Impact of cancer-associated fibroblasts on tumour micro-environment heterogeneity in response to chemotherapy

Abstract

Despite many advances in surgery, chemotherapy and personalised medicine, colorectal cancer (CRC) remains the third leading cause of cancer-related deaths worldwide. After curative treatment, 30% to 40% of patients relapse. The tumour micro-environment (TME), and the cancer-associated fibroblasts (CAFs) that reside in it, play a major role in CRC tumour progression and resistance to treatment. Here, we analyse two CAF subtypes with a mutually exclusive gene expression pattern that were identified from a biobank of patient-derived CAFs. CAFs from these subtypes are co-cultured in a 3D TME model with patient-derived organoids (PDOs) from CRC tumours to assess their influence on tumour growth via a luciferase reporter. Furthermore, tumour growth and gene expression dynamics are monitored upon treatment of the model with chemotherapy. We find that certain CAFs from both subtypes increase tumour growth and drive resistance to therapy. In addition, we see how CAFs from one subtype drive aggregation of the PDOs in our TME model. Lastly, we show how healthy fibroblasts in co-culture with PDOs increase expression of CAF markers upon oxaliplatin treatment. Taken together, this study underlines the bidirectional interactions of tumour cells and CAFs in the TME of CRC carcinomas to drive disease progression and resistance to treatment. These findings merit further research to distinguish CAF clusters that drive these interactions and discover new biomarkers.