The goal of the Systems Oncology group is to understand how aberrations in cellular signalling networks promote tumorigenesis and in particular how the tumour microenvironment affect tumour cell signalling and malignant progression.
Normal tissues consist of multiple cell types including epithelial cells, fibroblasts, immune cells and cells of the vascular system. To ensure optimal performance of individual tissues, individual cells constantly communicate through the exchange of signals to fine-tune their behaviour. Cell-cell communication is frequently deregulated in cancer. During malignant transformation, tumour cells acquire mutations that not only alter their intrinsic signalling pathways, but also change their ability to respond to signals from heterotypic cells in the tissue. Moreover, tumour cells recruit and co-opt genetically normal cells to create a microenvironment which facilitates tumour progression.
Recent data have revealed dichotomous pro-tumorigenic and anti-tumorigenic roles of the microenvironment, and suggest that blocking signals from the tumour microenvironment may increase sensitivity to novel therapies. Therefore, understanding the molecular underpinnings of tumour-stroma signalling and its impact on malignant behaviour can lead to the development of new therapeutics and biomarkers.
We are currently focusing on identifying and delineating the regulatory mechanisms whereby tumour cells co-opt stromal cells. Specifically, we are identifying and characterising how tumour cell initiated signals lead to changes in the tumour microenvironment and consequently how such changes facilitate tumour progression, metastasis and response to therapy. Specifically, we have recently identified a putative target important in stromal cells, which we are now further characterising with generous support from Pancreas Cancer Research Fund (PCRF).
Triplex immunohistochemical staining of orthotopic pancreatic tumours showing acinar cells in magenta, alphaSMA positive myofibroblasts in deep purple and cytokeratin positive epithelial cells in Green.
As tumour cells secrete and receive multiple signals simultaneously we are developing and using models where tumour cell signalling and behaviour are analysed in the presence of stromal cells. Moreover, we have developed and are deploying robust proteomic workflows, which enables us to interrogate changes in cell signalling in a cell-type specific manner. To establish the specificities of signalling networks and how they impinge on specific cellular processes, we are combining our proteomics analysis with orthogonal approaches such as RNA interference screening, sequencing and high content imaging to systematically perturb and measure changes to cellular behaviour. Through data-integrative approaches, we aim to integrate the data in order to describe how signals are processed in a cell-specific manner.
The long-term goals are to understand how specific signals are processed to promote tumour progression and how blocking these signals can enhance therapeutic response.
Our latest paper on reciprocal signalling explained (Tape et al. Cell)