Alice Sze Tsai Wong

Intratumoral heterogeneity in metastatic cancers complicates effective treatment, as distinct tumor subclones display varying drug sensitivities and metastatic capabilities, interacting through mechanisms that remain poorly understood. In this study, we utilized an isogenic ovarian cancer cell pair distinguished by differential β-catenin signaling: non-metastatic (NM) cells with low β-catenin and highly metastatic (HM) cells with elevated β-catenin signaling. Co-engrafting NM and HM cells synergistically enhances peritoneal metastasis compared to either subclone alone. Immunohistochemical analysis revealed a mosaic β-catenin expression in mixed tumors, recapitulating the heterogeneity observed in clinical ovarian cancer cases. Notably, both NM cells and β-catenin-knockout HM cells exhibited an intrinsic senescence-associated secretory phenotype (SASP), mechanistically driven by Hippo/YAP signaling, which was suppressed by β-catenin in HM cells. This phenotype in turn facilitated the metastatic dissemination of β-catenin-high subclones through paracrine signaling. Importantly, mixed in vivo tumors were more susceptible to treatment with fisetin, a senolytic agent, and YAP inhibition, leading to marked reduction in metastatic burden. Overall, our findings demonstrate the pre-existence of senescence-like tumor cells in untreated conditions and reveal a novel cooperative mechanism in which β-catenin heterogeneity facilitates ovarian cancer progression through SASP-mediated subclonal interactions. These results provide a basis for targeted therapeutic strategies to disrupt intratumoral communication and improve treatment outcomes in metastatic ovarian cancer.

Interferons (IFNs) are a family of cytokines that orchestrate a wide range of antiviral, immunoregulatory, and antitumor activities. This review provides a comprehensive overview of the molecular mechanisms underlying IFN signaling, including both canonical JAK (janus kinases)-STAT (signal transducers and activators of transcription) pathways and non-canonical branches such as MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase)-AKT (protein kinase B)-mTOR (mechanistic target of rapamycin). The intricate interplay between these signaling modules and transcriptional, epigenetic, and post-transcriptional regulators is essential for maintaining immune homeostasis and tailoring context-dependent immune responses. Under physiological conditions, IFNs are essential for host defense, driving antiviral gene expression, activating innate immune cells, and shaping adaptive immune responses, including T and B cells. Conversely, dysregulation of IFN signaling contributes to the development of autoimmune diseases, neuroinflammation, cardiovascular disorders, and cancer. Tumor cells can exploit IFN-induced suppressive molecules to evade immune attack. The currently emerging therapeutic strategies of IFN signaling have evolved into a dual strategy: replacement therapy in immunodeficient states, and pathway inhibition in autoimmune conditions. Additionally, IFN-based combination therapies with immune checkpoint blockade and radiotherapy have demonstrated synergistic potential but require precise control of dosing and timing to avoid immune exhaustion. Advances in single-cell transcriptomics, proteomics, and metabolomics are providing novel insights into IFN heterogeneity, enabling the development of personalized IFN-based treatments. This review highlights the clinical implications and emerging strategies to harness or restrain IFN signaling for therapeutic benefit.

Triclosan (TCS), a common antimicrobial agent, is widely detected in the global environments nowadays globally. Using marine medaka as a model, this study investigated and compared the transgenerational and multigenerational neurotoxic effects on fish. The environmentally realistic concentration of TCS can induce hyperlocomotor activities and increase heart rate, while higher concentrations (>500 μg/L) can inhibit hatching and cause cardiovascular malformations and neurotransmitter imbalances. Parental (F0) exposure to TCS resulted in transgenerational effects on locomotor activities manifested in F2, alongside with alterations in phototransduction and cell adhesion pathways. Global DNA methylation analyses indicated that the observed transgenerational effects are mediated through relevant epigenetic changes. Multigenerational exposure to TCS increased locomotor activities from F1 to F3, which is associated with changes in the expression of genes related to eye structure, phototransduction, and lipid and retinol metabolisms, thereby affecting energy metabolism and visual function. Results of this study highlight the difference between transgenerational and multigenerational effects of TCS exposure, and potential biases incurred in current risk assessment based exclusively on data derived from F0, which presents challenges for environmental management and regulatory standards.

​​Exosomes, as natural intercellular messengers, are gaining prominence as delivery vehicles in nanomedicine, offering a superior alternative to conventional synthetic nanoparticles for cancer therapeutics. Unlike lipid, polymer, or metallic nanoparticles, which often face challenges related to immunogenicity, targeting precision, and off-tumor toxicity, exosomes can effectively encapsulate a diverse range of therapeutic agents while exhibiting low toxicity, favorable pharmacokinetics, and organotropic properties. This review examines recent advancements in exosome bioengineering over the past decade. Innovations such as microfluidics-based platforms, nanoporation, fusogenic hybrids, and genetic engineering have significantly improved loading efficiencies, production scalability, and pharmacokinetics of exosomes. These advancements facilitate tumor-specific cargo delivery, resulting in substantial improvements in retention and efficacy essential for clinical success. Moreover, enhanced biodistribution, targeting, and bioavailability—through strategies such as cell selection, surface modifications, membrane composition alterations, and biomaterial integration—suggests a promising future for exosomes as an ideal nanomedicine delivery platform. We also highlight the translational impact of these strategies through emerging clinical trials. Additionally, we outline a framework for clinical translation that focuses on: cargo selection, organotropic cell sourcing, precision loading methodologies, and route-specific delivery optimization. In summary, this review emphasizes the potential of exosomes to overcome the pharmacokinetic and safety challenges that have long impeded oncology drug development, thus enabling safer and more effective cancer treatments.

Ovarian cancer is the leading cause of death among all gynecological malignancies, and drug resistance renders the current chemotherapy agents ineffective for patients with advanced metastatic tumors. We report an effective treatment strategy for targeting metastatic ovarian cancer involving a nanoformulation (Bola/IM)─bola-amphiphilic dendrimer (Bola)-encapsulated imatinib (IM)─to target the critical mediator of ovarian cancer stem cells (CSCs) CD117 (c-Kit). Bola/IM offered significantly more effective targeting of CSCs compared to IM alone, through a novel and tumor-specific β-catenin/HRP2 axis, allowing potent inhibition of cancer cell survival, stemness, and metastasis in metastatic and drug-resistant ovarian cancer cells. Promising results were also obtained in clinically relevant patient-derived ascites and organoids alongside high tumor-oriented accumulation and favorable pharmacokinetic properties in mouse models. Furthermore, Bola/IM displayed synergistic anticancer activity when combined with the first-line chemotherapeutic drug cisplatin in patient-derived xenograft mouse models without any adverse effects. Our findings support the use of Bola/IM as a nanoformulation to empower IM, providing targeted and potent treatment of metastatic ovarian cancer. Our study thus represents a significant advancement toward addressing the unmet medical need for improved therapies targeting this challenging disease.

With the revolutionary progress of immune checkpoint inhibitors (ICIs) in non–small cell lung cancer, identifying patients with cancer who would benefit from ICIs has become critical and urgent. Here, we report protein tyrosine phosphatase receptor type T (PTPRT) loss as a precise and convenient predictive marker independent of PD-L1 expression for anti–PD-1/PD-L1 axis therapy. Anti–PD-1/PD-L1 axis treatment markedly increased progression-free survival in patients with PTPRT-deficient tumors. PTPRT-deficient tumors displayed cumulative DNA damage, increased cytosolic DNA release, and higher tumor mutation burden. Moreover, the tyrosine residue 240 of STING was identified as a direct substrate of PTPRT. PTPRT loss elevated phosphorylation of STING at Y240 and thus inhibited its proteasome-mediated degradation. PTPRT-deficient tumors released more IFN-β, CCL5, and CXCL10 by activation of STING pathway and increased immune cell infiltration, especially of CD8 T cells and natural killer cells, ultimately enhancing the efficacy of anti–PD-1 therapy in multiple subcutaneous and orthotopic tumor mouse models. The response of PTPRT-deficient tumors to anti–PD-1 therapy depends on the tumor-intrinsic STING pathway. In summary, our findings reveal the mechanism of how PTPRT-deficient tumors become sensitive to anti–PD-1 therapy and highlight the biological function of PTPRT in innate immunity. Considering the prevalence of PTPRT mutations and negative expression, this study has great value for patient stratification and clinical decision-making.

Purpose:Uterine leiomyosarcoma (LMS) is an aggressive sarcoma and a subset of which exhibits DNA repair defects. Polo-like kinase 4 (PLK4) precisely modulates mitosis, and its inhibition causes chromosome missegregation and increased DNA damage. We hypothesize that PLK4 inhibition is an effective LMS treatment.Experimental Design:Genomic profiling of clinical uterine LMS samples was performed, and homologous recombination (HR) deficiency scores were calculated. A PLK4 inhibitor (CFI-400945) with and without an ataxia telangiectasia mutated (ATM) inhibitor (AZD0156) was tested in vitro on gynecologic sarcoma cell lines SK-UT-1, SKN, and SK-LMS-1. Findings were validated in vivo using the SK-UT-1 xenograft model in the Balb/c nude mouse model. The effects of CFI-400945 were also evaluated in a BRCA2-knockout SK-UT-1 cell line. The mechanisms of DNA repair were analyzed using a DNA damage reporter assay.Results:Uterine LMS had a high HR deficiency score, overexpressed PLK4 mRNA, and displayed mutations in genes responsible for DNA repair. CFI-400945 demonstrated effective antitumor activity in vitro and in vivo. The addition of AZD0156 resulted in drug synergism, largely due to a preference for nonhomologous end-joining DNA repair. Compared with wild-type cells, BRCA2 knockouts were more sensitive to PLK4 inhibition when both HR and nonhomologous end-joining repairs were impaired.Conclusions:Uterine LMS with DNA repair defects is sensitive to PLK4 inhibition because of the effects of chromosome missegregation and increased DNA damage. Loss-of-function BRCA2 alterations or pharmacologic inhibition of ATM enhanced the efficacy of the PLK4 inhibitor. Genomic profiling of an advanced-stage or recurrent uterine LMS may guide therapy.