Homeostasis of the extracellular matrix (ECM) is critical for correct organ and tissue function. Both the biochemical and biomechanical properties of the ECM contribute to modulating the behaviour of resident cells and are more than just passive bystanders. In tissue diseases such as cancer, the ECM undergoes significant change. These changes, driven by both tumour and stromal cells, feed into the pathological progression of the disease.
Genetically heterogeneous sub-populations of cancer cells are known to exist within tumours. Recent studies have also provided evidence that discrete subtypes of cancer associated fibroblasts (CAFs) also coexist within tumours. These CAFs are known to be able to both promote and restrain disease progression. Our recent work has shown that the specific mutational burden of cancer cells within a tumour, alters the paracrine education of local populations of CAFs within pancreatic ductal adenocarcinoma. These cancer cell educated CAFs have altered matrisomal secretomes, which leads to local remodelling of the tumour ECM. This remodelling underpins the generation of a pro-invasive and pro-metastatic environment for cancer cells, and also leads to alterations in the sensitivity of resident cancer cells to standard-of-care chemotherapy. Targeting this stromal remodelling is showing promise as a novel approach to normalise the tumour stroma and improve therapeutic outcomes.
Understanding at the molecular level how the changing ECM landscape facilitates tumour progression is an important step in the treatment of cancer.