Trajectory.

Nowadays the leading cause of cancer death in patients with solid tumors is the occurrence of local or distant recurrences after the first lines of treatment. Cancer relapses have a significant enrichment in treatment-resistance cells compared to primary tumors. This is because therapeutic pressure imposes additional stresses that contribute to tumor evolution and the acquisition of resistance . Different mechanisms of failure can explain our difficulties to treat relapsing patients. First, each solid tumor is composed of cancer cells heterogeneous in terms of their genetic, epigenetic, transcriptional and translational states that evolve under treatment pressure . If advances in genomic technologies, single-cell sequencing and spatial transcriptomics have allowed to depict a thorough ITH portrait of primary tumors, very little has been done to characterize cancer relapse ITH. Leveraging transitions dynamics between cellular states appears as a potential therapeutic strategy to target tumor relapses. Second, preclinical models are often not established in relapsed conditions whereas early phase clinical trials are implemented in relapsing diseases, where patients have already received one or several lines of therapy.