Visualizing programmed lineage trajectories at cancer initiation
The sequential accumulation of survival advantage traits – the cancer evolution hypothesis – implies that early detection and treatment of precancers can prevent cancer mortality. In practice, detection and treatment of breast precancer ductal  carcinoma in situ (DCIS) has had minimal impact on reducing breast cancer mortality. The evolution of precancer is not inevitable, suggesting that inciting neoplastic events lead to different trajectories of progression. Here we visualize distinct tumor driver gene programs of lineage specification occurring at cancer initiation. Crainbow fluorescent barcoding of wild-type HER2, d16-HER2, and p95-HER2 enables whole-gland lineage tracing and single-cell reconstruction of the origin of HER2+ breast cancer. Molecular pathology and Crainbow lineage tracing provide genotype:phenotype modules and gene signatures predictive of cancer progression. WT-HER2 neoplasms were rare and proliferative d16-HER2 neoplasms eventually progressed to metastasis, and p95-HER2 induced rapidly invasive and metastatic carcinomas. p95-HER2 carcinomas originate without detectable in situ stages – termed here a minimally detectable “nascent lethal carcinoma”. This nascent lethal program biases the commitment of tumor stem cells toward a metaplastic epithelial-mesenchymal transition-like (EMT) lineage promoting microenvironmental remodeling. Overall, these data suggest that lethality programs begin at initiation, indicating that detection must be improved to identify the nascent lethal lesion. Overall design: Singe cells obtained from 12 Her2+ tumors that are either d16 or p95.