The estrogen signaling pathway reprograms prostate cancer cell metabolism and supports proliferation and disease progression.

Just like the androgen receptor (AR), the estrogen receptor α (ERα) is expressed in the prostate and is thought to influence prostate cancer (PCa) biology. Yet the incomplete understanding of ERα functions in PCa hinders our ability to fully comprehend its clinical relevance and restricts the repurposing of estrogen-targeted therapies for the treatment of this disease. Using 2 human PCa tissue microarray cohorts, we first demonstrate that nuclear ERα expression was heterogeneous among patients, being detected in only half of the tumors. Positive nuclear ERα levels were correlated with disease recurrence, progression to metastatic PCa, and patient survival. Using in vitro and in vivo models of the normal prostate and PCa, bulk and single-cell RNA-Seq analyses revealed that estrogens partially mimicked the androgen transcriptional response and activated specific biological pathways linked to proliferation and metabolism. Bioenergetic flux assays and metabolomics confirmed the regulation of cancer metabolism by estrogens, supporting proliferation. Using cancer cell lines and patient-derived organoids, selective estrogen receptor modulators, a pure anti-estrogen, and genetic approaches impaired cancer cell proliferation and growth in an ERα-dependent manner. Overall, our study revealed that, when expressed, ERα functionally reprogrammed PCa metabolism, was associated with disease progression, and could be targeted for therapeutic purposes.

Isocitrate dehydrogenase 1 sustains a hybrid cytoplasmic-mitochondrial tricarboxylic acid cycle that can be targeted for therapeutic purposes in prostate cancer.

The androgen receptor (AR) is an established orchestrator of cell metabolism in prostate cancer (PCa), notably by inducing an oxidative mitochondrial program. Intriguingly, AR regulates cytoplasmic isocitrate dehydrogenase 1 (IDH1), but not its mitochondrial counterparts IDH2 and IDH3. Here, we aimed to understand the functional role of IDH1 in PCa. Mouse models, in vitro human PCa cell lines, and human patient-derived organoids (PDOs) were used to study the expression and activity of IDH enzymes in the normal prostate and PCa. Genetic and pharmacological inhibition of IDH1 was then combined with extracellular flux analyses and gas chromatography-mass spectrometry for metabolomic analyses and cancer cell proliferation in vitro and in vivo. In PCa cells, more than 90% of the total IDH activity is mediated through IDH1 rather than its mitochondrial counterparts. This profile seems to originate from the specialized prostate metabolic program, as observed using mouse prostate and PDOs. Pharmacological and genetic inhibition of IDH1 impaired mitochondrial respiration, suggesting that this cytoplasmic enzyme contributes to the mitochondrial tricarboxylic acid cycle (TCA) in PCa. Mass spectrometry-based metabolomics confirmed this hypothesis, showing that inhibition of IDH1 impairs carbon flux into the TCA cycle. Consequently, inhibition of IDH1 decreased PCa cell proliferation in vitro and in vivo. These results demonstrate that PCa cells have a hybrid cytoplasmic-mitochondrial TCA cycle that depends on IDH1. This metabolic enzyme represents a metabolic vulnerability of PCa cells and a potential new therapeutic target.

Comparison of Micro-US and Multiparametric MRI for Prostate Cancer Detection in Biopsy-Naive Men.

Background Multiparametric MRI has led to increased detection of clinically significant prostate cancer (csPCa). Micro-US is being investigated for csPCa detection. Purpose To compare multiparametric MRI and micro-US in detecting csPCa (grade group ≥2) and to determine the proportion of MRI nodules visible at micro-US for real-time targeted biopsy. Materials and methods This prospective, single-center trial enrolled biopsy-naive men with suspected prostate cancer (PCa) between May 2019 and September 2020. All patients underwent multiparametric MRI followed by micro-US; findings at both were interpreted in a blinded fashion, followed by targeted biopsy and nontargeted systematic biopsy using micro-US. Proportions were compared using the exact McNemar test. The differences in proportions were calculated. Results Ninety-four men (median age, 61 years; IQR, 57-68 years) were included. MRI- and micro-US-targeted biopsy depicted csPCa in 37 (39%) and 33 (35%) of the 94 men, respectively (P = .22); clinically insignificant PCa in 14 (15%) and 15 (16%) (P > .99); and cribriform and/or intraductal PCa in 14 (15%) and 13 (14%) (P > .99). The MRI- plus micro-US-targeted biopsy pathway depicted csPCa in 38 of the 94 (40%) men. The addition of nontargeted systematic biopsy to MRI- plus micro-US-targeted biopsy did not enable identification of any additional men with csPCa but did help identify nine additional men with clinically insignificant PCa (P = .04). Biopsy was avoided in 32 of the 94 men (34%) with MRI and nine of the 94 men (10%) with micro-US (P < .001). Among 93 MRI targets, 62 (67%) were prospectively visible at micro-US. Conclusion MRI and micro-US showed similar rates of prostate cancer detection, but more biopsies were avoided with the MRI pathway than with micro-US, with no benefit of adding nontargeted systematic biopsy to the MRI- plus micro-US-targeted biopsy pathway. Most MRI lesions were prospectively visible at micro-US, allowing real-time targeted biopsy. ClinicalTrials.gov registration no.: NCT03938376 © RSNA, 2022 Online supplemental material is available for this article.

Multiple metabolic pathways fuel the truncated tricarboxylic acid cycle of the prostate to sustain constant citrate production and secretion.

OBJECTIVE: The prostate is metabolically unique: it produces high levels of citrate for secretion via a truncated tricarboxylic acid (TCA) cycle to maintain male fertility. In prostate cancer (PCa), this phenotype is reprogrammed, making it an interesting therapeutic target. However, how the truncated prostate TCA cycle works is still not completely understood. METHODS: We optimized targeted metabolomics in mouse and human organoid models in ex vivo primary culture. We then used stable isotope tracer analyses to identify the pathways that fuel citrate synthesis. RESULTS: First, mouse and human organoids were shown to recapitulate the unique citrate-secretory program of the prostate, thus representing a novel model that reproduces this unusual metabolic profile. Using stable isotope tracer analysis, several key nutrients were shown to allow the completion of the prostate TCA cycle, revealing a much more complex metabolic profile than originally anticipated. Indeed, along with the known pathway of aspartate replenishing oxaloacetate, glutamine was shown to fuel citrate synthesis through both glutaminolysis and reductive carboxylation in a GLS1-dependent manner. In human organoids, aspartate entered the TCA cycle at the malate entry point, upstream of oxaloacetate. Our results demonstrate that the citrate-secretory phenotype of prostate organoids is supported by the known aspartate-oxaloacetate-citrate pathway, but also by at least three additional pathways: glutaminolysis, reductive carboxylation, and aspartate-malate conversion. CONCLUSIONS: Our results add a significant new dimension to the prostate citrate-secretory phenotype, with at least four distinct pathways being involved in citrate synthesis. Better understanding this distinctive citrate metabolic program will have applications in both male fertility as well as in the development of novel targeted anti-metabolic therapies for PCa.

Gleason grade 5 prostate cancer: sub-patterns and prognosis.

Since the conception of the Gleason grading system, several modifications have been made, including the definition of Gleason pattern 5 (GP5) and its reporting in biopsies and prostatectomy specimens. This includes the addition of a few GP5 sub-patterns over time such as single file, solid cylinders and pseudorosetting. Comedonecrosis was also adopted as a GP5 pattern, but in 2014 the International Society of Urological Pathology (ISUP) excluded intraductal carcinoma with comedonecrosis from the GP5 sub-patterns, although the vast majority of cases with comedonecrosis actually represent intraductal carcinoma. The 2019 conference on prostate cancer grading re-adopted comedonecrosis as GP5, also if found in intraductal carcinoma. It is well-established that presence of GP5 conveys an unfavourable prognosis for the patient with regards to risk of lymph node and distant metastasis as well as death of disease. However, there is a paucity of data on the prognostic impact of individual GP5 sub-patterns. In biopsies the frequency of diagnosis of GP5 is about 1-5% in most published series and the most common GP5 sub-pattern is single files and single cells. In an institutional biopsy review study we noted an increase in GP5 diagnosis over time which could not be attributed to the adoption of new GP5 sub-patterns or to overdiagnosis, but might be associated with changing biopsy indications. Further studies on the prognostic impact of GP5 sub-patterns and their molecular genetic profile are indicated.

Cystic clear cell papillary renal cell carcinoma: is it related to multilocular clear cell cystic neoplasm of low malignant potential?

AIMS: We report the morphological spectrum of nine cystic clear cell papillary renal cell carcinomas (CCP-RCC). METHODS AND RESULTS: Mean tumour size was 2.1 cm and the stage was pT1a in all cases. The original diagnosis was multilocular clear cell cystic renal neoplasm of low malignant potential (MCCN-LMP) in five and CCP-RCC in four patients. All examples were composed of variably sized cysts lined by one layer of clear cells. Two tumours were exclusively cystic, seven showed tubular formation in the septae and five in which the tubular growth was compact and pseudo-solid. Two tumours had foci of nests and single cells showing similarities to the cellular areas of MCCN-LMP. The tubular/pseudo-solid/nested/single-cells foci formed microscopic nodules with a mean size of 1.8 mm. Three tumours had intracystic micropapillary formation. Cells were of International Society of Urological Pathology (ISUP) grades 1-2/4. In all cases, the neoplastic nuclei were aligned away from the basement membranes at least focally. Tumours were positive for paired box gene 8 (PAX8), carbonic anhydrase IX (CAIX), cytokeratin (CK)7 and CK34BE12 and negative for CD10. CONCLUSIONS: Cystic CCP-RCC is a pattern that should be recognized, as it shows overlapping morphological features with both multilocular cyst and MCCN-LMP. This series raises the question of whether some reported MCCN-LMPs are actually cystic CCP-RCC.

Axillary metastasis from an occult tubal serous carcinoma in a patient with ipsilateral breast carcinoma: a potential diagnostic pitfall.

Axillary nodal metastasis from a nonmammary neoplasia is much rarer than diseases associated with a primary breast carcinoma. However, this has to be considered in the differential diagnosis of nodal disease in patients with a history of breast cancer. Here, we report the case of a 73-year-old female with a past medical history of breast cancer, presenting with an ipsilateral axillary metastatic carcinoma. The immunohistochemical profile of the metastatic lesion was consistent with a high grade serous carcinoma. After undergoing a total abdominal hysterectomy and salpingo-oophorectomy, thorough pathological examination revealed two microscopic foci of serous carcinoma in the right fallopian tube, not detectable by preoperative magnetic resonance imaging. In this context, the poorly differentiated appearance of the metastatic tumor and positive staining for estrogen receptor, might lead to a misdiagnosis of metastatic breast carcinoma. As the therapeutic implications differ, it is important for the pathologist to critically assess axillary lymph node metastases, even in patients with a past history of ipsilateral breast carcinoma and no other known primary tumors.