Lung cancer remains the leading cause of cancer-related mortality worldwide. Despite progress in treatments that harness anti-tumour immunity, acquired resistance limits clinical efficacy, keeping a cure for this disease out of reach. A shift to lung cancer prevention is therefore necessary. This requires understanding the biological basis of cancer progression across its physiological, environmental, and public health contexts.
We take a comprehensive approach to lung cancer research, progressing from developing complex cancer models to addressing individual human patients:
- Tumour-initiating biology is studied in murine models, comprised of common lung cancer driver mutations expressed in progenitor cells.
- Histopathology-selective profiling is applied to identify immunity- and signalling network-related drivers of malignancy.
- Functional precision medicine is implemented, using primary cells or tissue to identify treatments matched to the unique tumours of individual patients.
During recent years, our team studied how phenotypic heterogeneity arises in non-small cell lung cancer (NSCLC). We used murine models of lung cancer that combine conditional mutations with progenitor cell-targeted adenoviruses, permitting assessment of which oncogenic functions contribute to the histopathology, metastatic potential, and therapeutic response of various NSCLC subtypes.
Using preclinical models representing the most common drivers of human NSCLC, we showed that histopathology spectra are dependent on the tumour’s cell-of-origin. We further identified histopathology-selective gene expression profiles and immune microenvironments, as well as oncogenic signalling networks.
This understanding was applied to the design of novel diagnostic models, through FIMM’s Functional Precision Medicine in Cancer Grand Challenge efforts, as well as the IMI-PREDECT project (http://www.predect.eu; 2011-2016), a public-private EU consortium that developed sufficiently complex ex vivo cancer models to ameliorate industry’s target validation pipelines.
We optimised a workflow for cultivation of precision-cut tumour slice explants, which, unsurprisingly, was not an easy feat. Implementing these slice explants, we showed that response to combination treatment with signalling inhibitors corresponds with spatially-defined targeted pathway activities, and that combinatorial drug sensitivity aligns closely with histopathology type. This underscores a generally underappreciated need to incorporate lesion-specific phenotypic heterogeneity in clinical settings.
Given rapid advances in diagnostic technologies, we aim to fluidly apply existing and newly arising insights to improve the treatment and prevention of lung cancer. To achieve this, our team interfaces with biobanking and translational facilities at FIMM, local life science communities, and the Helsinki University Hospital. In collaboration with pulmonary surgeons, clinicians, and pathologists, we profile the functions of individual NSCLC patient samples. This will permit us to evaluate whether the diagnostic elucidation of tumour-selective treatments has the potential to improve the health of locally-treated patients.