Work from our consortium but also supported by recent publications from other groups indicates that fetal/embryonic conversion represents one of the main escape routes of colorectal tumors to chemotherapy, a mechanism that may be shared by other tumor types. In addition, the partners of the consortium identified a core fetal signature that is present in about 24% of all colorectal tumors at diagnosis, which would represent 600,000 cases per year in Europe and is predictive of poor prognosis, even at early tumor stages II and II+III. We have also identified the Hippo/YAP1 pathway as a potential regulator of fetal conversion in cancer and showed that YAP1 inhibitors sensitizes fetal-type patient-derived organoids (PDOs) to chemotherapeutic agents, ultimately leading to efficient tumor eradication.

Within this project, we will use fresh tumor tissues and PDOs and different OMIC strategies to identify candidate therapeutic targets for treating patients with fetal-type tumors. Integration of the data obtained from these analyses will allow the design of an in vitro medium throughput screening platform to validate the vulnerabilities of fetal-type tumors, which will be further confirmed in zebrafish avatars and murine PDX models. We assume that elements of the Hippo pathway will emerge in our analysis, but other potential druggable targets are expected. In addition, the use of PDOs with different mutational backgrounds will provide insight into additional players in fetal transformation in cancer. Our ultimate goal is to develop the first companion diagnostic strategy against fetal-type tumors combining a diagnostic/prescription device with a personalized treatment.