Removal of dead and damaged cells is critical for organismal health. Under stress conditions such as nutritional deprivation, infection, or temperature shift, the clearance of nonessential cells becomes a universal strategy to conserve energy and maintain tissue homeostasis. Typically, this task is performed by professional phagocytes such as macrophages. However, nonprofessional phagocytes (NPPs) can also adopt a phagocytic fate under specific circumstances. Similar to professional phagocytes, NPPs undergo transitions from immature to mature states and activation, but the precise cellular and molecular mechanisms governing their maturation, induction, and phagocytic execution remain largely unknown. A notable example of stress-induced phagocytosis is the removal of germline cells by follicle cell–derived NPPs during oogenesis in Drosophila . In this study, we report that the transformation of follicle cells (FCs) into NPPs is dependent on Notch signaling activation during mid-oogenesis. Moreover, Notch overactivation is sufficient to trigger germline cell death and clearance (GDAC). We further show that polyploidy, driven by Notch signaling-induced endoreplication, is essential for the transformation of FCs into NPPs. Polyploidy facilitates the activation of JNK signaling, which is crucial for the phagocytic behavior of these cells. Additionally, we show that polyploidy in epidermal cells, another type of NPPs, is important for their engulfment of dendrites during induced degeneration. Together, these findings suggest that polyploidy is a critical factor in the transformation of epithelial cells into NPPs, enabling their phagocytic functions, which are essential for maintaining cellular and organismal homeostasis during stress conditions.

Background: Cribriform pattern 4 (CP4) is an aggressive variant in prostate cancer linked to worse clinical outcomes, including biochemical recurrence, metastases, and prostate cancer-specific mortality. However, its prognostic significance across age groups remains unclear. This study investigates whether the impact of CP4 on progression-free survival (PFS) differs by age in patients undergoing radical prostatectomy (RP). Methods: This retrospective analysis used patient data from the TCGA database, evaluating patients who underwent RP stratified by CP4 status. The primary outcome was PFS, defined as the time from RP to biochemical recurrence, radiographic progression, or death from any cause. Multivariable Fine-Gray competing risk regression analyses assessed the association between CP4 and PFS, adjusting for preoperative prostate-specific antigen (PSA), Gleason score, tumor stage, and surgical margin status. An interaction term between age (dichotomized at 60 years to facilitate clinical interpretation and applicability, approximating the cohort median age of 61 years [interquartile range = 56-66]) and CP4 status was included in the analysis. Results: Of 431 patients, CP4 was present in 134 (31%). In multivariable analysis, CP4 was associated with significantly worse PFS in patients older than 60 years (adjusted hazard ratio [AHR]: 1.99, 95% confidence interval [CI]: 1.01-3.92, P < .001), but not in younger patients (⩽60 years; AHR: 1.00, 95% CI: 0.49-2.04, P = .997). Adjusted 5-year PFS was significantly lower in older CP4-positive patients (50.8%, 95% CI: 33.0%-78.2%) compared with older CP4-negative patients (74.6%, 95% CI: 63.6%-87.6%; P < .001). Conclusion: CP4 strongly predicts reduced PFS in patients above 60 years but not younger patients, suggesting that age may influence the clinical impact of CP4. These findings support age-specific risk stratification in CP4-positive prostate cancer. Prospective studies are needed to validate results and explore tailored treatment strategies based on age.

Background: Prostate cancer is a common malignancy among men worldwide, with various histopathologic features that influence its progression and prognosis. One such feature is perineural invasion (PNI), which has been associated with aggressive disease. In this retrospective study, we analyzed genomic alterations associated with PNI in patients who underwent radical prostatectomy. Methods: A total of 421 prostate cancer patients who underwent radical prostatectomy without neoadjuvant therapy were identified from The Cancer Genome Atlas. PNI was present in 378 patients (89.8%) and absent in 43 (10.2%). Differentially expressed genes were identified, and mRNA expression levels of key genes were analyzed. The prognostic significance of these genes was evaluated using log-rank tests and Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals. Results: Levels of COL9A3, ASPN, ESR1, MUC1, PIP, SFRP4, KRT19, CLDN1, and COMP were significantly higher in the tumor tissues of patients in the PNI group compared to those in the non-PNI group (q < 0.05), and RYR2, MME, and AZGP1 expression levels were significantly higher in the non-PNI group (q < 0.05). A high mRNA expression level of AZGP1 was associated with longer disease-free survival, whereas high mRNA expressions of ASPN, COMP, RYR2, and SFRP4 were associated with shorter disease-free survival. Conclusions: Prostate cancer patients with genomic alterations associated with PNI may face a higher risk of disease progression after prostatectomy, highlighting the need for further prospective studies to validate these findings.

Background/Objectives: Cribriform architecture is an adverse histopathologic feature in prostate cancer and has been associated with poor oncologic outcomes. Emerging evidence suggests that cribriform-positive tumors may behave as a biologically non-localized disease, raising the possibility of early occult dissemination. Lymphovascular invasion (LVI) is a key pathological marker of metastatic potential, but its relationship with cribriform architecture has not been evaluated. We examined the association between cribriform morphology and LVI to provide biological context for the aggressive clinical course of cribriform-positive prostate cancer. Methods: We performed a retrospective analysis of patients with prostate adenocarcinoma who underwent radical prostatectomy and had available clinicopathologic data. Cribriform architecture was determined by a centralized pathology review, and LVI status was obtained from original pathology reports. Unadjusted associations were evaluated using contingency tables. Multivariable logistic regression was used to assess whether cribriform architecture was independently associated with LVI after adjustments for Gleason score, tumor stage, and nodal status. Results: Among 338 patients, 28 (8.3%) had LVI and 123 (36.4%) had cribriform architecture. LVI was more common in cribriform-positive than cribriform-negative tumors (17.9% vs. 2.8%; p < 0.001), corresponding to a crude odds ratio (OR) of 7.6 (95% CI, 3.0–19.3). Cribriform architecture remained independently associated with LVI after adjustment (adjusted OR, 5.20; 95% CI, 2.12–1.40; p < 0.001). Conclusions: Cribriform architecture is strongly and independently associated with LVI, supporting a biological link between cribriform morphology and early metastatic dissemination. These findings support the design of prospective, biomarker-driven studies to evaluate treatment intensification strategies in this high-risk subgroup.

Lymphovascular invasion is an adverse pathologic feature in prostate cancer, but its independent molecular drivers remain unclear due to strong confounding by tumor grade and stage. We performed a confounder-adjusted transcriptomic analysis of 403 TCGA-PRAD samples. Differential expression was adjusted for Gleason score and pathological T stage. A transcriptional profile associated with LVI was derived and tested in multivariable logistic and Cox proportional hazards models for biochemical recurrence-free survival, with bootstrap internal validation. After multivariable adjustment, 129 genes were independently associated with LVI. This gene set was overwhelmingly enriched for interferon-alpha/beta signaling and antiviral response pathways. A continuous composite score derived from this profile predicted a reduced risk of biochemical recurrence independently of standard clinicopathological factors (adjusted HR per unit = 0.911, 95% CI: 0.835–0.993, p = 0.033). Multi-omics integration revealed subtle promoter hypomethylation and strong correlations between methylation and expression for key interferon genes, supporting transcriptional regulation. We identify a robust, interferon-response transcriptional profile that specifically defines LVI in prostate cancer after accounting for major clinical confounders. This transcriptional signature provides independent prognostic information, refines the biological understanding of LVI, and presents a novel targetable pathway for further investigation.