Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide and there is urgent need for more effective therapeutic approaches. The extracellular matrix (ECM) is a molecular network outside of cells, that provides chemical and biophysical cues that orchestrate cell behaviour. Different cell types remodel, and respond to, this ECM to regulate organ function in both health and disease. Emerging evidence indicates that the ECM is highly dysregulated in lung cancer. However, how the lung ECM is remodelled during tumour initiation and progression remains poorly understood. My research seeks to comprehensively characterise the ECM landscape in squamous and adenocarcinoma subtypes of NSCLC and determine the role of key ECM components in the progression of aggressive tumours.
In order to comprehensively map the NSCLC landscape, we have been integrating bulk, single cell and spatial interrogation of lung tumour transcriptomics and proteomics data in human tumours and animal models of lung cancer. In particular, we have developed an ECM-specific proteomic pipeline using MALDI imaging mass spectrometry to provide unbiased spatial localisation of ECM components across tissues, illustrating ECM remodelling beyond the invasive edge of tumours into the adjacent tissue field. Together with spatial transcriptomics data, this is revealing heterogeneous ECM neighbourhoods within and between tumours, and ongoing animal studies are profiling the temporal evolution of this important and understudied aspect of the tumour microenvironment. Using a computational methodology that is agnostic to cell type assignments we have identified neighbourhoods enriched in highly invasive lung tumours that have distinct biological processes.
By integrating this data with advanced microscopic techniques we are gaining further insight into the composition and importantly, the architecture of the ECM. These insights are revealing that dysregulation of the extracellular matrix occurs early in disease progression and may constitute a ‘field of cancerization’ that primes pre-invasive lesions to develop into aggressive metastatic NSCLC. Our analysis indicates that prognostic ECM programs, or matreotypes, substantially differ between adenocarcinoma and squamous tumours. Integration of spatial proteomics and transcriptomics technologies is now illuminating the spatial heterogeneity in these programs within tumours, and the contribution of different cell types to these matrix neighbourhoods.
Collectively, these insights are revealing actionable approaches to inform patient diagnosis and treatment as part of a matrix-centred precision medicine framework in aggressive non-small cell lung cancer.