role of AP-3 in supporting cancer cell growth under starvation conditions, using high-throughput imaging approaches
3. Assess the expression levels of AP-3 in human breast cancer samples, to determine whether AP-3 is a prognostic factor
Altogether, the outcome of this work will characterise the poorly understood mechanisms controlling integrin endosomal trafficking, as well as paving the way for a potentially novel therapeutic strategy to prevent cancer growth.
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