ETS-related gene (ERG) undermines genome stability in mouse prostate progenitors via Gsk3β dependent Nkx3.1 degradation

Lorenzoni, Marco; Felice, Dario De; Beccaceci, Giulia; Donato, Giorgia Di; Foletto, Veronica; Genovesi, Sacha; Bertossi, Arianna; Cambuli, Francesco; Lorenzin, Francesca; Savino, Aurora; Avalle, Lidia; Cimadamore, Alessia; Montironi, Rodolfo; Weber, Veronica; Carbone, Francesco Giuseppe; Barbareschi, Mattia; Demichelis, Francesca; Romanel, Alessandro; Poli, Valeria; Sal, Giannino Del; Julio, Marianna Kruithof-de; Gaspari, Marco; Alaimo, Alessandro; Lunardi, Andrea

doi:10.1016/j.canlet.2022.215612

Cited by 8 publications

(10 citation statements)

References 88 publications

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“… 32 , 33 Concerning PCa, one work has found increased levels (over 18-fold) of SEMA7A following the overexpression of ERG in mouse prostate organoids. 34 Based on this evidence, SEMA7A seems to have a role in establishing the microenvironment of premalignant, ERG-positive prostate lesions. Nevertheless, no experimental evidence relative to its expression or its potential role in PCa development has been reported.…”

Section: Resultsmentioning

confidence: 87%

“…Since the T-cell response plays a critical role in anticancer surveillance, this might suggest an involvement of this protein in preventing cancer development. Nevertheless, in other tumors, this protein was involved in promoting migration, invasion, and angiogenesis; in fact, some studies showed that elevated levels of SEMA7A are associated with the progression of breast cancer. , Concerning PCa, one work has found increased levels (over 18-fold) of SEMA7A following the overexpression of ERG in mouse prostate organoids . Based on this evidence, SEMA7A seems to have a role in establishing the microenvironment of premalignant, ERG-positive prostate lesions.…”

Section: Resultsmentioning

confidence: 98%

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Data-Independent Acquisition Mass Spectrometry of EPS-Urine Coupled to Machine Learning: A Predictive Model for Prostate Cancer

et al. 2023

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Prostate cancer (PCa) is annually the most frequently diagnosed cancer in the male population. To date, the diagnostic path for PCa detection includes the dosage of serum prostate-specific antigen (PSA) and the digital rectal exam (DRE). However, PSA-based screening has insufficient specificity and sensitivity; besides, it cannot discriminate between the aggressive and indolent types of PCa. For this reason, the improvement of new clinical approaches and the discovery of new biomarkers are necessary. In this work, expressed prostatic secretion (EPS)-urine samples from PCa patients and benign prostatic hyperplasia (BPH) patients were analyzed with the aim of detecting differentially expressed proteins between the two analyzed groups. To map the urinary proteome, EPS-urine samples were analyzed by data-independent acquisition (DIA), a high-sensitivity method particularly suitable for detecting proteins at low abundance. Overall, in our analysis, 2615 proteins were identified in 133 EPS-urine specimens obtaining the highest proteomic coverage for this type of sample; of these 2615 proteins, 1670 were consistently identified across the entire data set. The matrix containing the quantified proteins in each patient was integrated with clinical parameters such as the PSA level and gland size, and the complete matrix was analyzed by machine learning algorithms (by exploiting 90% of samples for training/testing using a 10-fold cross-validation approach, and 10% of samples for validation). The best predictive model was based on the following components: semaphorin-7A (sema7A), secreted protein acidic and rich in cysteine (SPARC), FT ratio, and prostate gland size. The classifier could predict disease conditions (BPH, PCa) correctly in 83% of samples in the validation set. Data are available via ProteomeXchange with the identifier PXD035942.

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Section: Resultsmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 98%

Data-Independent Acquisition Mass Spectrometry of EPS-Urine Coupled to Machine Learning: A Predictive Model for Prostate Cancer

et al. 2023

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“…The replacement of the standard B-27 supplement (hereafter B-27) with the vitamin A-free formulation (hereafter B-27 zero ) resulted in the loss of the small percentage of large hollow mPrOs, leaving only compact spheroids in culture (Figure 1D). Conversely, administration of B-27 zero complemented with concentrations between 6 and 16 nM of all-trans retinoic acid (ATRA) (hereafter B-27 plus or ENRAD A ) significantly boosted RA signaling (as demonstrated by activation of well-characterized target genes as Aldh1a1 and Rarb ) and enhanced the formation of mPrOs (Figure 1D-E, G-H and Supplementary Figure S1B-D) characterized by juxtaposed basal (Krt5) and luminal (Krt8) cells surrounding a well-defined expanded lumen ( 18 , 19 ) (Figure 1F). We observed proper polarization of luminal cells and epithelial barrier integrity, as visualized by immunostaining for apical ( e.g ., Zo1 and 3) and junctional markers ( e.g ., Cld4 and 7) ( 30 ) (Figure 1F).…”

Section: Resultsmentioning

confidence: 99%

“…The crucial role of endocrine and paracrine signals in prostate organogenesis is wellrecognized. However, limited evidence connects specific signaling pathways with prostate epithelium differentiation and homeostasis (17)(18)(19). In 1993, Pierre Chambon described Rargnull males as sterile due to squamous, instead of secretory, differentiation of the prostate epithelium and seminal vesicles (20), thus suggesting a critical function of retinoic signaling in 4 the establishment of the luminal compartment of mouse prostate.…”

Section: Introductionmentioning

confidence: 99%

Rarγ -Foxa1 signaling promotes luminal identity in prostate progenitors and is disrupted in prostate cancer

Felice,

Alaimo,

Bressan

et al. 2024

Preprint

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Retinoic acid (RA) signaling is a master regulator of vertebrate development with crucial roles in directing body axis orientation and tissue differentiation, including in the reproductive system. However, a mechanistic understanding of how RA signaling promotes cell lineage identity in different tissues is often missing. Here, leveraging prostate organoid technology, we demonstrated that RA signaling orchestrates the commitment of adult mouse prostate progenitors to glandular identity, epithelial barrier integrity, and ultimately, proper specification of the prostatic lumen. Mechanistically, RA-dependent RARγ activation promotes the expression of the pioneer factor Foxa1, which synergizes with the androgen pathway for proper luminal expansion, cytoarchitecture and function. FOXA1 nucleotide variants are common in human prostate and breast cancers and considered driver mutations, though their pathogenic mechanism is incompletely understood. Combining functional genetics experiments with structural modeling of FOXA1 folding and chromatin binding analyses, we discovered that FOXA1F254E255 is a loss-of-function mutation leading to compromised transcriptional function and lack of luminal fate commitment of prostate progenitors. Overall, we define RA as a crucial instructive signal for glandular identity in adult prostate progenitors. We propose deregulation of vitamin A metabolism as a risk factor for benign and malignant prostate disease, and identified cancer associated FOXA1 indels affecting residue F254 as loss-of-function mutations promoting dedifferentiation of adult prostate progenitors.

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“…RT-qPCR and end-point PCR amplification were carried out as described in ref. (Lorenzoni et al, 2022 ). Analyses were performed with at least three independent biological replicates unless stated in the figure legend, and results were normalized to GAPDH mRNA levels.…”

Section: Methodsmentioning

confidence: 99%

Sterile inflammation via TRPM8 RNA-dependent TLR3-NF-kB/IRF3 activation promotes antitumor immunity in prostate cancer

Alaimo,

Genovesi,

Annesi

et al. 2024

EMBO J

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Inflammation is a common condition of prostate tissue, whose impact on carcinogenesis is highly debated. Microbial colonization is a well-documented cause of a small percentage of prostatitis cases, but it remains unclear what underlies the majority of sterile inflammation reported. Here, androgen- independent fluctuations of PSA expression in prostate cells have lead us to identify a prominent function of the Transient Receptor Potential Cation Channel Subfamily M Member 8 (TRPM8) gene in sterile inflammation. Prostate cells secret TRPM8 RNA into extracellular vesicles (EVs), which primes TLR3/NF-kB-mediated inflammatory signaling after EV endocytosis by epithelial cancer cells. Furthermore, prostate cancer xenografts expressing a translation-defective form of TRPM8 RNA contain less collagen type I in the extracellular matrix, significantly more infiltrating NK cells, and larger necrotic areas as compared to control xenografts. These findings imply sustained, androgen-independent expression of TRPM8 constitutes as a promoter of anticancer innate immunity, which may constitute a clinically relevant condition affecting prostate cancer prognosis.

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ETS-related gene (ERG) undermines genome stability in mouse prostate progenitors via Gsk3β dependent Nkx3.1 degradation

Cited by 8 publications

References 88 publications

Data-Independent Acquisition Mass Spectrometry of EPS-Urine Coupled to Machine Learning: A Predictive Model for Prostate Cancer

Data-Independent Acquisition Mass Spectrometry of EPS-Urine Coupled to Machine Learning: A Predictive Model for Prostate Cancer

Rarγ -Foxa1 signaling promotes luminal identity in prostate progenitors and is disrupted in prostate cancer

Sterile inflammation via TRPM8 RNA-dependent TLR3-NF-kB/IRF3 activation promotes antitumor immunity in prostate cancer

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