Women with polycystic ovary syndrome (PCOS) have a substantially increased risk of endometrial cancer (EC), yet the biological mechanisms underpinning this association, to support future prevention and therapeutics, remain incompletely understood. Insulin-like growth factor (IGF)-associated signaling has been implicated, but existing evidence is conflicting. In this pilot translational study, serum IGF1 and IGFBP-3 were measured in women with PCOS (n = 12 for IGF1 and n = 6 for IGFBP-3) and controls (n = 24 for IGF1 and n = 7 for IGFBP-3). Pooled serum, stratified by IGF bioactivity, was applied to human EC cells to further assess effects on cell viability, cell cycle distribution, and downstream signaling. Computational analysis of publicly available endometrial cancer datasets was used to contextualize experimental findings. Serum IGF1 and IGFBP-3 levels did not differ significantly between PCOS and control groups. However, pooled PCOS serum was associated with increased EC cell viability, altered cell cycle progression and PI3K/AKT/mTOR signaling compared with control serum in this exploratory model. Pharmacological inhibition of IGF1R partially attenuated these effects, suggesting that IGF-associated pathways may contribute but are unlikely to act in isolation. In silico analysis identified frequent alterations in PI3K/AKT/mTOR-related genes in EC, consistent with pathway-level vulnerability rather than IGF1-specific dependence. These findings suggest that PCOS serum contains factors that are associated with increased EC cell viability and altered signaling pathways with partial involvement of IGF signaling; however, these findings should be interpreted cautiously given the exploratory pooled-serum design, small subgroup sizes, and use of a single EC cell line. However, multiple metabolic and hormonal pathways are likely to contribute. Larger, better-controlled studies incorporating insulin, sex steroids, and multiple EC models are required before causal inferences can be made.

Small-molecule kinase inhibitors offer a compelling therapeutic strategy for glioblastoma, yet their clinical efficacy remains severely limited by blood-brain barrier penetration and active efflux transporter extrusion. This review evaluates current medicinal chemistry approaches and translational paradigms to overcome these drug delivery and biological constraints. A critical analysis of the literature reveals that direct structural optimization faces a multidimensional balancing act; next-generation design must prioritize macrocyclization, structural rigidification, and bioisosteric capping to lower polar surface area and evade P-glycoprotein and BCRP efflux. Furthermore, carrier-mediated prodrugs targeting the LAT1 transporter provide a viable rescue strategy for highly potent scaffolds. Reviewing recent clinical failures, such as paxalisib and osimertinib, underscores that single-node monotherapies fail due to compensatory pathway hyperactivation and clonal heterogeneity, whereas multi-targeted agents or rational dual-node combinations prevent rapid tumor adaptation. Additionally, combining kinase inhibitors with DNA damage repair inhibitors, immune checkpoint modulation, or MR-guided focused ultrasound could provide powerful synergistic networks. Finally, bridging the translational gap requires complementing conventional serum-cultured cell lines with patient-derived glioma stem cells and orthotopic xenografts to better recapitulate the cellular architecture of the disease. Ultimately, overcoming the therapeutic challenges in glioblastoma demands a fundamental pivot toward rigorous neuro-pharmacological design and multi-lineage network oncology.

Cancer cells are able to survive under conditions of high endoplasmic reticulum (ER) stress by activating the adaptive unfolded protein response (UPR), which is closely linked with autophagy. On the other hand, excessive and prolonged ER stress leads to apoptosis. However, the relationships between different UPR branches and apoptosis or autophagy vary in cancer cells of different origins and depend on the extent and nature of the stress signal. This study was designed to establish the role of ER stress sensors protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1 (IRE1α) in apoptosis or autophagy signaling in T-lymphoblastic leukemia MOLT-3 cells via the RNA interference method. The cells were transfected with small interfering RNAs (si-PERK, si-IRE1α, or si-Cont) for 6 h and further cultured under normal conditions for 72 h to provide an insight into chronic effects of the gene silencing. The expression of apoptosis and autophagy effectors at the mRNA and protein levels was compared using RT-PCR and Western blot assays, respectively. Transfection of the cells with PERK siRNA led to a significant decrease in PERK protein and gene expression, and decreased phosphorylation of its downstream effector eukaryotic initiation factor 2α (eIF2α). PERK silencing was accompanied by activation of apoptosis-related genes and proteins-BCL2-associated X (Bax), caspase-3, C/EBP homologous protein (CHOP), while the levels of autophagy markers (Unc-51 like autophagy activating kinase 1 (ULK1), Beclin-1, and microtubule-associated proteins 1A/1B light chain 3 (LC3A/B)) remained stable. In contrast, treatment of the cells with si-IRE1α reduced the content of IRE1α, X-box-binding protein 1 (sXBP1), and glucose-regulated protein 78 (GRP78) proteins, but increased ERN1 gene expression. IRE1α RNA interference did not affect the levels of the pro-apoptotic marker Bax, but suppressed caspase-3, CHOP, c-Jun N-terminal kinase (JNK), and autophagy signaling molecules (ULK1, Beclin-1, LC3A/B) at both the transcriptional and translational levels. These results indicate that the PERK pathway is an important contributor to the survival of MOLT-3 cells under basal ER stress, while PERK depletion compromises the resistance of cells to UPR-mediated apoptosis. The IRE1α UPR branch is directly linked with autophagy-dependent signaling, although IRE1α knockdown exerted a more complicated influence on the cells, probably via activation of multiple pro-death and compensatory pro-survival regulatory mechanisms.

High-risk neuroblastoma (HR-NB) remains a major clinical challenge due to the emergence of therapy resistance. In this study, the anticancer effects of seven previously synthesized betulin (BET), betulinic acid (BA) and ursolic acid (UA) derivatives (1-7) and of their natural precursors BET, BA and UA (8-10) were investigated in HTLA NB cells, selected as the experimental model by MTT assay, to find a possible solution to drugs that have lost their effect. Dynamic light scattering (DLS) analysis showed that amphiphilic compounds 1 and 4-7 form nanovesicles (240-448 nm) in water, while all compounds have high positive ζ-potential (ζ-p, +28.5-+83.1 mV), supporting favourable membrane interaction and cellular uptake. Cytotoxic experiment results and related IC50 values were expressed as the mean ± SD of four independent experiments run in triplicate. Most derivatives exhibited a cytotoxic activity higher than that of their natural precursors and outperformed etoposide; they were particularly effective against the multidrug resistant (MDR) HTLA ER cells. Among them, the ursolic acid (UA) derivative 7 emerged as the most active compound, displaying sub-micromolar to low micromolar IC50 values and markedly improving the activity of native UA. Functional studies revealed that it induces complete suppression of clonogenic growth at low micromolar concentrations in both HTLA ER and parental HTLA 230 NB cells. In addition, a concentration-dependent downregulation of Akt, p-Akt, BMI1 and PARP, was observed consistently with a marked suppression of survival pathways and loss of cellular homeostasis. Collectively, our experiments, which need further direct investigation to confirm subsequent assumption, could suggest that compound 7 could kill cancer cells via a non-apoptotic, bioenergetic collapse mechanism. All of these findings suggest compound 7 as a promising mitochondria-targeted lead candidate and support amphiphilic triterpenoid derivatives as attractive platforms for overcoming multidrug resistance in high-risk NB.

Syntaphilin (SNPH), initially considered a neuron-specific protein, has recently been found to be widely expressed across various cancers. Mechanistically, SNPH inhibits mitochondrial transport to the cortical cytoskeleton, thereby suppressing cancer cell migration and metastasis. Although SNPH is known to participate in the metastatic progression of multiple malignancies, its precise underlying mechanism remains obscure. In this study, we investigated the role of SNPH in the epithelial-mesenchymal transition (EMT) and invasiveness of gastric cancer cells. Knockdown of SNPH in SNU-638 gastric cancer cells significantly enhanced their migratory and invasive capacities by approximately 1.4-fold and 2.5-fold, respectively. This knockdown concurrently increased focal adhesion kinase (FAK) phosphorylation, upregulated the EMT marker vimentin, and increased the expression of key EMT-related transcription factors, including Snail, Slug, and Twist. Furthermore, SNPH depletion induced the phosphorylation of nuclear factor kappa B (NF-κB), a transcription factor regulating matrix metalloproteinase-9 (MMP-9), which subsequently upregulated MMP-9 mRNA expression. This cascade promotes extracellular matrix degradation, thereby increasing metastatic potential. Notably, these phenotypic and molecular changes were completely reversed upon SNPH overexpression in SNU-638 cells. Taken together, our results demonstrate that SNPH deficiency enhances the migration and metastatic potential of gastric cancer cells by driving EMT and invasion via the FAK/NF-κB/MMP-9 signaling pathway. Consequently, we propose that SNPH represents a novel biomarker and a promising therapeutic target for mitigating gastric cancer metastasis.

Intratumor heterogeneity (ITH) of premalignant colorectal lesions is an important area of research for understanding the diverse biological behavior of colorectal cancer (CRC). Accurate assessment of ITH depends substantially on the sampling strategy used. We present a novel methodological approach termed whole tumor heterogeneity topography (WTHT) and compare it with three previously described sampling strategies: whole tumor homogenization, macrodissection of selected tumor regions, and multisampling. A cohort of 184 advanced precancerous colorectal lesions was processed into paraffin blocks, and the entire tumor mass was systematically divided into equally sized samples (~10 mm3). DNA was isolated from each sample separately and analyzed for hotspot mutations in APC, KRAS, BRAF, PIK3CA, and TP53. ITH was quantified using mutation variance and a newly introduced Heterogeneity Grade (HG). Results obtained by WTHT were statistically and graphically compared with three other modeled sampling strategies. Significant differences were observed among the analyzed sampling approaches. Macrodissection showed the greatest deviation from WTHT, indicating substantial sampling bias, whereas multisampling produced the closest results. WTHT enabled precise quantification and spatial mapping of mutational clones across the entire lesion. WTHT combined with HG provides a robust and reproducible framework for comprehensive assessment of ITH in colorectal adenomas.

Glioblastoma (GBM) is the most aggressive primary brain tumor and remains difficult to treat due to its invasive nature, therapeutic resistance, and the presence of the blood-brain barrier (BBB), which represents a major obstacle to effective drug delivery. This study describes the development of biocompatible solid lipid nanoparticles (SLNs) based on a novel arginine stearate derivative for the encapsulation of idebenone, a synthetic antioxidant with potential biological activity. The objective of this work was to design and characterize a lipid-based nanoparticulate system for idebenone delivery and to evaluate its physicochemical properties and preliminary in vitro biological effects. The nanoparticles were characterized by Dynamic Light Scattering (DLS) and Differential Scanning Calorimetry (DSC), and in vitro release profiles were investigated under different pH conditions. Antioxidant activity and cell viability assays were also performed in glioblastoma and non-tumorigenic cell lines. The results indicate successful formulation of idebenone-loaded SLNs with good encapsulation efficiency, maintained antioxidant activity, and promising physical stability over time as monitored by size analysis. The rationale behind the development of arginine stearate-based SLNSs is to optimize the performance of pharmaceutical active ingredients, such as idebenone, versus non-tumorigenic cells. Overall, these findings support the potential of the developed SLNs as a promising delivery system for further in vitro and in vivo investigations.

Estrogen receptor-positive breast cancer remains difficult to treat, driving the search for new therapeutic agents. Juncus effusus L., a medicinal plant rich in bioactive constituents, has shown preliminary anticancer activity, yet its efficacy in hormone-responsive tumor models in vivo has not been established. We evaluated the antitumor effects of the ethyl acetate sub-extract of J. effusus L. subsp. effusus in an N-methyl-N-nitrosourea (NMU)-induced rat mammary tumor model, assessing tumor burden, histopathology, and molecular markers. Thirty-six Sprague-Dawley rats were divided into six groups (n = 6): sham, control, reference, and three groups receiving the sub-extract at 100, 200, or 400 mg/kg. After NMU induction (50 mg/kg), treatment began once tumor volumes reached approximately 2000 mm3 and continued for eight weeks. The 200 mg/kg dose markedly reduced tumor volume relative to control (p < 0.0001) and lowered both ERα and PCNA expression (p < 0.001 and p < 0.0001). The 100 and 200 mg/kg groups also showed lower p53 and ERα mRNA levels than the other treatment groups. HIF-1α, though elevated in control tumors, declined only modestly and without statistical significance after treatment. These results indicate that J. effusus subsp. effusus, particularly at 200 mg/kg, suppresses proliferation and modulates ERα- and p53 expression, supporting its potential for further preclinical investigation.

Malignant ascites is characterized by extensive tumor dissemination within the peritoneal cavity, abnormal fluid accumulation, and progressive multiorgan dysfunction, including hepatic and renal impairment.

Glioblastoma (GBM) exhibits marked sex differences in incidence, outcome, and molecular regulation, yet the mechanisms underlying these disparities remain poorly defined. ZEB1 is a neurodevelopmental transcription factor implicated in GBM progression and cellular plasticity, but its prognostic and functional relevance may differ by sex. Here, we analyzed TCGA-GBM transcriptomic and clinical data to assess the relationship between ZEB1 expression, patient sex, and survival and to identify sex-specific transcriptional programs associated with ZEB1. Patients were stratified by ZEB1 expression and sex, followed by differential expression analysis, functional enrichment, and survival modeling. High ZEB1 expression was associated with improved overall survival in female patients but not in male patients. Sex-stratified transcriptomic analysis revealed distinct ZEB1-associated gene expression signatures, with enrichment of chromatin-modifying and demethylase-related pathways among male-female comparisons. Candidate Y-linked epigenetic regulators, including KDM5D and UTY, were differentially expressed in ZEB1-high male tumors. qPCR validation in male and female patient-derived GBM cell lines supported sex-dependent regulation of these candidates and showed that KDM5D and UTY expression was reduced following ZEB1 knockdown in male cells. Together, these findings identify a sex-dependent prognostic role for ZEB1 in GBM and suggest that ZEB1 interacts with sex-chromosome-linked epigenetic regulators to shape tumor transcriptional states.

Resistance to apoptosis, metabolic plasticity, and redox adaptation are major contributors to cancer progression and treatment failure. Ferroptosis and cuproptosis have therefore emerged as metal-dependent forms of regulated cell-death programs with potential relevance for tumours that survive conventional therapy. Ferroptosis is driven by iron-dependent phospholipid peroxidation when glutathione peroxidase 4 (GPX4)-dependent and parallel antioxidant systems fail, whereas cuproptosis depends on mitochondrial copper engagement of lipoylated tricarboxylic-acid-cycle proteins, lipoylated-protein aggregation, iron-sulfur protein destabilization, and proteotoxic stress. This review integrates the molecular basis, genetic architecture, long non-coding RNA (lncRNA)-mediated regulation, mechanistic crosstalk, and therapeutic implications of ferroptosis and cuproptosis in cancer. It emphasizes a critical evidence hierarchy: expression association, computational signature construction, metal accumulation, reactive oxygen species (ROS) generation, or reduced viability should not be interpreted as pathway dependency without pathway-defining biochemical endpoints and rescue experiments. The most credible translational opportunities will depend on functional stratification, tumour-selective delivery, and pharmacodynamic confirmation that distinguishes pathway-defined ferroptosis or cuproptosis from nonspecific metal-induced and oxidative cytotoxicity.

Triple-negative breast cancer (TNBC) remains a highly aggressive malignancy with limited therapeutic options and frequent resistance to platinum-based chemotherapy. Rosmarinic acid (RA), a naturally occurring polyphenol, has attracted considerable interest as a potential chemosensitising agent. This study investigated the anticancer activity and the underlying mechanisms of RA combined with cisplatin (CDDP) in 4T1 breast cancer cells while assessing the cytotoxic responses of non-cancerous HaCaT keratinocytes as a preliminary indicator of differential treatment sensitivity. Cytotoxicity was assessed using the MTT assay, followed by calculation of the Combination Index (CI), Drug Reduction Index (DRI), and Selectivity Index (SI). The generation of intracellular reactive oxygen species (ROS) was evaluated by DCFH-DA fluorescence imaging, and the functional contribution of oxidative stress was examined using N-acetyl-L-cysteine (NAC) rescue experiments. Apoptosis was analysed by Annexin V/PI flow cytometry, NucBlue nuclear staining, and Calcein-AM/propidium iodide (PI) Live/Dead fluorescence imaging. Three-dimensional (3D) tumour spheroids were used to assess treatment-induced alterations in spheroid morphology, morphometric parameters, viability based on adenosine triphosphate (ATP), and Live/Dead staining. The expression of genes related to apoptosis was determined by RT-qPCR, and potential molecular mechanisms were explored using the construction of protein-protein interaction (PPI) networks together with Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses. The combination of RA + CDDP exhibited strong synergistic cytotoxicity in 4T1 cells while demonstrating comparatively lower toxicity toward HaCaT keratinocytes. Combination treatment markedly increased intracellular ROS generation, whereas NAC significantly reduced ROS accumulation and partially restored cell viability, indicating that oxidative stress is a major but not exclusive mediator of cytotoxicity. Combined treatment significantly enhanced apoptotic cell death, increased chromatin condensation and membrane damage, upregulated the expression of Bax, Casp9, Cycs, and Trp53, and downregulated Bcl2, consistent with transcriptional regulation of intrinsic apoptotic signalling. In 3D tumour spheroids, the combination markedly reduced spheroid size, disrupted structural integrity, decreased ATP-based viability, and substantially increased tumour cell death compared to monotherapy. Bioinformatic analyses identified central genes related to apoptosis and cell survival and predicted significant enrichment of PI3K/Akt, p53, MAPK, and apoptosis signalling pathways. RA significantly potentiates the antitumor efficacy of CDDP through synergistic induction of ROS-associated apoptotic signalling while showing a more favourable cytotoxic response in 4T1 breast cancer cells than in non-cancerous HaCaT keratinocytes. The integrated findings from two-dimensional (2D) and 3D models, NAC rescue experiments, molecular analyses, and bioinformatics collectively support the potential of RA as a promising chemosensitising adjuvant for CDDP-based breast cancer therapy and warrant further validation in preclinical in vivo models.

Glioblastoma multiforme (GBM) remains one of the most aggressive and treatment-resistant brain tumors, characterized by rapid proliferation and poor patient prognosis. Novel therapeutic strategies are urgently needed to improve clinical outcomes. In this study, we investigated the cytotoxic and pro-apoptotic effects of bortezomib (BORT), a proteasome inhibitor, and graphene oxide (GO), a nanomaterial with known anticancer potential, on human glioblastoma cell lines. Treatment with BORT and GO, both individually and in combination, significantly reduced cell viability in a dose-dependent manner, as determined by MTT. In this study, we observed enhanced apoptotic cell death, accompanied by increased activation of both caspase-8 and caspase-9, indicating simultaneous engagement of extrinsic and intrinsic apoptotic pathways. Western blot analysis demonstrated downregulation of anti-apoptotic proteins Bcl-2 and upregulation of pro-apoptotic markers (NOXA, cleaved PARP). A central finding of this work is the pronounced increase in intracellular reactive oxygen species (ROS) levels following BORT-GO treatment. The elevated ROS levels observed in BORT-GO-treated cells compared with free bortezomib therefore suggest that GO-mediated oxidative stress may amplify proteasome inhibition-induced apoptosis, which is particularly visible in the A172 and LN229 cell lines. Notably, the combination of BORT and GO may suggest a potential cooperative mechanism through proteasome inhibition and oxidative stress induction. These findings indicate that graphene oxide may modulate the antitumor efficacy of bortezomib in a cell line-dependent manner and support further investigation of this combination as a promising therapeutic approach for glioblastoma.

Acute myeloid leukaemia (AML) is a therapeutically challenging malignancy driven by the self-renewal, quiescence, and therapy resistance of leukaemic stem cells (LSCs). CDK8, a kinase component of the Mediator complex, regulates oncogenic transcription, and the selective CDK8/CDK19 inhibitor RVU120 (Romaciclib) targets AML cells with CD34+/pSTAT5-high LSC-like characteristics; however, the epigenetic and transcriptional consequences of CDK8 blockade and actionable combinatorial strategies remain incompletely defined. Using the TEX cell line, an LSC-enriched surrogate model, we performed time-resolved RNA-seq, whole-proteome and phosphoproteomics mass spectrometry (MS), and CUT&Tag chromatin profiling following treatment with RVU120 and CCT251921. CDK8 protein-protein interactions were mapped by co-immunoprecipitation MS across five AML models, and synergy with Pelabresib (BET inhibitor) or CB6644 (RUVBL1/2 inhibitor) was assessed by high-content screening in three cell lines and three patient-derived xenograft (PDX) models. Both inhibitors suppressed STAT5 phosphorylation, induced loss of the CD34+/CD38- LSC-enriched phenotype, and drove erythromegakaryocytic differentiation. Transcriptomic and proteomic responses were concordant, and CDK8 inhibition triggered widespread enhancer activation with redistribution of RNAP2, BRD3, and NFRKB. CDK8 combined with Pelabresib acted synergistically in MOLM-16 cells and two of three PDX models. These findings identify CDK8 as a transcriptional node of LSC-associated programs and provide a mechanistic rationale for combined CDK8-BET inhibition in molecularly defined AML subsets, which will require validation in functional LSC assays and primary specimens.

Glutamate dehydrogenase (GLUD1) links glutamine metabolism and redox regulation, yet its prognostic and functional relevance across different glioma subtypes warrants further study. Here, we show that GLUD1 expression was inversely associated with tumor grade and positively associated with survival across glioma subtypes, a relationship not fully recapitulated by broader glutaminolysis-related gene signatures. To investigate the consequences of GLUD1 inhibition, we treated endogenous IDH-mutant and IDH-wildtype glioma cell lines with the reported GLUD1 inhibitor R162. GLUD1 inhibition reduced viability in all cell lines tested. This effect was not rescued by α-ketoglutarate (α-KG) supplementation, indicating that impaired tricarboxylic acid (TCA) cycle anaplerosis was not the primary mechanism underlying GLUD1 dependency. Instead, GLUD1 inhibition caused intracellular glutamate accumulation, increased reactive oxygen species (ROS), γ-H2AX induction, and elevated intracellular calcium, while complementary in silico analyses predicted disruption of mitochondrial membrane potential following R162 exposure. Together, these findings indicate that GLUD1 inhibition induces metabolic and redox stress associated with disrupted glutamate and calcium homeostasis and DNA damage. Our findings distinguish the favorable prognostic value of GLUD1 expression from the cellular vulnerability revealed by its inhibition, supporting further investigations of GLUD1 as both a prognostic biomarker and potential therapeutic target in glioma.

Cancer cachexia (CC) is a devastating, multi-organ syndrome historically defined by the progressive wasting of skeletal muscle and adipose tissue. However, emerging evidence suggests that the skeletal system is also a major, yet underappreciated target of this catabolic state. While bone loss in oncology is primarily attributed to skeletal metastasis or cancer treatment-induced bone loss (CTIBL), clinical and preclinical data has increasingly demonstrated that tumor and host-derived systemic signals can drive severe bone deterioration even in non-metastatic disease. This review synthesizes current information available on bone loss, osteopenia, and skeletal decline in the context of CC, with a specific focus on non-metastatic disease. By examining the available literature, we argue that bone loss is a "hidden" yet fundamental systemic manifestation of the cachectic state. Furthermore, we aim to highlight how concurrent muscle and bone deterioration (osteosarcopenia) dramatically worsens prognosis in several different cancers in both the adult and pediatric populations. Ultimately, this review highlights the potential contribution of cancer cachexia to osteoporosis and skeletal fragility, supporting the need for greater clinical awareness, improved musculoskeletal screening, and the development of targeted therapeutic strategies.

Despite the development of new drugs, chemoresistance constitutes a major obstacle in cancer treatment. To investigate mechanisms of resistance and potential therapeutic targets, we developed doxorubicin-resistant models of HER2- (D2F2/Dox) and HER2+ (D2F2E2/Dox) breast cancer cells. Compared with parental cells, the D2F2/Dox and D2F2E2/Dox differed in morphology, increased migratory potential, elevated levels of the transcription factor signal transducer and activator of transcription 3 (Stat3), and a lower proliferation rate in D2F2E2/Dox. Moreover, D2F2/Dox and D2F2E2/Dox differed in the expression profiles of genes related to cell stemness, apoptosis, and drug efflux. Stat3 gene silencing in both doxorubicin-resistant cell types reversed the expression profiles of some genes (different in each resistant cell line), and decreased migratory potential was observed only in D2F2 cells. These data indicate that the acquired doxorubicin resistance was associated with Stat3 status; however, HER2- and HER2+ breast cancer cells did not indicate the same mechanism of chemoresistance acquisition. Importantly, Stat3 silencing did not substantially restore doxorubicin sensitivity, suggesting that effective therapy may require simultaneous targeting of multiple pathways. Furthermore, we demonstrated that siStat3 therapeutics could be selectively delivered to HER2+ cancer cells using H2.1MS1:MS2KN silk spheres, indicating their potential for targeted drug delivery in vivo.

Obesity is associated with chronic adipose dysfunction characterized by oxidative stress, inflammation, senescence, and fibrosis, which can promote tumor progression. In prostate cancer, periprostatic adipose tissue may directly influence the prostate microenvironment. Radiation therapy is widely used in prostate cancer, but radiation-induced adipose dysfunction in obesity and its impact on the prostate microenvironment remain poorly understood. In the present study, we investigated the impact of obese and irradiated obese adipose microenvironments on prostate stromal remodeling, as well as the activation of prostate fibroblasts mediating prostate cancer progression. We utilized a high-fat diet obesity model with localized adipose irradiation in animal and in vitro studies using obese and irradiated obese adipocytes. Prostates from obese and irradiated obese mice exhibited epithelial hyperplasia, increased stromal activation markers, oxidative damage, and senescence. Interestingly, radiation maintained the obesity-induced pathological behavior in the prostate, rather than elevating it. The conditioned media from obese and irradiated obese adipocytes induced stromal activation markers, senescence, extracellular H2O2 production, pro-survival signaling, and inflammation. Notably, the only significant changes observed with the addition of radiation to obesity were enhancement of fibrosis-associated features and infiltration of CD4+ T cells. Functionally, prostate myofibroblasts or senescent fibroblasts promoted prostate cancer migration and induced epithelial-to-mesenchymal transition and elevated pro-tumorigenic pathways. Cytokine profiling identified elevated levels of CXCL10 and CXCL11 from myofibroblasts, and pharmacological inhibition of CXCR3 significantly reduced prostate cancer migration, implicating this signaling axis in activated fibroblast-driven tumor-promoting crosstalk. Collectively, these findings demonstrate obesity-associated adipose dysfunction reprograms the prostate microenvironment toward a pro-tumorigenic state, while radiation sustains rather than markedly amplifies these pathological changes, identifying obese adipose-stromal crosstalk and the CXCL10/CXCL11-CXCR3 axis as potential therapeutic targets to inhibit prostate cancer progression.

Cancer cells live in a dynamic and favorable ecosystem conducive to their growth and survival, known as the tumor microenvironment (TME). The TME is replete with various proinflammatory cell types that mediate crosstalk via the secretion of cytokines and chemokines to facilitate tumor growth and development. One cardinal proinflammatory cytokine that is present in the TME is interleukin-1 (IL-1). IL-1 promotes tumor angiogenesis and cancer cell metastasis; thus IL-1 receptor antagonist (IL-1Ra) is of clinical interest. Our lab previously reported that chronic exposure to exogenous IL-1 can select for cancer cells that evolve insensitivity to IL-1 signaling, thus rendering IL-1-targeting therapies, like IL-1Ra, irrelevant. While immune cells are the primary source of TME IL-1, cancer cells can also produce and secrete IL-1 to engage in autocrine and/or paracrine signaling. In this context, cancer cell exposure to multiple other sources of exogenous IL-1 beyond autocrine production might also amplify extrinsic IL-1 signaling in these cells, but the consequences of sustained amplified IL-1 signaling on the regulation, function, and therapeutic response of these cancer cells need to be explored.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with limited therapeutic options for patients at high risk of disease recurrence and metastasis. The cyclic nucleotide-degrading enzyme, phosphodiesterase 10A (PDE10), that hydrolyzes both cAMP and cGMP has been previously reported to be expressed in multiple cancers and regulates key cellular signaling pathways involved in cancer cell proliferation, survival, and maintenance of stem cell-like properties. We found that PDE10 overexpression was associated with poor relapse-free survival of TNBC patients and identified its potential as a therapeutic target for TNBC using a novel inhibitor, ADT-030. Our results showed that ADT-030 inhibited the growth of TNBC cells, reduced colony-forming efficiency and enhanced the therapeutic efficacy of paclitaxel. A TNBC mouse model demonstrated that oral administration of ADT-030 significantly suppressed syngeneic tumor growth and enhanced the antitumor efficacy of paclitaxel. ADT-030 treatment altered differentially expressed genes (DEGs), signaling pathways, and cellular processes. Overall, our findings suggest that ADT-030, as a monotherapy or in combination with standard-of-care chemotherapy, may be an effective therapeutic approach for TNBC. Further studies are warranted to better understand the oncogenic role of PDE10 in TNBC and the mechanisms by which ADT-030 modulates the tumor microenvironment (TME) and enhances chemotherapy response.