Biology subjects

Wilding, C.

Publications and source records attributed to Wilding, C..

3 recordsLinked to original sources

bioRxiv2023

Proteomic Features of Adolescents and Young Adults with Soft Tissue Tumours

Adolescents and young adult (AYA) patients with soft tissue tumours (STT) including sarcomas are an underserved group with disparities in treatment outcomes. To define the molecular features between AYA and older adult (OA) patients, we analysed the proteomic profiles of a large cohort of STT across 10 histological subtypes (AYA n=66, OA n=243). AYA tumours are enriched in proteins involved in mitochondrial metabolism while OA patients have elevated inflammatory and cell cycle signalling. By integrating the patient-level proteomic data with functional genomic profiles from sarcoma cell lines, we show that the mRNA splicing pathway is an intrinsic vulnerability in cell lines from OA patients and that components of the spliceosome complex are independent prognostic factors for metastasis free survival in AYA patients. Our study highlights the importance of performing age-specific molecular profiling studies to identify risk stratification tools and targeted agents tailored for the clinical management of AYA patients.

cancer biology↗

bioRxiv2023

Proteomic characterisation of Sarculator nomogram-defined risk groups in soft tissue sarcomas of the extremities and trunk wall

BackgroundHigh-risk soft tissue sarcomas of the extremities and trunk wall (eSTS), as defined by the Sarculator nomogram, are more likely to benefit from (neo)adjuvant anthracycline-based therapy compared to low/intermediate-risk patients. The biology underpinning these differential treatment outcomes remain unknown. MethodsWe analysed proteomic profiles and clinical outcomes of 123 eSTS patients. A Cox model for overall survival including the Sarculator was fitted to individual data to define 4 risk groups. A DNA replication protein signature - Sarcoma Proteomic Module 6 (SPM6) was evaluated for association with clinicopathological factors and risk groups. SPM6 was added as a covariate together with Sarculator in a multivariable Cox model to assess improvement in prognostic risk stratification. ResultsDNA replication and cell cycle proteins were upregulated in high risk versus very low risk patients. Evaluation of the functional effects of CRISPR-Cas9 gene knockdown of proteins enriched in high risk patients identified candidate drug targets. SPM6 was significantly associated with tumour malignancy grade (p = 1.6e-06), histology (p = 1.4e-05) and risk groups (p = 2.6e-06). Cox model analysis showed that SPM6 substantially contributed to a better calibration of the Sarculator nomogram (Index of Prediction Accuracy =0.109 for Sarculator alone versus 0.165 for Sarculator + SPM6). ConclusionsRisk stratification of patient with STS is defined by distinct biological pathways across a range of cancer hallmarks. Incorporation of SPM6 protein signature improves prognostic risk stratification of the Sarculator nomogram. This study highlights the utility of integrating protein signatures for the development of next-generation nomograms.

cancer biology↗

bioRxiv2022

Proteomic profiling identifies co-regulated expression of splicing factors as a characteristic feature of intravenous leiomyomatosis

Intravenous leiomyomatosis (IVLM) is a rare benign smooth muscle tumour that is characterised by intravenous growth in the uterine and pelvic veins. Previous DNA copy number and transcriptomic studies have shown that IVLM harbours unique genomic and transcriptomic alterations when compared to uterine leiomyoma (uLM), which may account for their distinct clinical behaviour. Here we undertake the first comparative proteomic analysis of IVLM and other smooth muscle tumours (comprising uLM, soft tissue leiomyoma and benign metastasising leiomyoma) utilising data-independent acquisition mass spectrometry. We show that, at the protein level, IVLM is defined by the unique co-regulated expression of splicing factors. In particular, IVLM is enriched in two clusters composed of co-regulated proteins from the hnRNP, LSm, SR and Sm classes of the spliceosome complex. One of these clusters (Cluster 3) is associated with key biological processes including nascent protein translocation and cell signalling by small GTPases. Taken together, our study provides evidence of co-regulated expression of splicing factors in IVLM compared to other smooth muscle tumours which suggests a possible role for alternative splicing in the pathogenesis of IVLM.

cancer biology↗