Metastatic Pheochromocytoma and Paraganglioma (MPP) currently lack definitive curative therapies. The treatment of MPP presents a formidable challenge. Anlotinib hydrochloride, characterized as a multi-targeted tyrosine kinase receptor inhibitor, has demonstrated potential in this domain. The principal aim of our study is to scrutinize the efficacy and safety profiles of anlotinib hydrochloride in patients suffering from MPP.

Paragangliomas (PGLs) are rare neuroendocrine tumors that arise from the paraganglionic tissues and are associated with the autonomic nervous system. Although traditionally classified conjointly, head and neck PGLs (HNPGLs) and PGLs located outside the head and neck (PGLOs) exhibit distinct embryological origins, genetic predispositions, functional profiles, clinical behavior, and therapeutic strategies. HNPGLs are typically nonfunctional and arise from parasympathetic tissues, whereas PGLOs often originate from sympathetic tissues, are frequently functional, and secrete catecholamines. Recent advances in molecular genetics, particularly those involving SDHx mutations, have revealed genotype-phenotype correlations that further differentiate these tumor groups. Despite overlapping histopathological features, the natural history, risk of malignancy, and surveillance strategies differ substantially. Although surgical resection remains the mainstay of treatment for both HNPGLs and PGLOs, the indications, risks, and outcomes vary according to tumor location and genetic context. This review aims to provide a comprehensive clinical comparison between HNPGLs and PGLOs, outlining their unique anatomical, genetic, and clinical characteristics. We emphasize the importance of site-specific management strategies that consider both functional status and prognosis. Based on these distinctions, we propose a revised diagnostic and therapeutic framework that surpasses a uniform classification and emphasizes precision medicine for the management of PGLs. This approach could reduce treatment-related morbidity, optimize long-term outcomes, and guide genetic counseling and surveillance in affected individuals and their families.

Locoregional therapies are a standard treatment for neuroendocrine tumors (NET) with predominant liver metastases. The efficacy of transarterial chemoembolization (TACE) using streptozotocin (STZ) has been poorly compared to transarterial embolization (TAE). Predictive biomarkers of TACE efficacy have never been explored. We studied all patients with pancreatic (panNET) or small intestine (siNET) NET and liver metastases treated between 2006 and 2022 using a standardized protocol of TACE-STZ (1,500 mg/m2) or TAE. The primary endpoint was the RECIST1.1-defined objective response rate (ORR). The variables associated with ORR were explored using a propensity score to account for confounding factors. Secondary endpoints included the impact of tumor expression of O6-methylguanine-methyltransferase (MGMT), alkylpurine-DNA-N-glycosylase (APNG), and carbonic anhydrase IX (CAIX), and progression-free survival (PFS). Among 116 patients, 58 received TACE (15 siNET and 43 panNET) and 58 received TAE (42 siNET and 16 panNET). TACE was associated with a higher ORR than TAE (43% vs. 22%, p=0.045), which remained statistically significant on propensity-adjusted multivariable analysis (OR 2.71, 95% CI [1.08-7.17], p=0.038). TACE provided longer PFS than TAE in panNET patients (12.9 vs. 6.4 months, p=0.026), but not in siNET patients (16.1 vs. 15.1 months, p=0.47). Low APNG expression was predictive of higher ORR with TACE (70% vs. 16%, p<0.001), while the expression of MGMT and CAIX had no impact. TACE-STZ provided a higher ORR than TAE, although yielded longer PFS only in patients with panNET. Low tumor expression of APNG might help select the best candidates for TACE-STZ, although this result was only exploratory.

Current guidelines recommend total thyroidectomy for all T3b differentiated thyroid carcinoma (DTC) with gross strap muscle invasion, yet evidence supporting this universal approach remains limited and conflicting.

Neuroendocrine neoplasms (NENs) are rare tumors with increasing incidence. Data on the prognosis of NEN patients in the real-world setting are limited. We aim to explore survival predictors and the impact of novel treatments in a cohort of patients with NENs from various primary sites. This was a retrospective study of subjects diagnosed with gastroenteropancreatic (GEP) or thoracic NENs and referred to a single institution over more than a decade (2010-2023). The primary objective was to describe the overall survival (OS) and progression-free survival (PFS) of patients with advanced-stage disease undergoing first, second, and third-line therapy. The secondary objectives were to identify predictors of OS and PFS. We included 239 NEN patients. Systemic antineoplastic therapies were administered to 149 subjects (62.3%). In patients treated only with first-line therapy, the OS rate was 75 and 74% at 12 and 18 months, respectively. We observed significant univariable associations between Ki-67 index, primary tumor site, morphology, clinical stage, and OS. The multivariable analysis confirmed a significant association between Ki-67 index, clinical stage, and OS. In patients undergoing second-line therapy, the OS rate was 72 and 61% at 12 and 18 months, respectively, and the Ki-67 index was again associated with OS in the multivariable analysis. GEP NEN patients who received 177Lu-Dotatate showed a numerically higher OS rate at 24 months compared to those who did not receive radioligand therapy. In this real-world study of patients with NENs, we confirmed Ki-67 as a strong prognostic parameter and suggested that 177Lu-Dotatate has the potential to prolong OS.

The burgeoning metabolic benefits of GLP1 receptor (GLP1R) agonists have led to their widespread use for treatment of type 2 diabetes mellitus and obesity. While the pharmacological GLP1R agonist semaglutide primarily activates GLP1R signaling in the pancreas, GLP1R is also expressed in advanced prostate cancer where GLP1R agonism could directly alter cellular signaling. Because metabolic disorders and their treatment are common among those with prostate cancer, understanding the effects of semaglutide in prostate cells is critical for deciphering its systemic effects and delineating potential impacts on prostate cancer outcomes. In prostate cancer models, semaglutide decreased cell proliferation, glycolytic function, and phosphokinase-mediated signaling. This overall suppression of signaling downstream of GLP1R is consistent with inhibitory GPCR signaling, which was confirmed by reduced cAMP levels. Furthermore, cell proliferation was decreased with semaglutide alone and in combination with enzalutamide, supporting that GLP1R agonism may provide therapeutic benefit as a standalone treatment or to augment the therapeutic benefits of androgen receptor signaling inhibitors. Interestingly, in a trans-differentiation model (n = 55), GLP1R and AR expression were negatively correlated, while GLP1R and NEPC markers (DLL3, ASCL1) were positively correlated, suggesting an association between GLP1R and neuroendocrine differentiation. Bioinformatic analyses on publicly available patient RNA sequencing data (n = 664) identified significantly higher GLP1R expression in advanced prostate cancer vs benign prostate, where it was associated with negative Notch signaling. Taken together, our data support a model wherein GLP1R agonism blocks oncogenic signaling pathways and growth of prostate cancer cells, which could be exploited therapeutically for men with advanced prostate cancer.

The thyroid differentiation score (TDS), calculated on the expression levels of 16 thyroid function genes, was reported to be lower in BRAF-like than in RAS-like papillary thyroid cancers, but scanty data are available in either other malignant histotypes or in benign thyroid nodules. The aims of the present study were to investigate the clinical relevance of the TDS in a large series of thyroid neoplasms, and its possible role in the differential diagnosis of cytologically indeterminate nodules. The TDS was calculated in 126 differentiated, 20 undifferentiated, 9 non-invasive follicular thyroid neoplasms with papillary-like nuclear features, and 44 benign neoplasms. Overall, TDS significantly and progressively decreased from benign to differentiated and undifferentiated tumors (P < 0.0001). A lower TDS was found in differentiated tumors with higher stage (P = 0.006) and American Thyroid Association (ATA) risk (P = 0.03), radio-iodine resistance (P = 0.008), and disease persistence (P = 0.009). Moreover, TDS independently correlated with progression-free survival, after adjusting for age at diagnosis and ATA risk (P = 0.02). In Bethesda III and IV nodules, the TDS was significantly lower in nodules found to be malignant at histology compared to benign neoplasms (P = 0.004). The combination of TDS with genetic test showed a sensitivity of 78.4%, a specificity of 77.3%, a PPV of 80%, and a NPV of 75.6% (P = 0.001). In conclusion, we found a lower TDS in malignant compared to benign thyroid neoplasms, and demonstrated the prognostic role of TDS in differentiated tumors. These findings could preoperatively improve both the differential diagnosis of cytologically indeterminate nodules and the selection of the best surgical approach.

Follicular thyroid carcinoma (FTC) and oncocytic thyroid carcinoma (OTC) are distinct entities with differing biological behaviors, yet optimal surgical and radioactive iodine (RAI) therapy management remains debated. Demographic, clinicopathological, and treatment characteristics were gathered from the Surveillance, Epidemiology, and End Results (SEER) database and compared between FTC and OTC according to tumor size. The Kaplan-Meier method and log-rank test were used to analyze cancer-specific survival (CSS). The effect of potential predictors associated with survival was estimated using the Cox regression model. 13,653 patients were included in our study. OTC patients were older and presented higher rates of extrathyroidal extension (ETE) and lymph node metastases (LNM), while FTC had higher distant metastasis (DM) rates. Increasing tumor size was correlated with worse features in both subtypes. Total thyroidectomy (TT) had no CSS benefit over less than TT (LTT) for FTC ≤2 cm or any OTC size group. TT was paradoxically associated with worse CSS for FTC >2 cm. RAI therapy did not improve CSS for patients with ETE (FTC or OTC) or DM (OTC). Multivariable analysis confirmed that TT was independently associated with worse CSS in FTC but not in OTC, while RAI therapy was beneficial in FTC but not in OTC. FTC and OTC exhibited distinct clinical behaviors. In conclusion, TT did not improve CSS for small FTC (≤2 cm) or any OTC, and appeared to be associated with worse outcomes in larger FTC. RAI therapy provided limited benefit in OTC, especially with DM. Treatment should be individualized, avoiding routine aggressive surgery or RAI.

Primary cilia have emerged as key regulators in cancer biology, influencing tumor progression and therapeutic response through diverse signaling pathways. In this study, we identify WDR60, a component of the dynein-2 complex essential for retrograde intraflagellar transport, as a novel modulator of pancreatic neuroendocrine tumor (Pa-NET) behavior. Transcriptomic analysis of the GEO dataset GSE73338 revealed that WDR60 is significantly upregulated in both primary and metastatic Pa-NETs compared to normal pancreatic islets. Moreover, WDR60 expression is higher in G2 compared to G1 Pa-NETs. Functional analyses in QGP-1 cells following WDR60 silencing demonstrated broad transcriptional reprogramming with enrichment of pathways related to cell adhesion and extracellular matrix (ECM) remodeling. Notably, WDR60 knockdown reduced cell migration and enhanced adhesion without affecting cell viability or proliferation. Among the key upregulated genes were PIK3AP1, RAP1B, and RFLNA, suggesting that WDR60 is involved in regulating PI3K/AKT signaling and cytoskeletal dynamics. To explore potential therapeutic implications, we examined the effects of Ciliobrevin A (HPI-04), an inhibitor of Hedgehog signaling and ciliogenesis. HPI-04 significantly reduced WDR60 expression, impaired cell migration, and increased adhesion. RT-qPCR confirmed overlapping gene expression changes between HPI-04 treatment and WDR60 silencing, although some differences, such as CD164 regulation, suggest WDR60-independent mechanisms. Collectively, these findings identify WDR60 as a critical regulator of cell motility and adhesion in Pa-NETs via ciliary signaling and cytoskeletal remodeling. They also support the therapeutic potential of targeting cilia-associated pathways, including WDR60 and Hedgehog signaling, in the treatment of Pa-NETs.

Prostate cancer (PC) remains a leading cause of cancer-related mortality in men, with recurrence contributing significantly to poor outcomes. Its molecular heterogeneity complicates effective risk stratification. We evaluated Sig27, a novel 27-gene panel, across 13 bulk RNA-seq datasets (n = 3,133 tumors) and 6 single-cell RNA-seq (scRNA-seq) datasets (n = 53 patients). Sig27 expression was elevated in PC compared to normal tissue and further increased in high-grade Gleason tumors, node-positive, and recurrent tumors. Sig27 demonstrated recurrence prediction comparable to Oncotype DX, with strong enrichment in immune regulatory pathways. To further investigate immune associations, we developed SigIC, a 22-gene immune checkpoint panel. Sig27 showed strong correlations with SigIC and individual immune checkpoints (e.g., HAVCR2, CD96, TIGIT) in both primary and metastatic PC. In scRNA-seq data, Sig27 was enriched in tumor-associated monocytes/macrophages (TAMs) and endothelial cells. We identified five key Sig27 genes - TFEC, FPR3, NOD2, LAMP3, and MCTP1 - and constructed Sig27IMG, a multigene panel formed by these five genes, and demonstrated their robust correlations with immune checkpoints and their strong enrichment in TAMs and endothelial cells. Sig27IMG strongly predicted PC recurrence and was dominantly expressed in TAMs, dendritic cells, and endothelial cells across 26 cancer types (n = 386 patients) in scRNA-seq studies and 17 cancer types (n = 5,672 patients) in bulk RNA-seq investigations. Notably, Sig27IMG stratified patients with a poor prognosis risk in these 17 cancer types. In summary, Sig27 and its derivative panel, Sig27IMG, offer a robust assessment of PC recurrence, highlighting immunosuppressive features mediated by TAMs, dendritic cells, and endothelial cells across multiple cancer types.

Active surveillance (AS) of low-risk papillary thyroid microcarcinoma (PTMC; T1aN0M0) in adults was initiated in 1993 at Kuma Hospital (Kobe, Japan) and in 1995 at the Cancer Institute Hospital (Tokyo, Japan). Since then, numerous studies from various countries have reported favorable outcomes for patients managed with AS. Notably, no cases of thyroid carcinoma-related death have been reported among patients who have undergone AS. Young age has been identified as a predictor of high tumor growth activity; however, previous studies have shown that young adult patients may still be suitable candidates for AS. Although surgery for PTMC is not technically complex, it carries risks, even when performed by experienced thyroid surgeons, including permanent recurrent laryngeal nerve paralysis and hypoparathyroidism. No significant difference in prognosis has been observed between patients managed with AS and those who undergo immediate surgery (IS). Some patients initially on AS later opt for conversion surgery (CS) for various reasons. Importantly, the postoperative prognosis and incidence of unfavorable events in patients undergoing CS do not differ significantly from those in patients undergoing IS. However, the overall incidence of unfavorable events has been reported to be higher among patients who initially chose IS than among those who began with AS. Patients managed with AS have demonstrated better physical quality of life (QOL) than those who underwent IS. Although findings on mental QOL have been inconsistent, this may depend on the attitudes and approach of the attending clinicians. Presently, AS is considered an excellent initial management strategy for patients with PTMC.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but can induce immune-related adverse events, most commonly hypothyroidism. The reversibility of ICI-induced hypothyroidism and the potential for discontinuing levothyroxine (LT4) treatment remain unclear. This retrospective study analyzed patients who developed hypothyroidism due to ICI treatment and were prescribed LT4 at a tertiary referral hospital from January 2016 to March 2024. Among 3,753 patients treated with ICIs, 254 (6.8%) developed hypothyroidism requiring LT4 treatment. Of the 184 patients who discontinued ICI, only 10 (5.4%) discontinued LT4 during a median follow-up of 13.2 months, while none did among those continuing ICIs. Multivariable Cox regression analysis revealed that the use of ICIs in early-stage cancer (HR 13.40, 95% CI: 1.99-90.06, P = 0.008) and TSH <20 μIU/mL before starting LT4 (HR 15.16, 95% CI: 2.17-105.85, P = 0.006) significantly increased the likelihood of discontinuing LT4. These findings suggest that while recovery from ICI-induced hypothyroidism is uncommon, patients treated for early-stage cancer and those with lower TSH levels before starting LT4 may have a greater likelihood of recovery.

Differentiated thyroid carcinoma (DTC) in children and adolescents is a rare but increasingly recognised entity with distinct biological behaviour, clinical presentation, and outcomes compared to adult DTC. While paediatric cases often present with advanced disease, long-term survival is excellent in contrast to adult cases where prognosis declines with age and risk factors. Historically, paediatric management was extrapolated from adult data, but recent guidelines reflect a shift towards age-specific, risk-adapted care. A narrative review was conducted using PubMed (2000-2025), including clinical trials, cohort studies, reviews, and guidelines. We aimed to compare paediatric and adult DTC across epidemiology, clinical presentation, molecular characteristics, treatment strategies, outcomes, and existing guidelines, with the aim of identifying knowledge gaps for future harmonisation. We found that paediatric DTC is characterised by higher rates of multifocal and metastatic disease at diagnosis, distinct molecular drivers (e.g. RET/NTRK fusions), and higher radioiodine avidity. Surgical management is typically more extensive in children, while risk-adapted radioactive iodine therapy is increasingly practised in low-risk paediatric patients. TSH suppression is initially more aggressive, followed by gradual de-escalation. Despite higher recurrence rates in children, survival exceeds 95-98% even with distant metastases. While paediatric-specific guidelines have advanced (ATA 2015, ETA 2022), prospective paediatric data remain limited. We conclude that paediatric DTC is biologically distinct from its adult counterpart and requires tailored management. Coordinated, prospective research is needed to address current evidence gaps and support future harmonised European practice.

Adrenocortical carcinoma (ACC) is a rare and highly aggressive carcinoma with a poor prognosis. The aim of our study is to summarize existing evidence on the potential usefulness of fluorine-18-fluorodeoxyglucose positron/computed tomography (18F-FDG PET/CT) in the management of patients affected with ACC. The current systematic review was registered to the PROSPERO registry (ID1103377). A comprehensive search of the PubMed/MEDLINE, Embase, and Cochrane Library databases was conducted until July 2025. A total of 19 studies that evaluated the role of 18F-FDG PET/CT in ACC were included. One of the fields investigated was the ability of PET/CT to discriminate between adrenal masses, particularly in the differential diagnosis between benign and malignant lesions. 18F-FDG PET/CT demonstrated good sensitivity and specificity but was affected by different cutoff values of SUV and SUV ratio applied. In addition, in the staging/restaging, despite heterogeneity of data, diagnostic performances were good and higher than conventional imaging tools. Moreover, PET/CT modified patient management in 9-21% of cases. The prognostic role of 18F-FDG PET/CT remains controversial, with seven studies reporting heterogeneous findings and different endpoints investigated, primarily OS and PFS. Semiquantitative parameters such as SUVmax and SUV ratio were analyzed, but their prognostic impact was inconsistent. Despite several limitations affecting this analysis, especially related to the heterogeneity of the studies included, 18F-FDG PET/CT seems to be a useful tool for the evaluation of ACC, especially in the differential diagnosis of adrenal masses and in the staging/restaging. Instead, the prognostic impact of PET/CT and its features remains inconclusive.

The CUT/Hox transcription factor ONECUT2 (OC2) promotes lineage plasticity and is a confirmed therapeutic target in prostate cancer and several other malignancies where cell phenotype plays a substantial role in treatment resistance. OC2 governs a broad growth and lineage identity process in prostate cancer that promotes neuroendocrine (NE) differentiation, androgen receptor (AR) suppression, and the emergence of a wide range of treatment-resistant pathways. The mode of action of OC2 includes incorporation of the protein into transcription complexes at gene promoters as an activator and repressor, alteration of chromatin accessibility and epigenetic marks, and extensive alteration of large-scale chromatin modifications, such as super-enhancers and chromatin loops. Notably, OC2 may be unique among NE drivers in that it can promote AR indifference in adenocarcinoma as a direct upstream activator of the glucocorticoid receptor, thus assuming indirect control of a portion of the AR cistrome. OC2 expression and activity increase substantially following hormone therapy in association with aggressive disease in prostate and breast cancer. Experiments in model systems have shown that OC2 has a survival function in both human castration-sensitive and castration-resistant prostate cancer cells. OC2 can be targeted directly with a family of novel small-molecule inhibitors that show therapeutic efficacy in vivo in prostate, breast, and gastric cancer models, including regression of established distant metastases in mice. These findings suggest that inhibition of OC2 clinically may confer substantial therapeutic benefit in some aggressive malignancies, including in localized hormone-sensitive disease.

Malignant pleural effusion (MPE) from differentiated thyroid cancer (DTC) is rare and carries a poor prognosis. This study evaluated clinical outcomes and the impact of multikinase inhibitor (MKI) therapy in patients with MPE from DTC. In this retrospective cohort study of 184 DTC patients with lung metastases, 31 (17%) had MPE. After excluding 10 with non-malignant effusion, 174 were analyzed. Patients with MPE were older (P < 0.001) at DTC diagnosis, had higher T stage (P = 0.004), developed pleural metastases earlier (P = 0.016), and had more frequent macro- and polymetastatic lung lesions (P < 0.001) than those without MPE. All MPE cases were radioactive iodine-refractory and developed a median of 6.3 years after DTC diagnosis. Symptomatic MPE occurred in 22 patients (71%), all requiring drainage, while 9 (29%) had asymptomatic MPE. Symptomatic MPE was associated with worse overall survival (OS) compared to patients without MPE (adjusted hazard ratio (HR) 4.62, 95% confidence interval (CI) 2.49-8.57, P < 0.001). Notably, patients initiating MKI therapy for symptomatic MPE had the worst OS (adjusted HR 9.78, 95% CI: 3.52-27.13, P < 0.001). Median OS after MPE diagnosis was 13 months. Symptomatic MPE also had worse post-MPE survival compared to asymptomatic MPE (adjusted HR 5.73, 95% CI: 1.52-21.52, P = 0.009). MKI therapy did not significantly improve OS or progression-free survival after MPE onset. MPE in DTC patients with lung metastases indicates poor prognosis, especially when symptomatic. MKI therapy showed limited survival benefits after MPE onset. Early identification and proactive management of patients at high risk of MPE may improve outcomes.

Radiotherapy is a mainstay treatment for localized prostate cancer (PCa). Yet, radiation resistance remains a major clinical obstacle. Here, radiation induced a BMP/CD105-dependent metabolic shift in the tumor microenvironment that facilitates PCa cell survival. Using prostate tumor models and fibroblast cultures, we show that radiation enhances epithelial BMP ligand production which promotes fibroblastic CD105 signaling. Metabolomic analysis upon radiation revealed that fibroblastic CD105 signaling elevated key enzymes involved in mitochondrial biogenesis (PGC1α) and ketogenesis (HMGCS2). The increased production of β-hydroxybutyrate in the tumor microenvironment sustained PCa cell energy metabolism and enhanced DNA repair upon radiation stress. Blocking BMP signaling through carotuximab (ENV105), a CD105-targeting antibody, disrupted epithelial-fibroblast crosstalk, resulting in decreased β-hydroxybutyrate within the tumor microenvironment. This attenuation of fibroblast-mediated metabolic support increased DNA damage and apoptosis, sensitizing PCa cells to radiation. In subcutaneous mouse models, grafting PCa cells with CD105-KO or HMGCS2-KO fibroblasts yielded smaller tumors following radiation compared with wild-type fibroblast controls. Across subcutaneous and orthotopic models, combined treatment with carotuximab and irradiation reproducibly achieved superior tumor volume reduction relative to single-agent therapy. This study identified the BMP/CD105 axis as a key pathway in radiation resistance, highlighting the potential of targeting fibroblastic CD105 with carotuximab to enhance radiation sensitivity.

Epitransciptomic marks, such as N6-methyladenosine (m6A) within RNA transcripts, have been implicated in multiple pro-tumorigenic activities. These modifications are controlled by writers, readers, and erasers, including the METTL3 m6A-methyltransferase. Recently, changes in expression or activity of epitranscriptomic enzymes have been shown to modulate metabolic pathways in multiple tumor types, including within endocrine-sensitive and -resistant estrogen receptor-positive (ERα+) breast cancer (ER+BC) cells. Yet, a broad analysis of metabolic alterations, specifically with respect to METTL3 inhibition, has not been explored in these BC subtypes. Herein, we investigated the magnitude of pharmacological targeting of METTL3 (STM2457) on overall cellular metabolism in endocrine-sensitive (MCF-7 and ZR-75-1) and -resistant (LCC9 and ZR-75-1-4-OHT) ER+BC cells. We found that STM2457 selectively decreased glycolytic activity in resistant cells and led to altered hexokinase 2 expression in LCC9 cells. STM2457 suppressed mitochondrial activity, while isotope tracing found diminished TCA glucose oxidation in MCF-7 and LCC9 cell lines. This was accompanied by increased glutamine uptake and glutaminolysis, which was more pronounced in the endocrine resistant LCC9 cells. We also observed differential expression of glutaminase 1 (GLS1) splice variants in the MCF-7 cells and an increase in the ASCT2 glutamine transporter. To determine combinatorial targeting potential, we co-treated cells with STM2457 and CB-839, which is a GLS1 inhibitor. CB-839 increased the potency of STM2457 only in the LCC9 and ZR-75-1-4-OHT endocrine-resistant cells. Our collective findings suggest that METTL3 inhibition leads to selective glycolytic and oxidative metabolic changes between these endocrine-sensitive and resistant BC cells that can be exploited for combinatorial therapy.

DCC protein functions as a tumor suppressor and is altered in various tumors, including neuroendocrine neoplasms. Netrin (NTN)-1 serves as the primary ligand for DCC. Acting as a dependence receptor, DCC induces apoptosis in the absence of NTN and promotes cell survival when NTN is present. In certain cancers, such as small-cell lung cancer and neuroblastoma, the upregulation of NTN-3 has been observed instead of NTN-1. However, the exact role of NTNs and DCC in PNEN remains unclear. We assessed DCC and netrin expression in pancreatic neuroendocrine neoplasm (PNEN) cells (BON-1). We examined the effect of netrin on cell viability using DCC knockdown and NP137, a netrin-inhibiting antibody. In vivo, PNEN cells were injected into nude mice and treated with NP137 or PBS. Tumor RNA sequencing was performed. A population-based analysis using TCGA data evaluated the impact of DCC and NTN3 expression on survival. BON-1 cells exhibited elevated expression of DCC and NTN-3. The addition of NTN-1 augmented BON-1 viability, a response that was lessened upon NTN blockade using NP137. Furthermore, DCC siRNA negated the effect of NTN-1 on cell viability. Mice bearing PNEN BON-1 xenografts treated with NP137 exhibited markedly diminished xenograft growth. RNA sequencing revealed upregulation of small nucleolar RNAs (SNORs) in NP137-treated tumors, with enriched pathways related to RNA processing. TCGA analysis showed a negative correlation between NTN3 expression and survival. In conclusion, our data suggest that NTN-3, NTN-1, and DCC have interdependent oncogenic roles in PNENs, which can be reversed by blocking NTN binding to DCC.

Neuroendocrine neoplasms (NENs) originate mainly in the digestive system and lungs and are classified as neuroendocrine carcinomas (NECs) or neuroendocrine tumors (NETs). Breast metastases from NENs are rare, accounting for only 1% of breast neoplasms, but may be more frequent than expected. This study aimed to characterize patients with breast metastatic NENs through a literature review.