Ling, S; Dexter, A; Race, A M; Sharma, S; Hamm, G; Polanska, U M; Rosetta Consortium Cancer Research UK; Marshall, J F; Takats, Z; Brindle, K; Yunera, M O; Poulogiannis, G; Campbell, A D; Sansom, O J; Goodwin, R J A; Bunch, J; Barry, S T (2025) Use of metabolic imaging to monitor the heterogeneity of tumour response following therapeutic mTORC1/2 pathway inhibition. Disease Models & Mechanisms, 18 (2). DMM050804

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Abstract

PI3K-mTOR-AKT pathway controls many cellular processes including proliferation, gene expression and metabolism, and inhibitors have been developed to treat solid tumours and haematological disorders. Inhibition of PI3K-mTOR-AKT signalling is commonly assessed by measuring changes in protein biomarkers including phosphorylated AKT, PRAS40, NDRG1 and S6, or nuclear translocation of FOXO. PI3K-mTOR-AKT pathway inhibition is associated with feedback reactivation of signalling which limits anti-tumour treatment response, however it has been challenging to measure the heterogeneity of pathway inhibition in tissues, assess feedback reactivation or resistance. Harnessing recent advances in multi-modal imaging methods and data integration a workflow was developed to assess heterogeneity of response to pathway inhibition in tumour tissue derived from the PTEN null renal cancer tumour xenograft model 786-0. Firstly, mass spectrometry imaging (MSI) of multiple metabolite biomarkers was used to monitor local-regional response following treatment with the mTORC1/2 inhibitor AZD2014, correlated to drug distribution. MSI analysis of control and treated tumours classified tumours into two distinct metabolic regions; one dominant metabolic phenotypic region associated with control tumours and a second associated with AZD2014 treated tumours. Imaging Mass Cytometry analysis of classical protein and phospho-protein biomarkers in these regions revealed that regions in AZD2014 treated tumours that classified as metabolically similar to control tumours had low phospho-S6 suggesting response to treatment. However, these “control-like” regions had retained high expression of the AKT regulated glucose transporter GLUT1 associated with a lack of metabolic change in these regions. Combining AZD2014 with the PI3Kb inhibitor AZD8186, which increases PI3K-AKT pathway inhibition, further decreased the relative area of the “control” metabolic signature. Collectively these data demonstrate that MSI analysis can reveal novel insights in the pharmacodynamic effects of mTORC1/2 inhibition in tumour tissue which classical biomarkers are not able to resolve. This workflow enables greater insights into segmentation of intra-tumoural response to therapy coupling two different spatial-omics approaches.

Item Type:	Article
Keywords:	Mass spectrometry imaging, Imaging mass cytometry, Spatial multi-omics, PI3K, AKT, mTOR, Pharmacodynamic
Subjects:	Nanoscience > Surface and Nanoanalysis
Divisions:	Chemical & Biological Sciences
Identification number/DOI:	10.1242/dmm.050804
Last Modified:	30 Jul 2025 13:45
URI:	https://eprintspublications.npl.co.uk/id/eprint/10213