Tracing the Equilibrium Phase of Cancer Immunoediting in Epidermal Neoplasms via Longitudinal Intravital Imaging.

Recognition of transformed cells by the immune system can sometimes generate a rate-limiting equilibrium phase, wherein tumor outgrowth is prevented without complete neoplasm elimination. Targeting premalignancies during this immune-controlled bottleneck is a promising strategy for rational cancer prevention. Thus far, immune equilibrium has been difficult to model in a traceable way, and most immunoediting systems have been limited to mesenchymal tumor types. Here, we introduce a mouse model for fluorescent tracing of somatic epithelial transformation. We demonstrate that transplantation can be used to prevent a confounding artificial tolerance that affects autochthonous inducible models. Using this system, we observe the expected dichotomy of outcomes: immune-deficient contexts permit rapid tumorigenesis, whereas initiated clones in immunocompetent mice undergo elimination or equilibrium. The equilibrium phase correlates with localization within hair follicles, which have been characterized previously as relatively immune-privileged sites. Given this, we posit that valleys in the immune surveillance landscape of a normal tissue can provide a cell-extrinsic alternative to the canonical cell-intrinsic adaptations believed to establish the equilibrium phase. Our model is a prototype for tracing immunoediting in vivo and could serve as a novel screening platform for therapies targeted against immune-controlled premalignancies.

The role of AKT isoforms in glioblastoma: AKT3 delays tumor progression.

The growth factor receptor/PI3K/AKT pathway is an important drug target in many cancers including Glioblastoma. AKT, a key node in the pathway, has 3 isoforms, AKT1, AKT2 and AKT3. Here we investigate their role in GBM. We find each activated, ser473 phosphorylated isoform is present in some GBMs but expression patterns vary. There is a direct relationship between human GBM patient outcome and both AKT1 and AKT2 mRNA levels, but an inverse relationship with AKT3 mRNA. Furthermore, AKT3 mRNA levels were high in a less aggressive GBM subtype. Overexpressing AKT3 improves survival in a rodent model of GBM and decreases colony forming efficiency, but not growth rate, in glioma cells. Silencing AKT3 slows cell cycle progression in one cell line and increases apoptosis in another. Our studies of AKT3 substrates indicate (1) silencing both AKT2 and AKT3 reduces GSK3 phosphorylation (2) only AKT2 silencing reduces S6 phosphorylation. Since S6 phosphorylation is a marker of mTORC1 activity this indicates that AKT2 activates mTORC1, but AKT3 does not. Our results indicate AKT isoforms have different roles and downstream substrates in GBM. Unexpectedly, they indicate AKT3 delays tumor progression. Therefore strategies that inhibit AKT3 may be unhelpful in some GBM patients.