Tracing Tumor Progression Illuminates Occult Cellular Behaviors Underlying Cancer Lethality

Abstract

Breast cancer is a disease of development where an oncogenic cell must progress to outcompete the host epithelium, adapt its microenvironment, and evade the immune system in order to succeed. The majority of clinical efforts focus on intercepting the stepwise progression from a screen detectable precancer to an invasive cancer, yet well documented principles of progression suggest that progression of invasive character occurs far earlier than clinical intervention can occur. Quantitative experimental evidence of the critical inflection points in the ontogeny of cancer is lacking, but molecular evidence suggests that this ‘occult’ phase of tumor progression, which precedes the formation of a detectable lesion by over a decade, may be the critical period during which tumor phenotype is determined. In order to study this process, we developed a Cancer rainbow mouse model of breast cancer to lineage trace multiple oncogenes across tumorigenesis. Utilizing this model, this dissertation tests the hypothesis that tumor behavior is determined by pro-invasive adaptations during an occult tumorigenic period. Characterization of the HER2 isoform expressing Crainbow mouse model (HBOW) revealed distinct tumor trajectories that are predetermined early during tumorigenesis by pro-invasive cellular plasticity. These early changes before any apparent tumor forms correlate with eventual tumor phenotype. In order to quantitatively measure tumor progression HBOW lineage tracing was paired with mathematical modeling. Early developmental programs and transition rates from a cell to a screen detectable tumor to a clinically relevant cancer was determined and correlated with metastatic potential. This process describes the principles of progression and demonstrates how metastatic behaviors can be acquired during a critical inflection point prior to detectable tumor formation. Applying newly developed imaging tools and genetically engineered mice identified a ‘guilty’ bystander epithelial in the invasive p95 HER2 tumor microenvironment. These bystander epithelial cells are normal hormone sensitive cells residing in the mammary duct that are induced by occult interactions with nascent oncogenic cells to secrete pro-inflammatory cytokines during tumor initiation. This work defines the importance of studying tumorigenesis in order to elucidate mechanisms driving the occult progression to lethality. The ability to predict invasive tumor behavior long before clinical detection is paramount to the successful prevention of nascent lethal cancers.