Abstract 482P
Background
Current chemotherapy regimens for colorectal cancer (CRC) have low selectivity for tumor cells alone and result in significant side effects. The most effective therapy remains surgical excision of the tumor, which is highly invasive procedure since large parts of the colon are removed. For novel and efficient therapeutic approaches, the tumor needs to be explored as a dynamic ‘biosystem’, which includes the surrounding stromal cells - tumor supporting fibroblasts, immune and endothelial cells. We hypothesize that targeting the stromal compartment, in addition to the tumor itself, could bring more effective anti-cancer treatment. We compared patient derived normal (NFs) and cancer associated fibroblasts (CAFs) to understand tumor enhancing pathways in CAFs and identify potential therapeutic targets.
Methods
We used label free mass-spectrometric protein quantification combined with human cytokine assay evaluating 150 different cytokines, to obtain the intracellular and extracellular profile of primary patient fibroblasts in culture. We compared 7 pairs of NFs versus CAFs at early passages. Finally, we evaluated if fibroblasts support growth of patient-derived organoids (healthy and tumor), derived from the matched tissues.
Results
We identified 145 significantly differentially expressed proteins using Perseus and a custom R script using the Differential Enrichment of Proteomics data package. To identify the specific role of the deregulated proteins, we used pathway and network analysis tools. The secretome analysis found 15 differentially expressed molecules among the 7 patient pairs. At last, organoid growth for 2 of the patient samples was evaluated in a co-culture model with matched NFs or CAFs. Organoids grown with CAFs showed enhanced growth compared to these grown with NFs.
Conclusions
Our data indicate that primary NFs and CAFs have significant differences in their protein expression profiles and provide a basis for identifying novel therapeutic targets. The expression differences combined with the growth differences in co-culture, indicate that CAFs are reprogrammed to enhance tumor growth. Inhibition of the CAFs supporting phenotype has the potential to improve anti-cancer therapies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Ludwig Boltzmann Society, Ludwig Boltzmann Institute Applied Diagnostics.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.