Precise control of morphogen signaling levels is essential for proper development. An outstanding question is: what mechanisms ensure proper morphogen activity and correct cellular responses? Previous work has identified Semaphorin (SEMA) receptors, Neuropilins (NRPs) and Plexins (PLXNs), as positive regulators of the Hedgehog (HH) signaling pathway. Here, we provide evidence that NRPs and PLXNs antagonize Wnt signaling in both fibroblasts and epithelial cells. Further, Nrp1/2 deletion in fibroblasts results in elevated baseline Wnt pathway activity and increased maximal responses to Wnt stimulation. Notably, and in contrast to HH signaling, SEMA receptor-mediated Wnt antagonism is independent of primary cilia. Mechanistically, PLXNs and NRPs act downstream of Dishevelled (DVL) to destabilize β-catenin (CTNNB1) in a proteosome-dependent manner. Further, NRPs, but not PLXNs, act in a GSK3β/CK1-dependent fashion to antagonize Wnt signaling, suggesting distinct repressive mechanisms for these SEMA receptors. Overall, this study identifies SEMA receptors as novel Wnt pathway antagonists that may also play larger roles integrating signals from multiple inputs.

Postchemotherapy postpubertal-type yolk sac tumors (YST) with glandular and solid phenotypes are aggressive and commonly resistant to systemic chemotherapy. These neoplasms show morphologic features that significantly overlap with those of somatic carcinomas with \"enteroblastic\" or \"fetal\" phenotype (the preferred terminology depends on the site of origin). They often present as late or very late recurrences, and their diagnosis is challenging because they frequently affect patients in an age group at risk for carcinomas of somatic origin. Recently, we incidentally identified examples of postchemotherapy glandular and solid YST with \"enteroblastic\" phenotypes and nuclear expression of beta-catenin, prompting us to further evaluate the prevalence of this phenomenon. We found nuclear expression of beta-catenin in 10 (29%) of 34 such tumors. A subset of cases with nuclear beta-catenin expression was further analyzed with a DNA sequencing panel (n = 6) and fluorescence in situ hybridization for isochromosome 12p [i(12p); n = 5]. Sequencing identified exon 3 CTNNB1 variants in 3 (50%) of 6 analyzed cases, and fluorescence in situ hybridization was positive for i(12p) in 5 of 5 cases. In conclusion, a significant subset of postchemotherapy YST with glandular or solid architecture and \"enteroblastic\" phenotype demonstrates beta-catenin alterations, suggesting that activation of Wnt signaling may play a role in the progression of these neoplasms. Moreover, nuclear beta-catenin expression in these tumors represents a potential diagnostic pitfall given that carcinomas of true somatic origin with overlapping morphology may also be positive for this marker.

Desmoid tumors are locally aggressive, benign neoplasms originating in connective tissues. Although the exact pathophysiology remains unknown, antecedent trauma or surgery are believed to be important contributing factors. The occurrence of paraspinal desmoid tumor in pediatric patients is extremely uncommon. Here, we present an exceedingly rare case of a pediatric patient with no surgical or family history who developed a paraspinal desmoid tumor. A 9-year-old female patient presented with 4 months of progressive back pain, right lower extremity weakness, and numbness. Spinal imaging revealed a left epidural paraspinal mass compressing her thoracic spinal cord and extending into the left thoracic cavity. A multidisciplinary approach with neurosurgery and thoracic surgery enabled gross total resection of the lesion. The patient had complete resolution of her symptoms with no signs of residual tumor on postoperative imaging. Pathology revealed a desmoid tumor that avidly stained for beta-catenin. On her last follow-up, she developed a recurrence, to which she was started on sorafenib therapy. Desmoid tumors are rare connective tissue neoplasms that often occur after local tissue trauma, such as that caused by surgery. This report presents a rare case of a pediatric paraspinal desmoid tumor that occurred in a patient with no surgical or family history. Such tumors should undergo surgical resection for symptomatic relief and tissue diagnosis. Close clinical and radiographic surveillance are essential in these patients due to the high recurrence rates of desmoid tumor.

Mutations in the gene for β-catenin cause liver cancer cells to release fewer exosomes, which reduces the number of immune cells infiltrating the tumor.

The reprogramming of glutamine metabolism is a key event in cancer more generally and in hepatocellular carcinoma (HCC) in particular. Glutamine consumption supplies tumours with ATP and metabolites through anaplerosis of the tricarboxylic acid cycle, while glutamine production can be enhanced by the overexpression of glutamine synthetase. In HCC, increased glutamine production is driven by activating mutations in the CTNNB1 gene encoding β-catenin. Increased glutamine synthesis or utilisation impacts tumour epigenetics, oxidative stress, autophagy, immunity and associated pathways, such as the mTOR (mammalian target of rapamycin) pathway. In this review, we will discuss studies which emphasise the pro-tumoral or tumour-suppressive effect of glutamine overproduction. It is clear that more comprehensive studies are needed as a foundation from which to develop suitable therapies targeting glutamine metabolic pathways, depending on the predicted pro- or anti-tumour role of dysregulated glutamine metabolism in distinct genetic contexts.

Most cases of desmoid-type fibromatosis (DTF) exhibit a mutation in APC or CTNNB1. We report a case of mesenteric DTF in which no mutation in APC or CTNNB1 was found, but a germline variant of uncertain significance (VUS) in RAD51C and a subclonal mutation in MYST3 were identified. Whether these genetic changes are important in DTF in this case, or whether genetically conventional DTF cells were present at a density below detection is unknown; it will be of interest to see results in further studies of wild-type APC/CTNNB1 cases.

UNASSIGNED: Platinum-based chemotherapy regimens are a mainstay in the management of ovarian cancer (OC), but emergence of chemoresistance poses a significant clinical challenge. The persistence of ovarian cancer stem cells (OCSCs) at the end of primary treatment contributes to disease recurrence. Here, we hypothesized that the extracellular matrix protects CSCs during chemotherapy and supports their tumorigenic functions by activating integrin-linked kinase (ILK), a key enzyme in drug resistance.
UNASSIGNED: TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models.
UNASSIGNED: In response to increased fibronectin (FN) secretion and integrin β1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and showed a strong correlation with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/β-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice.
UNASSIGNED: This \"outside-in\" signaling mechanism is potentially actionable, and combined targeting of ILK-Fzd7 may represent a new therapeutic strategy to eradicate OCSCs and improve patient outcomes.

OBJECTIVE: Nasopharyngeal carcinoma (NPC), a common cancer in Southern China, is associated with Epstein-Barr Virus (EBV) infection. Although many therapies for NPC have been established, the definite role of EBV in NPC remains unclear. Therefore, this work focuses on LMP2A, a latent EBV gene, and investigates whether LMP2A is related to peroxiredoxin 1 (PRDX1) in EBV-positive NPC.
METHODS: The mRNA and protein expression levels of LMP2A, PRDX1, and beta-catenin were compared in patient samples. To identify molecular mechanisms, EBV-negative NP69 and EBV-positive C666-1 NPC cell lines were used. After making an agar cell block for cell slides, the intensity of LMP2A expression was observed visually. To measure the level of reactive oxygen species, both fluorescence microscope and flow cytometry were used. To investigate the intracellular signaling molecular mechanisms with and without the LMP2A gene, reverse transcription polymerase chain reaction and western blotting were used.
RESULTS: Both patient samples and cells of nasopharyngeal carcinoma infected with EBV had increased expression of LMP2A compared with controls, and high ROS levels were identified. Cell viability assay showed that LMP2A promoted cell growth by regulating gene expression. Furthermore, LMP2A induced the expression of PRDX1 and beta-catenin. LMP2A also increased the expression of both cyclin B1 and cyclin D1.
CONCLUSIONS: In NPC cells, PRDX1 and beta-catenin were regulated through LMP2A expression, which reduced cell growth through cell cycle-related gene expression. This study suggests that LMP2A could be a target molecule for inhibiting cancer progression in NPC cells infected with EBV.

OBJECTIVE: To investigate the synergistic effects of polyphyllin I (PPI) combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the growth of osteosarcoma cells through downregulating the Wnt/β-catenin signaling pathway.
METHODS: Cell viability, apoptosis and cell cycle distribution were examined using cell counting kit-8 and flow cytometry assays. The morphology of cancer cells was observed with inverted phase contrast microscope. The migration and invasion abilities were examined by xCELLigence real time cell analysis DP system and transwell assays. The expressions of poly (adenosine diphosphate-ribose) polymerase, C-Myc, Cyclin B1, cyclin-dependent kinases 1, N-cadherin, Vimentin, Active-β-catenin, β-catenin, p-glycogen synthase kinase 3β (GSK-3β) and GSK-3β were determined by Western blotting assay.
RESULTS: PPI sensitized TRAIL-induced decrease of viability, migration and invasion, as well as increase of apoptosis and cell cycle arrest of MG-63 and U-2 OS osteosarcoma cells. The synergistic effect of PPI with TRAIL in inhibiting the growth of osteosarcoma cells was at least partially realized through the inactivation of Wnt/β-catenin signaling pathway.
CONCLUSIONS: The combination of PPI and TRAIL is potentially a novel treatment strategy of osteosarcoma.

BACKGROUND: Beta-catenin-mutated hepatocellular adenomas (β-HCAs) can appear iso- to hyperintense at the hepatobiliary phase (HBP) at magnetic resonance imaging (MRI). Given the relatively lower prevalence of β-HCAs, prior studies had limited power to show statistically significant differences in the HBP signal intensity between different subtypes.
OBJECTIVE: To assess the diagnostic performance of HBP MRI to discriminate β-HCA from other subtypes.
METHODS: Systemic review and meta-analysis.
METHODS: Ten original studies were included, yielding 266 patients with 397 HCAs (9%, 36/397 β-HCAs and 91%, 361/397 non-β-HCAs).
UNASSIGNED: 1.5 T and 3.0 T, HBP.
RESULTS: PubMed, Web of Science, and Embase databases were searched from January 1, 2000, to August 31, 2023, for all articles reporting HBP signal intensity in patients with histopathologically proven HCA subtypes. QUADAS-2 was used to assess risk of bias and concerns regarding applicability.
METHODS: Univariate random-effects model was used to calculate pooled estimates. Heterogeneity estimates were assessed with I2 heterogeneity index. Meta-regression (mixed-effect model) was used to test for differences in the prevalence of HBP signal between HCA groups. The threshold for statistical significance was set at P < 0.05.
RESULTS: HBP iso- to hyperintensity was associated with β-HCAs (pooled prevalence was 72.3% in β-HCAs and 6.3% in non-β-HCAs). Pooled sensitivity and specificity were 72.3% (95% confidence interval 54.1-85.3) and 93.7% (93.8-97.7), respectively. Specificity had substantial heterogeneity with I2 of 83% due to one study, but not for sensitivity (I2  = 0). After excluding this study, pooled sensitivity and specificity were 77.4% (59.6-88.8) and 94.1% (88.9-96.9), with no substantial heterogeneity. One study had high risk of bias for patient selection and two studies were rated unclear for two domains.
CONCLUSIONS: Iso- to hyperintensity at HBP MRI may help to distinguish β-HCA subtype from other HCAs with high specificity. However, there was heterogeneity in the pooled estimates.
METHODS: 3 TECHNICAL EFFICACY: Stage 2.