Search Results (12,693)

Mitochondria play essential roles in cellular metabolism and signaling, regulating biosynthetic pathways, calcium homeostasis, redox balance, and cell fate beyond ATP production. Their continual remodeling through fusion, fission, and mitophagy maintains mitochondrial quality control and adapts organelle function to cellular demands. Here, we review how mitochondrial dynamics, fusion, fission, and mitophagy modulate metabolic reprogramming and signaling to drive cancer progression and therapy resistance. Emerging evidence indicates that in cancer, mitochondrial fusion enhances respiratory efficiency and oxidative phosphorylation, whereas fission promotes glycolytic adaptation, rapid biomass accumulation, and stress tolerance. Mitophagy further refines metabolic fitness by eliminating damaged mitochondria and sustaining redox homeostasis. Together, these processes underscore that dysregulation of mitochondrial dynamics is a hallmark of cancer and a key driver of metabolic reprogramming and therapeutic resistance. In this review, we summarize how mitochondrial fusion, fission, and mitophagy govern metabolic circuitry in cancer development and therapy resistance. We highlight their functional impact on tumor progression and discuss emerging therapeutic strategies targeting mitochondrial dynamics and associated machinery. Understanding this dynamic metabolic crosstalk may reveal new vulnerabilities and guide the development of mitochondria-targeted cancer therapies. Full article

Background: Sphingolipids are essential structural and signaling lipids that support membrane integrity and govern cell fate decisions. While the consequences of chronic sphingolipid inhibition have been extensively explored, the immediate cellular responses to acute suppression of sphingolipid synthesis remain poorly defined. Methods: We analyzed subcellular proteomic changes following an acute reduction in sphingolipid levels induced by myriocin, an inhibitor of de novo sphingolipid synthesis. We then evaluated the cytotoxicity of co-treatment with myriocin and inhibitors of the altered pathways in cancer cells. Results: We found that de novo sphingolipid synthesis is sensitive to myriocin, an inhibitor of serine palmitoyltransferase (SPT), and can be efficiently inhibited within 4 h of treatment. Cells respond to reduced sphingolipid levels by rapidly remodeling their proteome. Mass spectrometry analysis revealed changes in the abundance of hundreds of proteins across the membrane, cytosolic, and nuclear fractions. Gene set enrichment analysis revealed alterations in the proteome across several pathways involved in protein and lipid homeostasis and stress responses, including upregulation of cholesterol homeostasis and lysosome. Co-treatment with myriocin and cholesterol synthesis or lysosomal function inhibitors synergistically reduced cancer cell viability by promoting apoptosis rather than other forms of programmed cell death. Conclusions: Together, our work provides insights into how cells rapidly rewire the abundance of certain protein classes in response to reduced sphingolipid levels and identifies signaling and metabolic pathways that can be exploited for therapeutic intervention. Full article

Background: While exercise is critical for breast cancer survivors, identifying prescriptions that promote long-term adherence is a challenge. This study evaluated whether survivors could maintain fitness gains during a 6-month self-managed phase following two distinct 12-week supervised programs. Specifically, we compared whether transitioning from one-on-one training to either individualized (Ind) or group-based (Gr) sessions influenced a participant’s ability to sustain improvements in strength, range of motion (ROM), and cardiorespiratory endurance (VO₂peak). Methods: Thirty breast cancer patients from diverse backgrounds completed an initial 12-week supervised individual training program. They were then randomized into either Ind (n = 13) or Gr (n = 17) supervised sessions for a second 12-week phase. Fitness assessments were conducted at baseline, 3 months (post-initial training), and 1 year (after the 6-month self-managed phase). Data were analyzed using generalized estimating equations to evaluate the effects of time and training format. Results: Significant improvements were observed across all fitness categories over time. Muscular strength (bench press, plank, and squats) and VO₂peak increased significantly by 3 months and were successfully maintained at the 1-year follow-up mark. Shoulder ROM also showed significant improvement at 1 year. Notably, the training format (group vs. individual) had no significant impact on these outcomes, with the exception of one ROM metric. Conclusions: Initial supervised exercise leads to significant fitness gains that breast cancer survivors can successfully maintain for at least six months through self-management. These gains are sustained regardless of whether the preceding supervised training was delivered in a group or individual format, suggesting flexibility in clinical exercise prescriptions. Full article

Pancreatic cancer remains one of the most lethal malignancies worldwide, with pancreatic ductal adenocarcinoma accounting for the vast majority of cases and characterized by extensive desmoplasia, immune exclusion, and resistance to systemic therapies. Increasing evidence implicates lysosomal cathepsins as important regulators of these defining features of pancreatic tumor biology. Cathepsin-dependent proteolysis and lysosome-associated signaling pathways contribute to extracellular matrix remodeling, regulate immune cell trafficking, and influence antigen processing and presentation. Beyond their classical degradative functions, cathepsins participate in stress-adaptive cellular programs linked to autophagy, metabolic regulation, and proteostasis, supporting tumor cell survival under hypoxic, nutrient-limited, and therapy-induced stress conditions. Within the tumor microenvironment, dysregulated cathepsin activity promotes immune evasion by reshaping cytokine networks, impairing effective antigen presentation, and reinforcing physical and functional barriers to cytotoxic T-cell infiltration. Collectively, these mechanisms position the lysosome–cathepsin system as a central regulator of proteolytic remodeling, immune exclusion, and adaptive therapy resistance in pancreatic cancer, highlighting its potential relevance for emerging combinatorial therapeutic strategies. Full article

Systemic administration of antibodies that target immune checkpoint inhibitor pathways is a highly effective approach to cancer immunotherapy, but systemic toxicity can limit clinical utility. In preclinical testing, a peri-tumor injection of a low dose of hydrogel-encapsulated cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody was shown to selectively activate T cells in tumor-draining lymph nodes, induce tumor infiltration by cytotoxic T cells, and result in tumor regression, protective immunity, and long-term survival. In contrast to systemic therapy, there was limited systemic exposure or risk for autoimmune toxicity. The current study focuses on translating this platform into a biocompatible human therapeutic. The hydrogel matrix was reformulated using a low-molecular-weight hyaluronic acid. A recombinant human hyaluronidase (rHuPH20) was incorporated to promote lymph node targeting and self-resorbing features. Formulations were optimized to operate at neutral pH and with gelation kinetics allowing a 5 to 10 min administration window. Performance features were assessed including the capacity to encapsulate human IgG or ipilimumab antibody at proposed therapeutic doses (1–15 mg/mL), impact of rHuPH20 and antibody on rheologic properties and three-dimensional microstructure, and payload delivery profiles in vitro and in vivo. Results confirm the capacity for this unique hydrogel platform to be adapted for human testing. Full article

Background/Objectives: Schisandrin B (Sch B), a bioactive lignan of Schisandra chinensis has been commonly investigated for its antitumor activities, yet its radiosensitizing effect and mechanism remain unclear. This study was conducted to investigate the radiosensitizing effects of Sch B in breast cancer (BC) and elucidate its molecular mechanisms, with a specific focus on the gut microbiota–immune axis. Methods: In vitro, CCK-8, colony formation, and 3D spheroid assays were used to evaluate the effects of Sch B on proliferation inhibition and radiosensitization, flow cytometry and immunofluorescence were used to elucidate the mechanisms involved. In vivo, 4T1 tumor-bearing mice were treated with Sch B, and 16S rDNA sequencing and LC-MS/MS were used to analyze the gut microbiota and short-chain fatty acid (SCFA) metabolism. IHC and qPCR detected antitumor immune responses. Results: Sch B inhibited the proliferation of BC cells in a time- and dose-dependent manner with negligible toxicity to the mammary epithelial cell line MCF-10A. Furthermore, Sch B enhanced the radiosensitivity (sensitization enhancement ratio: 1.20~1.77) of BC by inducing G1 phase cell cycle arrest and delaying radiation-induced DNA double-strand break repair. In vivo, Sch B suppressed BC growth in BALB/c mice without causing obvious systemic toxicity. Sch B reversed tumor-induced gut microbiota dysbiosis (restoring species abundance and the Firmicutes/Bacteroidetes ratio, enriching beneficial genera such as Lactobacillus and Butyrobacter) and normalized SCFA profiles (correlative evidence). Furthermore, Sch B modulated systemic immune responses by increasing the expression of Ifng, Cxcl10, Ddx58 and promoting CD3⁺ and CD8⁺ T-cell infiltration in tumors. Conclusions: Sch B exerts BC radiosensitization through dual mechanisms, direct regulation of the cell cycle and DNA repair, and indirect modulation of the gut microbiota-immune axis (correlative evidence), highlighting it as a safe and effective candidate for improving the efficacy of BC radiotherapy. Full article

The body’s microbiota plays a fundamental role in maintaining homeostasis and influences immune function, metabolism, and tissue integrity. A growing body of research suggests that fluctuations in the composition and abundance of individual microbiota populations may influence cancer development and the effectiveness of therapy. The condition of microbiota dysbiosis has been demonstrated to induce chronic inflammation, immune system dysregulation, and, most significantly, modulation of molecular pathways that promote tumorigenesis. The efficacy and toxicity of cancer treatment can be influenced by the composition of the microbiota. Bacteria can modify the effectiveness and toxicity of chemotherapy and immunotherapy by affecting drug metabolism and the body’s immune response. In contrast, the development of anticancer therapies that utilize bacteria is gaining increasing interest. This alternative to conventional treatment utilizes the natural ability of certain bacterial species to selectively colonize hypoxic and necrotic environments. The exploration of natural and genetically modified bacteria as vectors for the delivery of cytotoxins, immunomodulators, or therapeutic genes in the combat of cancer is a current area of research. In addition, their capacity to stimulate an antitumor immune response is also exploited. Preclinical investigations in animals have demonstrated the efficacy of this therapeutic approach, underscoring the promise of bacterial therapies as either an adjunct to conventional treatment or as a standalone strategy for combating cancer. This article synthesizes the current knowledge regarding the role of microbiota in carcinogenesis in animals and discusses recent developments in the field of bacterial therapies. The text also addresses the challenges, safety considerations, and future perspectives associated with translating microbiota-targeted and bacterial therapies into veterinary and comparative oncology. Full article

Background/Objectives: Mammary serine protease inhibitor (maspin) was originally identified as a tumor suppressor gene, as loss of its expression in breast cancer cell lines promotes invasiveness and tumorigenicity. In contrast, normal pancreatic ductal epithelium does not express the maspin protein, and its expression frequency increases as pancreatic intraepithelial neoplasia (PanIN) progresses to pancreatic ductal adenocarcinoma (PDAC). We have previously reported that cytoplasmic-only localization of maspin (cytMaspin) is an independent indicator of poor prognosis in patients with PDAC. However, the functional role of maspin in PDAC remains unclear. Methods: We investigated the subcellular localization and biological function of maspin in PDAC cell lines using Western blotting, immunofluorescence, RNA-seq, wound-healing assays, and invasion assays. Results: Endogenous maspin was detected in most PDAC cell lines, and RNA-seq was performed in S2-007 (panMaspin; nuclear and cytoplasmic localization of maspin) and S2-028 (cytMaspin), which were derived from the same parental cell line (SUIT-2). The invasive capability of S2-028 cells (cytMaspin) was higher than that of S2-007 cells (panMaspin), showing upregulation of the ErbB family and axon-guidance pathways. Furthermore, maspin overexpression in PANC-1 and S2-020 cells resulted in panMaspin and cytMaspin, respectively. PANC-1 cells overexpressing maspin showed decreased invasive capability via suppression of HER2 expression and Akt activation. Conclusions: Although maspin expression has generally been considered an unfavorable prognostic indicator in patients with PDAC, our findings suggest that its biological effects may differ depending on its subcellular localization. Specifically, nuclear localization is linked to less aggressive phenotypes, whereas cytoplasmic localization is associated with more malignant behavior. Full article

Background: Folate receptor alpha (FRα), commonly expressed in epithelial ovarian cancers, is a clinically actionable biomarker following approval of the antibody–drug conjugate mirvetuximab soravtansine (MIRV). Pivotal trials showed that high FRα expression predicts MIRV benefit, creating the need for standardized testing to ensure timely, equitable access. Methods: To address the need for guidance on FRα testing, the Society of Gynecologic Oncology of Canada convened a multidisciplinary Expert Panel to review the evidence and integrate Canadian clinical, pathology, laboratory, and patient perspectives. Consensus recommendations were developed through structured evidence review, expert discussion, iterative revision, and patient partner input. Results: The panel issued recommendations on the clinical role and timing of FRα testing, tissue requirements, assay selection and validation, interpretation and reporting standards, laboratory quality assurance, reimbursement, and equitable access. It is recommended that FRα testing be available to all patients with epithelial ovarian cancer, with results available no later than platinum-resistant disease, using a validated assay, preferably the Ventana FOLR1 RxDx assay or an appropriately validated laboratory-developed test. Standardized synoptic reporting, participation in external quality assurance programs, and clear patient communication were deemed essential. Conclusions: These recommendations aim to promote integrated, equitable, standardized FRα testing across Canada and support timely identification of patients eligible for FRα-directed therapy, clinical trial enrollment, and future biomarker-driven treatment strategies. Full article

Oncogenic viruses, which are causative for some cancers, are typically acquired in youth and suppressed until older age. These malignancies account for over 10% of the cancer burden and often reprogram cellular metabolic pathways to promote their own survival and proliferation, often targeting lipogenic pathways to increase bioavailability of cellular products. The isoprenoid biosynthesis pathway (IBP) is an important lipogenic pathway that has been explored extensively for its dysregulation contributing to carcinogenesis, with notable discussion of statin therapy as a means of perturbing neoplasia. To our knowledge, we are the first group to provide a comprehensive discussion of the seven known oncogenic viruses and their reliance upon the IBP to promote tumorigenesis. As knowledge on this topic is limited, we aim to draw attention to a neglected area of the oncogenic research space, while also highlighting the use of inhibitors of the IBP as potential avenues for novel treatment options. Full article

Objectives: The response to radioiodine therapy (RAI) in differentiated thyroid cancer (DTC) patients is one of the most important factors that determines the treatment outcome and overall prognosis. The objective of this study is to determine the correlation between BRAF^V600E and TERT promoter (TERTp) mutation in tumor samples of DTC patients with the response to RAI as well as correlation with clinical and pathohistological features. Methods: Samples of 110 DTC patients (80 with intermediate and high risk of disease recurrence-IHR and 30 with distant metastases) were analyzed for BRAF^V600E and TERTp mutation (BRAF/TERT) and 89 patients were assessed for the response to RAI. Results: Sixty-one (55.5%) patients had BRAF^V600E mutation, 30 (27.3%) had TERTp mutation, while 21 (19.1%) patients had both mutations. In the IHR group, the study showed a statistically significant association between genotype BRAF/TERTp and treatment outcome (p = 0.04). IHR DTC patients with BRAF-/TERT- finding showed in general an excellent response to RAI, while patients with BRAF/TERT co-mutation had a predominantly incomplete or indeterminate response. In DTC patients with BRAF/TERT co-mutation that presented with distant metastases, a tendency to a higher frequency of RAI-refractory (RAI-R) disease was recorded, but without statistical significance. The pathohistological and clinical features that significantly correlated with BRAF/TERT status are age at diagnosis, locoregional lymph node involvement, the largest positive lymph node diameter, tumor angioinvasion and the presence of distant metastases. Conclusions: BRAF/TERT co-mutation may be associated with a less favorable disease course and poorer response to RAI. However, findings in patients with distant metastases should be considered exploratory due to the limited sample size. Full article

Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver malignancy with a rising global incidence and limited therapeutic options. Vascular invasion (VI) is a hallmark of advanced disease, correlating with early recurrence and dismal prognosis, yet its tumor microenvironment (TME) drivers remain elusive. We analyzed single-cell RNA sequencing (scRNA-seq) data from 25 ICC samples to systematically characterize the cellular composition and molecular features related to VI. By integrating bulk RNA-seq data, spatial transcriptomics, and multiplex immunofluorescence, we identified a distinct subset of tumor-like cancer-associated fibroblasts (CAFs), termed tCAFs, enriched in VI-positive tumors. Functional enrichment analyses revealed that tCAFs were prominently associated with hypoxia and angiogenesis pathways, findings corroborated by the significant upregulation of tCAF markers (MME and NT5E) in ICC-derived CAFs under hypoxic conditions in vitro. Cell–cell communication analysis and spatial mapping uncovered that tCAFs might promote VI primarily through VEGF signaling interactions with endothelial cells. Integrative bioinformatics and RT-qPCR validation identified three key functional genes in tCAFs: SLC2A1, PTGS2, and PLOD2. In endothelial sprouting assays, pharmacological inhibition of SLC2A1 exerted a pronounced suppressive effect. Consistently, sprouting assays using ICC-derived CAFs with SLC2A1 knockdown confirmed that its downregulation significantly reduced endothelial sprouting capacity. Importantly, administration of the SLC2A1 inhibitor BAY-876 effectively suppressed tumor progression and intrahepatic metastasis in the orthotopic ICC mouse model. Our findings define a VI-associated cellular ecosystem and molecular landscape in ICC, unveiling a novel hypoxia–tCAFs–endothelial cells axis. Furthermore, we identify SLC2A1 as a clinically relevant therapeutic target, offering new insights into tumor VI. Full article

Pancreatic cancer (PC) usually results in poor survival with limited treatment options. Reactive oxygen species (ROS) play a key role in the action of HDAC inhibitors. In combination with a ROS generator, it can increase sensitivity to HDAC inhibitors and also overcome resistance to HDAC inhibitors. NQO1-bioactivatable drugs are efficient ROS generators. Therefore, to reduce HDAC inhibitor resistance and enhance its anti-pancreatic cancer activity, in this study, we reported a novel NQO1/HDAC dual-targeting agent, STY12, which exhibited potent anti-pancreatic cancer activity through ROS-mediated DNA damage. STY12 strongly inhibited HDAC1 and HDAC6 activity (IC₅₀ = 29 nM and 10 nM, respectively) and exhibited excellent reduction rates by NQO1 (k_cat/K_m = 5.59 × 10⁶ M⁻¹s⁻¹). STY12 showed good anti-proliferative effects on PC MIA PaCa-2, SW1990, and Capan-2 cells, with IC₅₀ values of 0.23 ± 0.01, 0.25 ± 0.01 and 0.14 ± 0.02 μM, respectively, and lower anti-proliferative effects against normal hTERT-HPNE and BEAS-2B cells. Mechanistic analysis revealed that STY12 suppressed the proliferation of MIA PaCa-2 cells by increasing the acetylation of histone 3 (H3) and α-tubulin, and increasing ROS-mediated DNA damage. Moreover, STY12 arrested the cell cycle at the S phase, inhibited the metastasis of MIA PaCa-2 cells, and promoted their apoptosis. Moreover, compared to SAHA and β-Lap, STY12 exhibited prominent in vivo antitumor activity with negligible toxic effects. Therefore, STY12 can serve as an effective NQO1/HDAC dual-targeting agent for the treatment of PC. Full article

Colorectal cancer (CRC) is an increasing health concern in low- and middle-income countries (LMICs), especially in Africa, driven by dietary shifts, urbanisation, infections, and limited treatment access. The gut microbiome plays a central role in CRC, while soil-transmitted helminths (STHs) exert complex effects that can promote or mitigate risk depending on species, infection intensity, and host context. This systematic review synthesised 17 human studies (2000–2026) examining helminth impacts on gut microbial diversity, revealing a dualistic pattern. Several studies reported that chronic or moderate helminth infections, such as Ascaris lumbricoides and Trichuris trichiura, were associated with increased bacterial richness and the expansion of beneficial taxa, including Paraprevotellaceae, Parabacteroides, Agathobacter, Ruminococcaceae, and Lactobacillus. These taxa are associated with the production of short-chain fatty acids (SCFAs), protection of the epithelial barrier, and regulation of the immune system, suggesting a potential buffering effect against inflammation-driven carcinogenesis. On the contrary, other studies demonstrated helminth-associated dysbiosis characterised by reduced diversity and enrichment of pro-inflammatory and oncogenic taxa. T. trichiura and Strongyloides stercoralis infections were associated with the expansion of Treponema succinifaciens, Streptococcus gallolyticus, Enterobacteriaceae, and Ruminococcus torques, which are linked to reduced gut microbiome diversity, pro-inflammatory states, and oncogenic processes. Furthermore, A. lumbricoides infections altered the host microbiome at the phylum level, with increased Proteobacteria and reduced Firmicutes and Bacteroidetes, alongside metabolome shifts in amino acid and lipid pathways that have been associated with tumourigenic processes. Collectively, the evidence shows that helminthiasis may either enrich potentially protective microbes or be associated with pro-tumourigenic dysbiosis, with outcomes shaped by species, infection intensity, and host context. Notably, none of the included studies directly assessed CRC, underscoring the fact that current evidence is indirect and mechanistic. Overall, helminths are associated with gut microbiome shifts in both potentially protective and potentially harmful directions. This systematic synthesis of human evidence provides an integrated understanding of how helminth-associated microbiome shifts may influence colorectal carcinogenesis and highlights the need for longitudinal mechanistic studies to clarify causality and inform biomarker discovery and prevention in endemic regions. Full article