Decoding the Extracellular matrix at the immunosuppressive tumor microenvironment: the forgotten partner
Mª Jose Oliveira
i3S-Institute for Research and Innovation in Health, University of Porto, Portugal
The extracellular matrix (ECM) is a dynamic entity known to play an important role in cancer progression, influencing the behaviour of both cancer and stromal cells. In colon cancer, high stromal content is associated to poor patient prognosis. However, it is still unclear what is the specific contribution of the ECM for cancer cell stemness and immune escape.
Aiming to dissect the differences in ECM properties between non-malignant and malignant colon tissues, while considering the sidedness of the tumours, paired normal and tumor tissues, obtained from right or left colon tumours, were decellularized and analysed by label-free mass spectrometry (LC-MS/MS) and by rheology. Major biomechanical and biochemical differences were identified between normal and tumor matrices and specificities regarding sidedness were unveiled.
In addition, the impact of tumour decellularized matrices on cancer cell stemness and macrophage polarization was investigated. Our results revealed that tumor matrices promote the expression of stem-like markers and drive monocytes towards a more anti-inflammatory phenotype, secreting high levels of CCL18, an immunosuppressive and pro-fibrotic chemokine. Differential expression analysis revealed 143 upregulated and 33 downregulated proteins in tumor matrices. Integrating proteomics data with RNA levels from the cBioPortal database facilitated the identification of 9 proteins whose gene expression correlates with CCL18 mRNA levels, and that are currently being validated in clinical cohorts.
We strongly believe that the detailed analysis of the ECM paves the way for identifying new therapeutic targets, ultimately improving clinical management and patient outcomes.