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.
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.
Cellular heterogeneity poses tremendous challenges for developing cell-targeted therapies and biomarkers of clinically significant prostate cancer. The origins of this heterogeneity within the cellular complexities of normal adult and aging tissue remain unknown leaving important cellular states and transcriptional programs that allow the expansion of malignant clones in early cancer unidentified. These unresolved questions hamper the development of novel therapies designed to block the deregulated proliferation of prostate epithelial cells. To define cell states that contribute to early cancer development, we performed in vivo lineage tracing with multicolor reporters, whole organ mapping and single cell transcriptomics of normal and malignant prostate from genetically-engineered mouse models. We show here that the long-term luminal homeostasis is maintained by multiple clones with various fitness levels. Long-term clonal expansions are enabled by a luminal transcriptional state harboring basal markers (Luminal Intermediate, LumI) and controlled by Wnt/p63 signaling. Moreover, LumI cells greatly expand during early stages of tumorigenesis in several mouse models of prostate cancer. Specific genetic ablation of p63 from luminal cells in vivo decreases clonal activity in homeostasis and reduces the formation of aggressive clones in 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. Our models reveal a continuity of this cell state from normal homeostasis to aging and early cancer with specific alterations at each stage. Understanding how the luminal intermediate cell state is regulated in homeostasis and deregulated in hyperproliferative contexts is crucial for the development of prognostic markers and new therapeutic interventions for prostate diseases. Citation Format: Fu Luo, Lara F. Tshering, Karis Tutuska, Mariola Szenk, Diana Rubel, James G. Rail, Savanah Russ, Jingxuan Liu, Alice Nemajerova, Gábor Balázsi, Flaminia Talos. A luminal intermediate cell state maintains long-term prostate homeostasis and contributes to tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A085.
Age-related prostate diseases are among the most frequently encountered conditions in the male population and age remains a major risk for prostate cancer (PCa) development. Understanding the cellular origins of age-related prostate hyperplasia and dysplasia and finding novel ways to halt progression towards malignancy remain fundamental challenges of PCa treatment, prevention, and patient stratification. Elucidating how aging alters the barriers posed by normal homeostasis to tumor cells expansions is of paramount importance for understanding PCa initiation. To date, it remains elusive how prostate clonal activity maintains the constant prostate size and what homeostatic barriers need to be disrupted for the age-related hyperproliferations to occur and lead to cancer. Moreover, altered aging prostate epithelial cell types and mechanisms that facilitate clonal expansion of tumor cells in aging are not well understood. These unresolved questions hamper the development of anti-proliferative therapies designed to block the deregulated activity of aged prostate epithelial cells. We used in vivo lineage tracing with multicolor reporters, whole organ mapping and single cell transcriptomics to study clonal dynamics of the luminal epithelial layer at single cell resolution. We report here the molecular characterization of a newly identified “intermediate” hybrid state in the luminal compartment with increased basal features. These luminal intermediate cells are associated with increased clonal activity and Wnt signaling, including the atypical and understudied Wnt4 ligand. This cell state becomes dominant in aging mouse and human prostate tissue. Within a set of adult/middle age and advanced age normal human prostate samples, we have identified increased levels of Wnt4 expression in aging luminal cells. Moreover, this “pro-proliferative” state has exacerbated growth in oncogenic set-ups leading to clonal expansions in early stages of prostate cancer. We further delineated the master regulators of these luminal intermediate state and singled out p63 as a putative critical activator. In sum, our results suggest that the luminal lineage is maintained by a balancing act of luminal cells activating a “basal-like” pro-proliferative program in response to cellular loss due to normal turnover. These cells are less dependent on androgens, and thus survive better in the low androgen milieu of aging prostate. This active pro-proliferative program is susceptible to hyperproliferation alterations and potentially contributes to the onset of early prostate cancer and might serve as a cell of origin. Our ongoing studies address the targetable vulnerabilities in the Wnt4-p63 luminal signaling in order to provide new venues for therapeutic interventions against age-related prostate hyperproliferations. Citation Format: Fu Luo, Lara F. Tshering, Karis Tutuska, Mariola Szenk, Diana Rubel, James Rail, Savanah Russ, Gábor Balázsi, Flaminia Talos. Clonal dynamics and single cell transcriptomics of prostate luminal epithelial cells in aging and cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3076.
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