A luminal intermediate cell state maintains long-term prostate homeostasis and contributes to tumorigenesis.

Cellular heterogeneity poses tremendous challenges for developing cell-targeted therapies and biomarkers of clinically significant prostate cancer. The origins of this heterogeneity within normal adult and aging tissue remain unknown, leaving cellular states and transcriptional programs that allow expansions of malignant clones unidentified. To define cell states that contribute to early cancer development, we performed clonal analyses and single cell transcriptomics of normal prostate from genetically-engineered mouse models. We uncovered a luminal transcriptional state with a unique "basal-like" Wnt/p63 signaling ( luminal intermediate , LumI) which contributes to the maintenance of long-term prostate homeostasis. Moreover, LumI cells greatly expand during early stages of tumorigenesis in several mouse models of prostate cancer. Genetic ablation of p63 in vivo in luminal cells reduced the formation of aggressive clones in mouse prostate tumor models. Finally, the LumI cells and Wnt signaling appear to significantly increase in human aging prostate and prostate cancer samples, highlighting the importance of this hybrid cell state for human pathologies with potential translational impact.

Immune mechanisms shape the clonal landscape during early progression of prostate cancer.

Understanding the role of the immune microenvironment in modulating intratumor heterogeneity is essential for effective cancer therapies. Using multicolor lineage tracing in genetically engineered mouse models and single-cell transcriptomics, we show that slowly progressing tumors contain a multiclonal landscape of relatively homogeneous subpopulations within a well-organized tumor microenvironment. In more advanced and aggressive tumors, however, the multiclonal landscape develops into competing dominant and minor clones accompanied by a disordered microenvironment. We demonstrate that this dominant/minor landscape is associated with differential immunoediting, in which minor clones are marked by an increased expression of IFNγ-response genes and the T cell-activating chemokines Cxcl9 and Cxcl11. Furthermore, immunomodulation of the IFNγ pathway can rescue minor clones from elimination. Notably, the immune-specific gene signature of minor clones exhibits a prognostic value for biochemical recurrence-free survival in human prostate cancer. These findings suggest new immunotherapy approaches for modulating clonal fitness and tumor progression in prostate cancer.

Statin as anti-cancer therapy in autochthonous T-lymphomas expressing stabilized gain-of-function mutant p53 proteins.

An important component of missense mutant p53 gain-of-function (mutp53 GOF) activities is the ability of stabilized mutp53 proteins to upregulate the mevalonate pathway, providing a rationale for exploring the statin family of HMG-CoA reductase inhibitors as anticancer agents in mutp53 tumors. In this small exploratory study we report on the effects of statin treatment in autochthonous mouse models of clinically advanced T-cell lymphoma expressing two different GOF mutp53 alleles. We find that Rosuvastatin monotherapy shows a modest, p53 allele-selective and transient anti-tumor effect in autochthonous T-lymphomas expressing the p53 R248Q DNA contact mutant, but not in tumors expressing the p53 R172H conformational mutant. p53 null mice also do not benefit. In vitro statin sensitivity is not a strong predictor for in vivo sensitivity, while subcutaneous allografts are. Future explorations of statins in combination therapies are justified to improve its anti-tumor effects and to better define the most statin-sensitive alleles and tumor types among mutp53-stabilized cancers.