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Cancer cells develop mechanisms to escape immunosurveillance, among which modulating the expression of immune suppressive messenger RNAs is most well-documented. However, how this is molecularly achieved remains largely unresolved. Here, we develop an in vivo mouse model of liver cancer to study oncogene cooperation in immunosurveillance. We show that MYC overexpression ( MYC Tg ) synergizes with KRAS G12D to induce an aggressive liver tumor leading to metastasis formation and reduced mouse survival compared with KRAS G12D alone. Genome-wide ribosomal footprinting of MYC Tg ; KRAS G12 tumors compared with KRAS G12D revealed potential alterations in translation of mRNAs, including programmed-death-ligand 1 (PD-L1). Further analysis revealed that PD-L1 translation is repressed in KRAS G12D tumors by functional, non-canonical upstream open reading frames in its 5′ untranslated region, which is bypassed in MYC Tg ; KRAS G12D tumors to evade immune attack. We show that this mechanism of PD-L1 translational upregulation was effectively targeted by a potent, clinical compound that inhibits eIF4E phosphorylation, eFT508, which reverses the aggressive and metastatic characteristics of MYC Tg ; KRAS G12D tumors. Together, these studies reveal how immune-checkpoint proteins are manipulated by distinct oncogenes at the level of mRNA translation, which can be exploited for new immunotherapies. Oncogene cooperation enhances PD-L1 translation to promote immune evasion and metastasis in a novel model of liver cancer.

In order to proliferate in unfavourable conditions, cancer cells can take advantage of the naturally occurring endoplasmic reticulum-associated unfolded protein response (UPR) via three highly conserved signalling arms: IRE1α, PERK and ATF6. All three arms of the UPR have key roles in every step of tumour progression: from cancer initiation to tumour growth, invasion, metastasis and resistance to therapy. At present, no cure for metastatic prostate cancer exists, as targeting the androgen receptor eventually results in treatment resistance. New research has uncovered an important role for the UPR in prostate cancer tumorigenesis and crosstalk between the UPR and androgen receptor signalling pathways. With an improved understanding of the mechanisms by which cancer cells exploit the endoplasmic reticulum stress response, targetable points of vulnerability can be uncovered.The unfolded protein response has an important role in prostate cancer tumorigenesis. Here, the authors discuss its involvement in prostate cancer development and progression, interactions with androgen receptor signalling, and the therapeutic implications for the treatment of metastatic disease.

Concurrent readout of sequence and base modifications from long unamplified DNA templates by Pacific Biosciences of California (PacBio) single-molecule sequencing requires large amounts of input material. Here we adapt Tn5 transposition to introduce hairpin oligonucleotides and fragment (tagment) limiting quantities of DNA for generating PacBio-compatible circular molecules. We developed two methods that implement tagmentation and use 90–99% less input than current protocols: (1) single-molecule real-time sequencing by tagmentation (SMRT-Tag), which allows detection of genetic variation and CpG methylation; and (2) single-molecule adenine-methylated oligonucleosome sequencing assay by tagmentation (SAMOSA-Tag), which uses exogenous adenine methylation to add a third channel for probing chromatin accessibility. SMRT-Tag of 40 ng or more human DNA (approximately 7,000 cell equivalents) yielded data comparable to gold standard whole-genome and bisulfite sequencing. SAMOSA-Tag of 30,000–50,000 nuclei resolved single-fiber chromatin structure, CTCF binding and DNA methylation in patient-derived prostate cancer xenografts and uncovered metastasis-associated global epigenome disorganization. Tagmentation thus promises to enable sensitive, scalable and multimodal single-molecule genomics for diverse basic and clinical applications. Two low-input tagmentation-based long-read sequencing methods, single-molecule real-time sequencing by tagmentation (SMRT-Tag), which identifies genetic variation and CpG methylation, and single-molecule adenine-methylated oligonucleosome sequencing assay by tagmentation (SAMOSA-Tag), which detects chromatin accessibility, are presented. Application of SAMOSA-Tag to prostate cancer patient-derived xenograft samples identifies metastasis-associated epigenomic alterations.

The androgen receptor (AR) is a central driver of aggressive prostate cancer. After initial treatment with androgen receptor signaling inhibitors (ARSi), reactivation of AR signaling leads to resistance. Alternative splicing of AR mRNA yields the AR-V7 splice variant, which is currently an undruggable mechanism of ARSi resistance: AR-V7 lacks a ligand binding domain, where hormones and anti-androgen antagonists act, but still activates AR signaling. We reveal PKCβ as a druggable regulator of transcription and splicing at the AR genomic locus. We identify a clinical PKCβ inhibitor in combination with an FDA-approved anti-androgen as an approach for repressing AR genomic locus expression, including expression of AR-V7, while antagonizing full-length AR. PKCβ inhibition reduces total AR gene expression, thus reducing AR-V7 protein levels and sensitizing prostate cancer cells to current anti-androgen therapies. We demonstrate that this combination may be a viable therapeutic strategy for AR-V7-positive prostate cancer.

IntroductionMen with a detectable PSA after radical prostatectomy (RP) are often offered salvage therapy while those with an undetectable PSA are monitored. We aim to better characterize the natural history of men with an initially undetectable PSA who subsequently developed a detectable PSA > 6 months after RP.MethodsRetrospective analysis of men who underwent RP for clinically localized prostate cancer at the University of California, San Francisco from 2000 to 2022. The primary outcome was biochemical recurrence, defined as 2 consecutive PSA > = 0.03 ng/mL starting 6 months after surgery. Secondary outcomes were salvage treatment, post-salvage treatment, metastasis free survival (MFS), prostate cancer specific mortality (PCSM), and all-cause mortality (ACM). This cohort was compared to a previously described cohort who had an immediately detectable post-operative PSA.ResultsFrom our cohort of 3348 patients, we identified 2868 men who had an undetectable post-op PSA. Subsequently, 642 men had a delayed detectable PSA at a median of 25 months (IQR 15, 43) with median follow-up of 72 months after RP. PSA at time of failure was <0.10 ng/mL for 65.7% of men. Of those with a delayed detectable PSA, 46% underwent salvage treatment within 10 years after RP at a median PSA of 0.08 ng/mL (IQR 0.05, 0.14). High CAPRA-S score (HR 1.09, CI 1.02–1.17, p = 0.02) and PSA doubling time (PSA-DT) of <6 months (HR 7.58, CI 5.42–10.6, p < 0.01) were associated with receiving salvage treatment. After salvage treatment, 62% of men had recurrent PSA failure within 10 years. Overall, MFS was 92%, PCSM 3%, and ACM 6% at 10 years. For those who received tertiary treatment for recurrent PSA failure, MFS was 54%, PCSM 23% and ACM 23% at 10 years’ time.ConclusionsMen who develop a detectable PSA > 6 months post-operatively may have excellent long-term outcomes, even in the absence of salvage therapy.

PurposeTo identify predictors of when systematic biopsy leads to a higher overall prostate cancer grade compared to targeted biopsy.Methods and materials918 consecutive patients who underwent prostate MRI followed by MRI/US fusion biopsy and systematic biopsies from January 2015 to November 2019 at a single academic medical center were retrospectively identified. The outcome was upgrade of PCa by systematic biopsy, defined as cases when systematic biopsy led to a Gleason Grade (GG) ≥ 2 and greater than the maximum GG detected by targeted biopsy. Generalized linear regression and conditional logistic regression were used to analyze predictors of upgrade.ResultsAt the gland level, the presence of an US-visible lesion was associated with decreased upgrade (OR 0.64, 95% CI 0.44–0.93, p = 0.02). At the sextant level, upgrade was more likely to occur through the biopsy of sextants with MRI-visible lesions (OR 2.58, 95% CI 1.87–3.63, p < 0.001), US-visible lesions (OR 1.83, 95% CI 1.14–2.93, p = 0.01), and ipsilateral lesions (OR 3.89, 95% CI 2.36–6.42, p < 0.001).ConclusionSystematic biopsy is less valuable in patients with an US-visible lesion, and more likely to detect upgrades in sextants with imaging abnormalities. An approach that takes additional samples from regions with imaging abnormalities may provide analogous information to systematic biopsy.

BackgroundUrinary incontinence after radical prostatectomy affects many men. In addition to surgical and patient factors, longer preoperative membranous urethral length (MUL) has been suggested to be associated with improved postoperative urinary continence outcomes. Here, we assess the association of preoperative MUL and the risk of persistent postoperative urinary incontinence after robot-assisted radical prostatectomy (RARP) for prostate cancer on extended follow-up.MethodsAll participants underwent RARP at the University of California, San Francisco between 2000-2018. Patients were excluded if preoperative MRI-measured MUL was not performed by a radiologist. A single, blinded urologist remeasured MUL retrospectively. Logistic regression models examined associations between radiologist- and urologist-measured MUL and likelihood of persistent incontinence post-RARP by two definitions: strict incontinence (>0 pad/day) and social incontinence (>1 pad/day).ResultsIn 251 men with a median follow-up of 42 months (IQR 29–76), the median MUL measurements were 14 mm ([IQR 12–17], radiologist) and 15 mm ([IQR 12–18], urologist) with poor agreement (interclass correlation coefficient 0.34). On logistic regression, urologist-measured longer MUL was associated with lower likelihood of strict incontinence within 6 months (odds ratio [OR] 0.87; 95% confidence interval [CI] 0.81–0.94) and 12 months (OR 0.90; 95% CI 0.82–0.98) and social incontinence within 6 months (OR 0.93; 95% CI 0.86–1.00) and 12 months (OR 0.84; 95% CI 0.74–0.95). Radiologist-measured longer MUL was associated with lower likelihood of strict incontinence within 6 months (OR 0.93; 95% CI 0.87–1.00) and social within 12 months (OR 0.87; 95% CI 0.77–1.00). MUL was not associated with likelihood of strict or social incontinence within 24 months.ConclusionPreoperative MRI-measured MUL was not associated with urinary incontinence after 12 months post-RARP. Poor agreement between radiologists’ and urologist’s measurements supports standardizing MUL measurements to establish the likelihood of early incontinence.

Adenosine has been described as playing a role in the control of inflammation, but it has not been certain which of its receptors mediate this effect. Here, we generated an A2B adenosine receptor-knockout/reporter gene-knock-in (A2BAR-knockout/reporter gene-knock-in) mouse model and showed receptor gene expression in the vasculature and macrophages, the ablation of which causes low-grade inflammation compared with age-, sex-, and strain-matched control mice. Augmentation of proinflammatory cytokines, such as TNF-alpha, and a consequent downregulation of IkappaB-alpha are the underlying mechanisms for an observed upregulation of adhesion molecules in the vasculature of these A2BAR-null mice. Intriguingly, leukocyte adhesion to the vasculature is significantly increased in the A2BAR-knockout mice. Exposure to an endotoxin results in augmented proinflammatory cytokine levels in A2BAR-null mice compared with control mice. Bone marrow transplantations indicated that bone marrow (and to a lesser extent vascular) A2BARs regulate these processes. Hence, we identify the A2BAR as a new critical regulator of inflammation and vascular adhesion primarily via signals from hematopoietic cells to the vasculature, focusing attention on the receptor as a therapeutic target.

Inadequate patient education and preparation for office-based procedures often leads to delayed care, poor patient satisfaction, and increased costs to the health care system. We developed and deployed a mobile health (mHealth) reminder and education program for patients scheduled for transrectal prostate biopsy. We aimed to evaluate the impact of an mHealth reminder and education program on appointment cancellation rates, communication frequency, and patient satisfaction. We developed a text message (SMS, short message service)-based program with seven reminders containing links to Web-based content and surveys sent over an 18-day period (14 days before through 3 days after prostate biopsy). Messages contained educational content, reminders, and readiness questionnaires. Demographic information, appointment cancellations or change data, and patient/provider communication events were collected for 6 months before and after launching the intervention. Patient satisfaction was evaluated in the postintervention cohort. The preintervention (n=473) and postintervention (n=359) cohorts were composed of men of similar median age and racial/ethnic distribution living a similar distance from clinic. The postintervention cohort had significantly fewer canceled or rescheduled appointments (33.8% vs 21.2%, P<.001) and fewer same-day cancellations (3.8% vs 0.5%, P<.001). There was a significant increase in preprocedural telephone calls (0.6 vs 0.8 calls per patient, P=.02) in the postintervention cohort, but not a detectable change in postprocedural calls. The mean satisfaction with the program was 4.5 out of 5 (SD 0.9). An mHealth periprocedural outreach program significantly lowered appointment cancellation and rescheduling and was associated with high patient satisfaction scores with a slight increase in preprocedural telephone calls. This led to fewer underused procedure appointments and high patient satisfaction.