Dr. Oliver Reinhardt
Tumor heterogeneity and chemotherapy resistance in the murine syngeneic WAP-T breast cancer mouse model
In breast cancer patients, the main cause of death is usually not the primary tumor itself, but rather the development of a locoregional or distant recurrence. Despite an apparently complete tumor resection, the combination with adjuvant and / or neoadjuvant radiation or chemotherapy is often not able to eliminate all tumor cells, since individual tumor cells acquire / have resistance capabilities and are the starting point for the recurrent tumor.
We investigate i) the effect of cyclophosphamide, doxorubicin and 5-fluoracil (CAF) chemotherapy on tumor growth and phenotype (tumor heterogeneity) in the syngeneic WAP-T breast cancer mouse model; ii) the characterization of the CAF-resistant tumor cells, which make up the majority of the remitted tumors after CAF therapy, and iii) the description of resistance-mediating signaling pathways that are initiated by CAF therapy. For this purpose, murine H8N8 breast cancer cells are transplanted orthotopically into immune-competent WAP-T mice and treated once with CAF therapy after the development of H8N8 tumors.
Our previous results show that the single administration of CAF chemotherapy is not able to eliminate all tumor cells and remitted tumor cells initiate the progressive regrowth of the tumor approx. 6 days after the start of the therapy. Tumor cells treated once with CAF were isolated, retransplanted after several cycles of cultivation in vitro, and treated again with CAF chemotherapy in vivo. Based on the results, we assume that one round of CAF chemotherapy can trigger resistance mechanisms, by which CAF-treated H8N8 tumor cells gain protective advantages towards CAF chemotherapy, resulting in increased chemotherapy resistance and more H8N8 tumor cell survival. Further, these generated CAF-resistant H8N8 tumors and tumor cells enable us to analyse the influence of chemotherapy-resistant tumor cells in interaction with the microenvironment of the tumor cell niche and the description of resistance-inducing mediators.