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Although it is known that inflammation plays a critical role in prostate tumorigenesis, the underlying processes are not well understood. Based on analysis of genetically engineered mouse models combined with correlative analysis of expression profiling data from human prostate tumors, we demonstrate a reciprocal relationship between inflammation and the status of the NKX3.1 homeobox gene associated with prostate cancer initiation. We find that cancer initiation in aged Nkx3.1 mutant mice correlates with enrichment of specific immune populations and increased expression of immunoregulatory genes. Furthermore, expression of these immunoregulatory genes is similarly increased in human prostate tumors having low levels of NKX3.1 expression. We further show that induction of prostatitis in Nkx3.1 mutant mice accelerates prostate cancer initiation, which is coincident with aberrant cellular plasticity and differentiation. Correspondingly, human prostate tumors having low levels of NKX3.1 have de-regulated expression of genes associated with these cellular processes. We propose that loss of function of NKX3.1 accelerates inflammation-driven prostate cancer initiation potentially via aberrant cellular plasticity and impairment of cellular differentiation..

Despite recent advances in discovering a wide array of novel chemotherapy agents, identification of patients with poor and favorable chemotherapy response prior to treatment administration remains a major challenge in clinical oncology. To tackle this challenge, we present a generalizable genome-wide computational framework pathCHEMO that uncovers interplay between transcriptomic and epigenomic mechanisms altered in biological pathways that govern chemotherapy response in cancer patients. Our approach is tested on patients with lung adenocarcinoma who received adjuvant standard-of-care doublet chemotherapy (i.e., carboplatin-paclitaxel), identifying seven molecular pathway markers of primary treatment response and demonstrating their ability to predict patients at risk of carboplatin-paclitaxel resistance in an independent patient cohort (log-rank p -value = 0.008, HR = 10). Furthermore, we extend our method to additional chemotherapy-regimens and cancer types to demonstrate its accuracy and generalizability. We propose that our model can be utilized to prioritize patients for specific chemotherapy-regimens as a part of treatment planning.

Background Although men on active surveillance for prostate cancer (PCa) may benefit from intervention with 5α-reductase inhibitors (5-ARIs), it has not been resolved whether 5-ARIs are effective for delaying disease progression and, if so, whether specific patients are more likely to benefit. Objective To identify molecular features predictive of patient response to 5-ARIs. Design, setting, and participants Nkx3.1 mutant mice, a model of early-stage PCa, were treated with the 5-ARI finasteride, and histopathological and molecular analyses were performed. Cross-species computational analyses were used to compare expression profiles for treated mice with those of patients who had received 5-ARIs before prostatectomy. Intervention Finasteride administered to Nkx3.1 mutant mice. 5-ARI-treated patient specimens obtained retrospectively. Outcome measurements and statistical analysis Endpoints in mice included histopathology, immunohistochemistry, and molecular profiling. GraphPad Prism software, R-studio, and Matlab were used for statistical and data analyses. Results and limitations Finasteride treatment of Nkx3.1 mutant mice resulted in a significant reduction in prostatic intraepithelial neoplasia (PIN), as evident from histopathological and expression profiling analyses. Cross-species computational analysis comparing finasteride-treated mice with two independent 5-ARI–treated patient cohorts showed that reduced NKX3.1 expression is predictive of response to 5-ARI. A limitation of the study is that these retrospective human cohorts have relatively few patients with limited clinical outcome data. Future prospective clinical trials are needed to validate whether stratifying patients on the basis of NKX3.1 expression improves the benefit of 5-ARIs during active surveillance. Conclusions This co-clinical study implicates NKX3.1 status as a predictor of response to 5-ARIs, and suggests that molecular features, including NKX3.1 expression, may help to identify PCa patients most likely to benefit from 5-ARIs during active surveillance. Patient summary The aim of precision cancer prevention is to tailor interventions on the basis of individualized patient characteristics. We propose that patients with low NKX3.1 expression are optimal candidates for intervention with 5α-reductase inhibitors as an adjunct to active surveillance.

Mitochondria provide the first line of defense against the tumor-promoting effects of oxidative stress. Here we show that the prostate-specific homeoprotein NKX3.1 suppresses prostate cancer initiation by protecting mitochondria from oxidative stress. Integrating analyses of genetically engineered mouse models, human prostate cancer cells, and human prostate cancer organotypic cultures, we find that, in response to oxidative stress, NKX3.1 is imported to mitochondria via the chaperone protein HSPA9, where it regulates transcription of mitochondrial-encoded electron transport chain (ETC) genes, thereby restoring oxidative phosphorylation and preventing cancer initiation. Germline polymorphisms of NKX3.1 associated with increased cancer risk fail to protect from oxidative stress or suppress tumorigenicity. Low expression levels of NKX3.1 combined with low expression of mitochondrial ETC genes are associated with adverse clinical outcome, whereas high levels of mitochondrial NKX3.1 protein are associated with favorable outcome. This work reveals an extranuclear role for NKX3.1 in suppression of prostate cancer by protecting mitochondrial function. Significance: Our findings uncover a nonnuclear function for NKX3.1 that is a key mechanism for suppression of prostate cancer. Analyses of the expression levels and subcellular localization of NKX3.1 in patients at risk of cancer progression may improve risk assessment in a precision prevention paradigm, particularly for men undergoing active surveillance. See related commentary by Finch and Baena, p. 2132. This article is highlighted in the In This Issue feature, p. 2113

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Therapeutic resistance is a central problem in clinical oncology. We have developed a systematic genome-wide computational methodology to allow prioritization of patients with favorable and poor therapeutic response. Our method, which integrates DNA methylation and mRNA expression data, uncovered a panel of 5 differentially methylated sites, which explain expression changes in their site-harboring genes, and demonstrated their ability to predict primary resistance to androgen-deprivation therapy (ADT) in the TCGA prostate cancer patient cohort (hazard ratio = 4.37). Furthermore, this panel was able to accurately predict response to ADT across independent prostate cancer cohorts and demonstrated that it was not affected by Gleason, age, or therapy subtypes. We propose that this panel could be utilized to prioritize patients who would benefit from ADT and patients at risk of resistance that should be offered an alternative regimen. Such approach holds a long-term objective to build an adaptable accurate platform for precision therapeutics.