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

41 Background: TMPRSS2, a cell surface protease which is commonly upregulated in prostate cancer (PC) and regulated by androgens, is a necessary component for SARS-CoV2 cellular entry into respiratory epithelial cells. PC patients receiving ADT were reported to have a lower risk of SARS-CoV-2 infection. However, whether ADT may have an impact on the severity of COVID-19 illness in this population is poorly understood. Methods: In this study performed across 7 US medical centers, we retrospectively evaluated patients with active PC and SARS-COV-2 viral detection by PCR between 03/01/20 and 05/31/20. We collected information on demographics; medical comorbidities; medications; PC Gleason score at initial diagnosis; presence of active disease, metastases, and castration resistance; ADT use as defined by GnRH analog or antagonist within 3 months or castration levels of testosterone < 50 ng/dL within 6 months of COVID-19 diagnosis, or history of bilateral orchiectomy; active non-ADT systemic therapies including, but not limited to, androgen-receptor-targeted therapies and chemotherapy; and COVID-19-related outcomes including hospitalization, supplemental oxygen use, mechanical ventilation requirement, WHO COVID-19 ordinal scale for clinical improvement, follow-up duration, and vital status. Multivariable mixed-effect logistic regression was performed to evaluate any difference in COVID-19 clinical outcomes between patients on and not on ADT. Survival analysis was done using adjusted Cox proportion-hazards regression model. All tests were two-sided at 0.05 significance level. Results: We identified 465 evaluable patients with median age of 71 (61-81) years. Median duration of follow-up was 60 (12-114.2) days. In this follow up period, there were 195 (41.9%) hospitalizations and 111 (23.9%) deaths. When adjusted for age, BMI, and PC clinical disease state, overall survival (HR 1.28 [95%CI 0.79-2.08], P = 0.32), hospitalization status (HR 1.07 [0.61-1.87], P = 0.82), supplemental oxygen use (HR 1.29 [0.77-2.17], P = 0.34), and use of mechanical ventilation (HR 1.07 [0.51-2.23], P = 0.87) were not statistically different between ADT and non-ADT cohorts. Similarly, in subgroup analysis, no statistical difference in overall survival was found between ADT and non-ADT cohorts for hospitalized patients (HR 1.42 [0.82-2.47], P = 0.21) and those receiving supplemental oxygen (HR 1.10 [0.65-1.85], P = 0.73). Conclusions: In this retrospective cohort of PC patients, use of ADT prior to COVID-19 diagnosis does not protect against severe COVID-19 illness as defined by hospitalization, supplemental oxygen use, or death. Further preclinical work in understanding TMPRSS2 expression and androgen regulation in respiratory epithelial cells is needed. As well, longer clinical follow-up and additional clinical studies inclusive of prospective data are warranted to fully address this question.

Bladder cancer is a common urinary tract cancer with a difficult clinical course. With frequent recurrence, patients with a history of bladder cancer often undergo surveillance that involves invasive cystoscopies and biopsies. Not only is this financially burdensome for patients but it is also mentally and physically intensive. Given this predicament, the field has shifted towards the use of non-invasive urinary tests to detect bladder cancer earlier in the disease course and to avoid unnecessary procedures. The first noninvasive test developed was urine cytology; however, that was found to have a low sensitivity, especially for low-grade lesions. There are many tests that are available that utilize common protein biomarkers to enhance the sensitivity of detection. However, many of these tests lack the specificity seen with cytology. With recent technological and research advancements, there are newer detection systems such as RNA sequencing and microfluidics along with novel bladder cancer biomarkers including mRNAs, methylation patterns and exosomes, which have potential to be used in clinical practice. The aim of this review is to highlight established non-invasive bladder cancer diagnostic tests as well as innovative methodologies that are on the horizon for use in bladder cancer detection.

<p>Supplementary Figures and Figure legends</p>

<div>Abstract<p>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 <i>NKX3.1</i> associated with increased cancer risk fail to protect from oxidative stress or suppress tumorigenicity. Low expression levels of <i>NKX3.1</i> 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.</p>Significance:<p>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.</p><p><i>See related commentary by Finch and Baena, p. 2132</i>.</p><p><i>This article is highlighted in the In This Issue feature, p. 2113</i></p></div>