Cancer treatments involve a combination of surgery, radiotherapy, and chemotherapy (e.g., cisplatin), which has significantly improved survival rates. However, these benefits come with severe side effects as skin and hair issues, as well as an increased risk of developing a new primary tumor later in life. Indeed, nearly 10% of cancer survivors develop subsequent malignant neoplasms (SMNs), which are fatal in more than 50% of these cases.

This statement is particularly true for cisplatin and platinum-based chemotherapy in general. For example, cisplatin-based testicular cancer treatment has led to over 90% of patients achieving long-term survival, but these patients have a higher risk of developing SMNs such as leukemia or colorectal cancer (CRC) later in life (Hazard Ratio of 3.9). Unfortunately, experimental evidence supporting and explaining these observations remains extremely limited.

Our objective is to explain and decipher whether the increased risk of developing CRC after cisplatin exposure is solely due to its mechanism of action (i.e., DNA damage leading to the gain/accumulation of mutations) or if it can also affect the fate of wild-type or mutated intestinal stem cells (ISCs).

To explain the side effects of cisplatin, our method is based on whole-genome sequencing and computational models to detect specific cisplatin signatures in human colorectal adenomas from patient treated for a previous cancer with cisplatin and in healthy human colon organoids exposed in vitro to cisplatin. Furthermore, we used different inducible transgenic mouse models for APC inactivation in the intestinal epithelium to study the effect of cisplatin on lesion number and size. Finally, the fate of ISCs/crypts, wild-type or mutated for Kras, has been compared with or without cisplatin exposure by combining elegant traceable mouse models and intravital microscopy (IVM).

Our results indicate that cisplatin can create potential tumor-initiating cells through mutagenesis of CRC onco-driver genes, but not in every case. In our mouse models, we observe that cisplatin increases the number and size of lesions. In line with these results, early observations of ISCs fate upon cisplatin exposure show that ISC competition occurs faster and mutant crypt fission is boosted.

In conclusion, our work highlights how cisplatin potentially acts as a mutagenic compound on ISCs and/or how it disturbs the intestinal limiting steps of mutant ISCs.