Inhibit Tumor Metastasis Research Articles

Phytoconstituent-derived zingerone nanoparticles disrupt the cell adhesion mechanism and suppress cell motility in melanoma B16F10 cells

Combining phytochemicals and nanotechnology to improve the unfavorable innate properties of phytochemicals and develop them into potent nanomedicines to enhance antitumor efficacy has become a novel strategy for cancer chemoprevention. Melanoma is the most aggressive, metastatic, and deadly disease of the primary cutaneous neoplasms. In this study, we fabricated phytoconstituent-derived zingerone nanoparticles (NPs) and validated their effects on cell adhesion and motility in melanoma B16F10 cells. Our data indicated that zingerone NPs significantly induced cytotoxicity and anti-colony formation and inhibited cell migration and invasion. Moreover, zingerone NPs dramatically interfered with the cytoskeletal reorganization and markedly delayed the period of cell adhesion. Our results also revealed that zingerone NPs-mediated downregulation of MMPs (matrix metalloproteinases) activity is associated with inhibiting cell adhesion and motility. We further evaluated the effects of zingerone NPs on Src/FAK /Paxillin signaling, our data showed that zingerone NPs significantly inhibited the protein activities of Src, FAK, and Paxillin, indicating that they play important roles in zingerone NP-mediated anti-motility and anti-invasion in melanoma cells. Accordingly, the phytoconstituent-zingerone NPs can strengthen the inhibition of tumor growth, invasion, and metastasis in malignant melanoma. Altogether, these multi-pharmacological benefits of zingerone NPs will effectively achieve the purpose of melanoma prevention and invasion inhibition.

Petaloid Metal-Organic Frameworks for Resiquimod Delivery To Potentiate Antitumor Immunity.

The morphological features of materials significantly influence their interactions with cells, consequently affecting the cellular uptake of these materials. In this study, we examine the cellular uptake behavior of spherical metal-organic frameworks (MOFs) and petaloid MOFs, both possessing similar sizes and compositions. In comparison to spherical MOFs, dendritic cells (DCs) and macrophages exhibit superior phagocytic uptake of petaloid MOFs. Next, the results demonstrate that R848@petaloid MOFs more effectively promote the repolarization of tumor-associated macrophages (TAMs) from the M2 to M1 phenotype and the maturation of DCs. More importantly, the R848-loaded petaloid MOFs are found to significantly enhance the therapeutic effects of radiotherapy (RT) by eliciting antitumor responses. Furthermore, R848@petaloid MOFs combined with RT and αPD-L1 elicit a potent abscopal effect, effectively suppressing tumor metastasis. Therefore, this work proposes a new strategy to enhance the uptake of immunomodulators by immune cells through modulating the morphology of drug delivery carriers.

Carbon Free Radical (R⋅) Inactivates NF‐κB for Radical Capping Therapy

AbstractInactivating hyperactivated transcription factors can overcome tumor therapy resistance, but their undruggable features limit the development of conventional inhibitors. Here, we report that carbon‐centered free radicals (R⋅) can inactivate NF‐κB transcription by capping the active sites in both NF‐κB and DNA. We construct a type of thermosensitive R⋅ initiator loaded amphiphilic nano‐micelles to facilitate intracellular delivery of R⋅. At a temperature of 43 °C, the generated R⋅ engage in electrophilic radical addition towards double bonds in nucleotide bases, and simultaneously cap the sulfhydryl residues in NF‐κB through radical chain reaction. As a result, both NF‐κB nuclear translocation and NF‐κB‐DNA binding are suppressed, leading to a remarkable NF‐κB inhibition of up to 94.1 %. We have further applied R⋅ micelles in a clinical radiofrequency ablation tumor therapy model, showing remarkable NF‐κB inactivation and consequently tumor metastasis inhibition. Radical capping strategy not only provides a method to solve the heat‐sink effect in clinic tumor hyperthermia, but also suggests a new perspective for controllable modification of biomacromolecules in cancer therapy.

Carbon Free Radical (R⋅) Inactivates NF-κB for Radical Capping Therapy.

Inactivating hyperactivated transcription factors can overcome tumor therapy resistance, but their undruggable features limit the development of conventional inhibitors. Here, we report that carbon-centered free radicals (R⋅) can inactivate NF-κB transcription by capping the active sites in both NF-κB and DNA. We construct a type of thermosensitive R⋅ initiator loaded amphiphilic nano-micelles to facilitate intracellular delivery of R⋅. At a temperature of 43 °C, the generated R⋅ engage in electrophilic radical addition towards double bonds in nucleotide bases, and simultaneously cap the sulfhydryl residues in NF-κB through radical chain reaction. As a result, both NF-κB nuclear translocation and NF-κB-DNA binding are suppressed, leading to a remarkable NF-κB inhibition of up to 94.1 %. We have further applied R⋅ micelles in a clinical radiofrequency ablation tumor therapy model, showing remarkable NF-κB inactivation and consequently tumor metastasis inhibition. Radical capping strategy not only provides a method to solve the heat-sink effect in clinic tumor hyperthermia, but also suggests a new perspective for controllable modification of biomacromolecules in cancer therapy.

Colloidal Hydrogel for Sensitizing Microwave Ablation‐Induced in Situ Tumor Vaccination and Modulating Innate and Adaptive Immunotherapy

AbstractDrawing inspiration from recent advances in microwave ablation (MWA) induced in situ tumor vaccination, a colloidal hydrogel comprising amphoteric gelatin nanoparticles and poly (acrylic acid) (PAA)‐calcium carbonate nanorods (PAA‐CaCO3 NRs) is developed to deliver the microwave‐sensitive agent sodium fluoride (NaF) which can also act as a glycolysis inhibitor in conjunction with the blockade of the T‐cell Ig and ITIM domain (TIGIT), a coinhibitory receptor expressed by both natural killer (NK) cells and T cells. The combination of NaF with microwave (MW) thermal‐dynamic sensitization effectively reversed the acidic and immunosuppressive tumor microenvironment (TME). Moreover, the incorporation of anti‐TIGIT monoclonal antibody (aTIGIT) molecules amplified both the innate and adaptive immune responses by counteracting the exhaustion of NK and effective CD8+ T cells. This augmentation resulted in enhanced tumor elimination and suppression of tumor metastasis and recurrence. Thus, this study underscores the potential of colloidal hydrogel‐sensitized MWA therapy, in conjunction with aTIGIT treatments, as a promising clinical strategy for in situ cancer vaccination.

A homologous membrane-camouflaged self-assembled nanodrug for synergistic antitumor therapy

Limited success has been achieved in ferroptosis-induced cancer treatment due to the challenges related to low production of toxic reactive oxygen species (ROS) and inherent ROS resistance in cancer cells. To address this issue, a self-assembled nanodrug have been investigated that enhances ferroptosis therapy by increasing ROS production and reducing ROS inhibition. The nanodrug is constructed by allowing doxorubicin (DOX) to interact with Fe2+ through coordination interactions, forming a stable DOX-Fe2+ chelate, and this chelate further interacts with sorafenib (SRF), resulting in a stable and uniform nanoparticle. In tumor cells, overexpressed glutathione (GSH) triggers the disassembly of nanodrug, thereby activating the drug release. Interestingly, the released DOX not only activates nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) to produce abundant H2O2 production for enhanced ROS production, but also acts as a chemotherapeutics agent, synergizing with ferroptosis. To enhance tumor selectivity and improve the blood clearance, the nanodrug is coated with a related cancer cell membrane, which enhances the selective inhibition of tumor growth and metastasis in a B16F10 mice model. Our findings provide valuable insights into the rational design of self-assembled nanodrug for enhanced ferroptosis therapy in cancer treatment. Statement of significanceFerroptosis is a non-apoptotic form of cell death induced by the iron-regulated lipid peroxides (LPOs), offering a promising potential for effective and safe anti-cancer treatment. However, two significant challenges hinder its clinical application: 1) The easily oxidized nature of Fe2+ and the low concentration of H2O2 leads to a low efficiency of intracellular Fenton reaction, resulting in poor therapeutic efficacy; 2) The instinctive ROS resistance of cancer cells induce drug resistance. Therefore, we developed a simple and high-efficiency nanodrug composed of self-assembling by Fe2+ sources, H2O2 inducer and ROS resistance inhibitors. This nanodrug can effectively deliver the Fe2+ sources into tumor tissue, enhance intracellular concentration of H2O2, and reduce ROS resistance, achieving a high-efficiency, precise and safe ferroptosis therapy.

Repurposing hemostatic drug desmopressin in AVPR2-expressing triple-negative breast cancer: Target expression analysis and preclinical antineoplastic effects on tumor growth and metastatic progression.

e15087 Background: Desmopressin (dDAVP) is a hemostatic drug that acts as an agonist of the arginine vasopressin receptor 2 (AVPR2) that is present in vascular and malignant cells. Preclinical data show that dDAVP triggers cytostatic mechanisms, blocking angiogenesis and reducing metastases by limiting the survival of circulating tumor cells. Triple-negative breast cancer (TNBC) is associated with poor prognosis due to limited response to therapy and frequent early metastatic recurrence. Considering the unsatisfied clinical need for novel therapeutic options in TNBC, we evaluated the antitumoral activity of dDAVP on experimental models of TNBC, alone or in addition to chemotherapy. We also assessed the expression and clinical impact of AVPR2 in breast cancer samples. Methods: Human and murine TNBC cell lines were used for in vitro experiments. Target expression was assessed by qPCR and immunohistochemistry (IHC), in experimental or clinical tumors (NCT01606072). Effects of dDAVP were evaluated by proliferation, clonogenic, 3D growth and chemotaxis assays, qPCR arrays, and confocal microscopy. Local and distant tumor progression were assessed in vivo in nude or BALB/c mice. TIMER2.0 and UCSC Xena platforms (BRCA TCGA /n = 1260) were used for bioinformatic studies. Results: dDAVP significantly reduced growth and chemotaxis of AVPR2-expressing TNBC cells. Cytostatic effects of dDAVP were associated with altered actin cytoskeleton dynamics and differential expression of angiogenesis and metastasis-related genes. Cooperative effects were observed in vitro and in vivo after combining dDAVP with taxane or alkylating therapy. Tumor-bearing mice were treated with intravenous injections of dDAVP (0.3 µg/kg, thrice weekly) in combination with weekly cycles of paclitaxel (10 mg/kg i.p.) or carmustine (25 mg/kg i.p.). Combination regimens resulted in greater survival and tumor growth and metastasis inhibition. Bioinformatic analysis of the TCGA database showed that AVPR2 had a positive prognostic impact on overall survival in breast cancer patients, especially in the basal-like molecular subtype. AVPR2 also correlated with different immune cell infiltrates such as NK and dendritic cells, and CD4+ and CD8+ T cells. Moreover, AVPR2 expression was detected by IHC in 6/18 breast cancer clinical samples using a small cohort of surgical specimens. Conclusions: AVPR2 expression is associated with improved outcomes in patients with TNBC. Agonist activation of AVPR2 using dDAVP leads to cancer cell growth inhibition in TNBC cell lines and mouse models. We propose dDAVP as a potential novel therapeutic option for treating TNBC either as monotherapy or in combination with chemotherapy. The therapeutic impact of its addition to immune checkpoint inhibitors remains to be explored.

Genome-wide CRISPR screening identifies the pivotal role of ANKRD42 in colorectal cancer metastasis through EMT regulation.

Colorectal cancer (CRC), a pervasive and lethal malignancy of gastrointestinal cancer, imposes significant challenges due to the occurrence of distant metastasis in advanced stages. Understanding the intricate regulatory mechanisms driving CRC distant metastasis is of paramount importance. CRISPR-Cas9 screening has emerged as a powerful tool for investigating tumor initiation and progression. However, its application in studying CRC distant metastasis remains largely unexplored. To establish a model that faithfully recapitulates CRC liver metastasis in patients, we developed an in vivo genome-wide CRISPR-Cas9 screening approach using a spleen-injected liver metastasis mouse model. Through comprehensive screening of a whole-genome sgRNA library, we identified ANKRD42 as a pivotal regulatory gene facilitating CRC liver metastasis. Analysis of the TCGA database and our clinical cohorts unveiled heightened ANKRD42 expression in metastases. At the cellular level, the attenuation of ANKRD42 impaired the migration and invasion processes of tumor cells. In vivo experiments further validated these observations, highlighting the diminished liver metastatic capacity of tumor cells upon ANKRD42 knockdown. To unravel the specific mechanisms by which ANKRD42 regulates CRC distant metastasis, we leveraged patient-derived organoid (PDO) models. Depleting ANKRD42 in PDOs sourced from liver metastases precipitated the downregulation of pivotal genes linked to epithelial-mesenchymal transition (EMT), including CDH2 and SNAI2, thereby effectively suppressing tumor metastasis. This study not only establishes a conceptual framework but also identifies potential therapeutic avenues for advanced-stage distant metastasis in CRC patients.

Bioelectrocatalytic Activity of One-Dimensional Porous Pt Nanoribbons for Efficient Inhibition of Tumor Growth and Metastasis.

Designing and synthesizing one-dimensional porous Pt nanocrystals with unique optical, electrocatalytic, and theranostic properties are gaining lots of attention, especially to overcome the challenges of tumor recurrence and resistance to platinum-based chemotherapy. Herein, we represented an interesting report of a one-step and facile strategy for synthesizing multifunctional one-dimensional (1D) porous Pt nanoribbons (PtNRBs) with highly efficient therapeutic effects on cancer cells based on inherent electrocatalytic activity. The critical point in the formation of luminescent porous PtNRBs was the use of human hemoglobin (Hb) as a shape-regulating, stabilizing, and reducing agent with facet-specific domains on which fluorescent platinum nanoclusters at first are aggregated by aggregation-induced emission phenomena (AIE) and then crystallized into contact and penetration twins, as intermediate products, followed by shaping of the final luminescent porous ribbon nanomaterials, owing to oriented attachment association via the Ostwald ripening mechanism. From a medical point of view, the key strategy for effective cancer therapy occured via using low-dosage ethanol in the presence of electroactive porous PtNRBs based on intracellular ethanol oxidation-mediated reactive oxygen species (ROS) generation. The role of heme groups of Hb, as electrocatalytically active centers, was successfully demonstrated in both kinetically controlled anisotropic growth of NRBs for slowing down the reduction of Pt(II) followed by oligomerization of Pt(II)-Hb complexes via platinophilic interactions as well as electrocatalytic ethanol oxidation for therapy. Interestingly, hyaluronic acid-targeted (HA) Hb-PtNRB in the presence of low-dose ethanol caused extraordinary arrest of tumor growth and metastasis with no recurrence even after the treatment course stopped, which caused elongation of tumor-bearing mice survival. HA/Hb-PtNRB was completely biocompatible and exhibited high tumor-targeting efficacy for fluorescent imaging of breast tumors. Therefore, the synergistic electrocatalytic activity of PtNRBs is presented as an efficient and safe cancer theranostic method for the first time.

Combination of MHI148 Targeted Photodynamic Therapy and STING Activation Inhibits Tumor Metastasis and Recurrence.

Metastasis and recurrence are notable contributors to mortality associated with breast cancer. Although immunotherapy has shown promise in mitigating these risks after conventional treatments, its effectiveness remains constrained by significant challenges, such as impaired antigen presentation by dendritic cells (DCs) and inadequate T cell infiltration into tumor tissues. To address these limitations, we developed a multifunctional nanoparticle platform, termed GM@P, which consisted of a hydrophobic shell encapsulating the photosensitizer MHI148 and a hydrophilic core containing the STING agonist 2'3'-cGAMP. This design elicited robust type I interferon responses to activate antitumor immunity. The GM@P nanoparticles loaded with MHI148 specifically targeted breast cancer cells. Upon exposure to 808 nm laser irradiation, the MHI148-loaded nanoparticles produced toxic reactive oxygen species (ROS) to eradicate tumor cells through photodynamic therapy (PDT). Notably, PDT stimulated immunogenic cell death (ICD) to foster the potency of antitumor immune responses. Furthermore, the superior photoacoustic imaging (PAI) capabilities of MHI148 enabled the simultaneous visualization of diagnostic and therapeutic procedures. Collectively, our findings uncovered that the combination of PDT and STING activation facilitated a more conducive immune microenvironment, characterized by enhanced DC maturation, infiltration of CD8+ T cells, and proinflammatory cytokine release. This strategy stimulated local immune responses to augment systemic antitumor effects, offering a promising approach to suppress tumor growth, inhibit metastasis, and prevent recurrence.

Dendrimer/metal-phenolic nanocomplexes encapsulating CuO2 for targeted magnetic resonance imaging and enhanced ferroptosis/cuproptosis/chemodynamic therapy by regulating the tumor microenvironment

The combination of ferroptosis, cuproptosis, and chemodynamic therapy (CDT) would be a potential strategy for tumor diagnosis and enhanced treatment. However, the therapeutic effect was severely limited by the lack of specific delivery of catalytic ions and the low Fenton reaction efficiency in tumor microenvironment (TME) with excess glutathione, limited acidity and insufficient endogenous hydrogen peroxide. In this work, p-carboxybenzenesulfonamide (BS), a carbonic anhydrase IX (CA IX) inhibitor, was modified on the surface of generation-5 poly(amidoamine) dendrimer to load copper peroxide nanoparticles, which were complexed with iron (Fe)-tannic acid (TF) networks for targeted magnetic resonance (MR) imaging and enhanced ferroptosis/cuproptosis/CDT by regulating TME. The formed CuO2@G5-BS/TF nanocomplexes with an average size of 39.4 nm could be specifically accumulated at tumor site and effectively internalized by metastatic 4T1 cells via the specific interaction between BS and CA IX over-expressed on tumor cells. Meanwhile, the inhibition of CA IX activity could not only decrease the intracellular pH to accelerate Fe3+/Cu2+ release, H2O2 self-supply and Fenton reaction, but also suppress tumor metastasis by alleviating the extracellular acidity in TME. Moreover, the reduction of Fe3+/Cu2+ by intracellular glutathione (GSH) could further amplify ROS generation and enhance CDT efficacy, and the GSH depletion could in turn inhibit GPX-4 mediated antioxidant reaction to induce ferroptosis, resulting in effective therapeutic efficacy. In vivo experimental results demonstrated that CuO2@G5-BS/TF could provide better tumor MR imaging, effectively inhibit the growth and metastasis of 4T1 breast tumors, and be metabolized without significant systemic toxicity. Thus, CuO2@G5-BS/TF nanocomplexes provided a new approach for targeted MR imaging and enhanced ferroptosis/cuproptosis/CDT of triple-negative breast cancer. Statement of significanceTaking the advantage of dendrimer and metal-phenolic system, stable CuO2@G5-BS/TF nanocomplexes with an average size of 39.4 nm were synthesized to efficiently load Fe3+ and CuO2 nanoparticles for TNBC treatment and MR imaging. CuO2@G5-BS/TF nanocomplexes could target tumor cells overexpressing CAIX via the specific binding with BS, and the inhibition of CAIX activity could not only decrease the intracellular pH to accelerate Fe3+/Cu2+ release, H2O2 self-supply and Fenton reaction, but also suppress tumor metastasis by alleviating the extracellular acidity. The reduction of Fe3+/Cu2+ by intracellular GSH could further amplify ·OH generation, and the GSH depletion could in turn inhibit GPX-4 mediated antioxidant reaction to induce ferroptosis, resulting in effective therapeutic efficacy by enhanced ferroptosis/cuproptosis/CDT via tumor microenvironment regulation.

Personalized Nanovaccines Enhance Lymph Node Accumulation and Reprogram the Tumor Microenvironment for Improved Photodynamic Immunotherapy.

Tumor immunotherapy has emerged as an efficacious therapeutic approach that mobilizes the patient's immune system to achieve durable tumor suppression. Here, we design a photodynamic therapy-motivated nanovaccine (Dex-HDL/ALA-Fe3O4) co-delivering 5-aminolevulinic acid and Fe3O4 nanozyme that demonstrate a long-term durable immunotherapy strategy. After vaccination, the nanovaccine exhibits obvious tumor site accumulation, lymph node homing, and specific and memory antitumor immunity evocation. Upon laser irradiation, Dex-HDL/ALA-Fe3O4 effectively generates reactive oxygen species at the tumor site not only to induce the immunogenic cell death-cascade but also to trigger the on-demand release of full types of tumor antigens. Intriguingly, Fe3O4 nanozyme-catalyzed hydrogen peroxide generated oxygen for alleviating tumor hypoxia and modifying the inhibitory tumor microenvironment, thereby exhibiting remarkable potential as a sensitizer. The intravenous administration of nanovaccines in diverse preclinical cancer models has demonstrated remarkable tumor regression and inhibition of postoperative tumor recurrence and metastasis, thereby enabling personalized treatment strategies against highly heterogeneous tumors.

MOF-based nanoparticles for tumor-targeted protein degradation and photodynamic therapy induce enhanced anti-tumor immunity

Combining proteolysis targeting chimeras (PROTACs) with photodynamic therapy (PDT) is a promising strategy for cancer treatment. However, the therapeutic efficacy is impaired due to the poor water solubility or the unsatisfactory tumor distribution of drugs. Herein, we developed a Hyaluronan (HA) coating MOF-based nanoplatform (ZMCH) to achieve the combined therapy of PROTACs and PDT with tumor-specific delivery and local drug release. The PROTACs molecules and photosensitizers could be easily wrapped into the nanoparticles via the self-assembly of zinc ions and 2-methylimidazole, which is a universal encapsulation approach for the conventional PROTACs or photosensitizers. As a proof-of-concept, we demonstrated that the designed ZMCH nanoreactor effectively suppresses tumor growth in the 4T1-tumor-bearing mice model, resulting from the synergistic effect of MZ1-mediated protein degradation and the Ce6-mediated reactive oxygen species (ROS) damage. Importantly, the ZMCH-induced therapy exhibited the enhanced antitumor T-cell immunity by regulating immunosuppressive tumor microenvironment, thereby effectively inhibiting tumor metastasis in the lungs. This work thus provides a novel approach and insights for the combination therapy of protein degradation and PDT in clinical cancer treatment.

Self‐Delivered Transformable Nanosystem Capable of Enhancing Photodynamic Effectiveness and Multi‐Target Ameliorating Immunosuppression for Treatment of Breast Cancer and Lung Metastasis

AbstractHomogeneous distribution and adequate accumulation of photosensitizer in tumor are essential for effective photodynamic therapy (PDT). However, the intricate tumor microenvironment (TME) often poses great challenges to the deep penetration and retention of therapeutic agents in tumor. Moreover, the important effect of PDT to induce specific antitumor immune response is impeded by multiple immunosuppressive mechanisms within TME. Confronting these issues, here a rationally designed nanosystem (SUN‐NPA) with acid‐responsive sphere‐to‐fiber transformation ability by leveraging the characters of drug molecules is proposed to achieve self‐delivery of photosensitizer Chlorin e6 (Ce6) and two small‐molecule immunomodulators, metformin (MET) and sunitinib (SUN). The spatiotemporal controlled transformation enables homogeneous distribution and high accumulation of drugs to achieve enduring PDT and complete tumor elimination. Meanwhile, the co‐delivered MET and SUN alleviate tumor immunosuppression from multiple aspects, effectively synergizing with PDT to ignite potent host immune response and long‐lasting immunological memory against tumor cells. The artful integration of enhanced PDT and activated antitumor immunity realized by SUN‐NPA leads to the significant inhibition of tumor growth and metastasis, exhibiting great potential for oncotherapy.

Self-Adaptive Photodynamic-to-Photothermal Switch for Smart Antitumor Photoimmunotherapy.

Photodynamic therapy (PDT) and photothermal therapy (PTT) possess different merits in cancer phototherapy, but the tumor microenvironment becomes unfavorable during the phototheranostic progress. Herein, we report a self-adaptive cyanine derivative Cy5-TPA with the PDT-dominated state to PTT-dominated state autoswitch feature for enhanced photoimmunotherapy. The incorporation of rotatable triphenylamine (TPA) moiety renders Cy5-TPA with the temperature or intramolecular-motion regulated photoactivities, which shows preferable reactive oxygen species (ROS) generation at lower temperature while stronger photothermal conversion at higher ones. Such a promising feature permits the in situ switch from PDT-dominated state to PTT-dominated state along with intratumoral temperature increase during laser irradiation, which also works in line with the concurrently reduced intratumoral oxygen level, exhibiting a self-adaptive phototherapeutic behavior to maximize the phototherapeutic antitumor outcome. Most importantly, the self-adaptive PDT-dominated state to PTT-dominated state switch also facilitates the sequential generation and release of damage-associated molecular patterns during immunogenic cell death (ICD). Hence, Cy5-TPA demonstrates excellent photoimmunotherapy performance in ICD induction, dendritic cell maturation, and T cell activation for tumor eradication and metastasis inhibition.

Smart Nanoassembly Enabling Activatable NIR Fluorescence and ROS Generation with Enhanced Tumor Penetration for Imaging-Guided Photodynamic Therapy.

Fluorescence imaging-guided photodynamic therapy (FIG-PDT) holds promise for cancer treatment, yet challenges persist in poor imaging quality, phototoxicity, and insufficient anti-tumor effect. Herein, a novel nanoplatform, LipoHPM, designed to address these challenges, is reported. This approach employs an acid-sensitive amine linker to connect a biotin-modified hydrophilic polymer (BiotinPEG) with a new hydrophobic photosensitizer (MBA), forming OFF-state BiotinPEG-MBA (PM) micelles via an aggregation-caused quenching (ACQ) effect. These micelles are then co-loaded with the tumor penetration enhancer hydralazine (HDZ) into pH-sensitive liposomes (LipoHPM). Leveraging the ACQ effect, LipoHPM is silent in both fluorescence and reactive oxygen species (ROS) generation during blood circulation but restores both properties upon disassembly. Following intravenous injection in tumor-bearing mice, LipoHPM actively targets tumor cells overexpressing biotin-receptors, contributing to enhanced tumor accumulation. Upon cellular internalization, LipoHPM disassembles within lysosomes, releasing HDZ to enhance tumor penetration and inhibit tumor metastasis. Concurrently, the micelles activate fluorescence for tumor imaging and boost the production of both type-I and type-II ROS for tumor eradication. Therefore, the smart LipoHPM synergistically integrates near-infrared emission, activatable tumor imaging, robust ROS generation, efficient anti-tumor and anti-metastasis activity, successfully overcoming limitations of conventional photosensitizers and establishing itself as a promising nanoplatform for potent FIG-PDT applications.

Abstract PO4-24-06: The function of GATA3-PARP1 complex in breast cancer during GATA3-mediated cellular reprogramming

Abstract In eukaryotic cells, genomic DNA is packaged into chromatin, a complex of DNA, histones, and other proteins. Chromatin acts as a physical barrier for many transcription factors, preventing them from efficiently binding to their recognition sequences within the nucleosome. Pioneer factors are a class of transcription factors that bind to nucleosomes and activate silent chromatin. Pioneer factors are frequently involved in various immune cell pathways, tissue development, and homeostasis, thereby, underscoring their important roles in development and disease. Previous research found that pioneer factors have at least three fundamental properties: However, the molecular mechanisms of pioneer factor-mediated cellular reprogramming (mesenchymal-to-epithelial transition (MET)) are largely unknown. For this study, I will use GATA3-mediated MET to study the pioneer factor-mediated cellular reprogramming. GATA3 is a transcription factor that plays a pivotal role in mammary gland development, luminal epithelial differentiation, and cellular reprogramming. Additionally, it has been implicated in various cellular processes such as proliferation, migration, and invasion and is a critical regulator in breast cancer, including triple-negative breast cancer (TNBC). In TNBC, GATA3 expression is often downregulated, correlating with poor prognosis. Our lab and others have shown that GATA3 functions as a pioneer factor that actively changes the chromatin state from closed to open. In luminal breast cancer cells, ER-alpha and FOXA1 are well-known GATA3 co-factors. In mesenchymal breast cancer cells, GATA3 can suppress tumor metastasis by inducing MET in the absence of well-known GATA3 co-factors FOXA1 and ER-alpha1. These findings suggest that GATA3 works with additional, unknown co-factors during MET. We have been studying how GATA3 activates silent chromatin. More than 7 million GATA3 motifs exist in the human genome, yet the experimental data from GATA3 ChIP-seq analysis indicates less than 1% of the motifs are occupied by the pioneer factor, GATA3. In addition to binding selectivity, we have shown that the pioneer factor action is site-specific (context-dependent) and only induces chromatin opening and enhancer formation at a subset of binding sites. To identify a novel co-factor that is involved in GATA3-mediated MET, we performed a rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) assay, which identified the chromatin-modification enzyme, Poly ADP-ribose polymerase 1 (PARP1), as a potential GATA3 co-factor. PARP1 is essential for gene expression regulation and initiating DNA repair. Previous studies have shown PARP1 as a co-factor to the pioneer factor, SOX2. Our genomics data strongly suggest that PARP1 is involved in such context-dependent action of GATA3. Our overall goal is to investigate GATA3-PARP1 interaction during MET to understand the role of pioneer factors in cellular reprogramming. To do so, we are dissecting the GATA2-PARP1 function in two distinct steps: Citation Format: Mikhala Cooper, Motoki Takaku. The function of GATA3-PARP1 complex in breast cancer during GATA3-mediated cellular reprogramming [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-24-06.

Honokiol Suppresses Cell Proliferation and Tumor Migration through ROS in Human Anaplastic Thyroid Cancer Cells.

Honokiol is a natural polyphenolic compound extracted from Magnolia officinali, which is commonly used material in Chinese herbal medicine, has a variety of biological functions, including anti-tumor, anti-oxidant, anti-inflammation, anti-microbial and anti-allergy. Although honokiol has numerous beneficial effects on human diseases, the underlying mechanisms of tumor metastasis are still unclear. Previously, we reported that honokiol suppresses thyroid cancer cell proliferation with cytotoxicity through cell cycle arrest, apoptosis, and dysregulation of intracellular hemostasis. Herein, we hypothesized that the antioxidant effect of honokiol might play a critical role in thyroid cancer cell proliferation and migration. The cell viability assays, cellular reactive oxygen species (ROS) activity, cell migration, and immunoblotting were performed after cells were treated with honokiol. Based on this hypothesis, we first demonstrated that honokiol suppresses cell proliferation in two human anaplastic thyroid carcinoma (ATC) cell lines, KMH-2 and ASH-3, within a dosage- and time-dependent manner by cell counting kit-8 (CCK-8) assay. Next, we examined that honokiol induced ROS activation and could be suppressed by pre-treated with an antioxidant agent, N-acetyl-l-cysteine (NAC). Furthermore, the honokiol suppressed cell proliferation can be rescued by pre-treated with NAC. Finally, we demonstrated that honokiol inhibited ATC cell migration by modulating epithelial-mesenchymal transition (EMT)-related markers by Western blotting. Taken together, we provided the potential mechanism for treating ATC cells with honokiol, which significantly suppresses tumor proliferation and inhibits tumor metastasis in vitro through reactive oxygen species (ROS) induction.

Fish‐Derived Collagen: A Promising Biomaterial for Regulating the Migration Behavior of MCF‐7 Cells

The uncontrollable migration of cancer cells is one of the reasons for the poor prognosis. The interaction between collagen and cellular processes is usually dominated by the full triple‐helix structure of collagen. However, it remains to be explored how the collagen configuration affects the migration behaviors of cancer cells. Michigan cancer foundation‐7 cells are chosen to study this relationship. Meanwhile, the grass carp is one of the representative fish species in Hubei and is virtually unaffected by zoonotic diseases. Therefore, grass carp‐derived collagen is prepared and used to modulate the migration behaviors. The collagen sample is pretreated via several procedures including the hydrothermal process and EDC/NHS, respectively. The underlying mechanisms affecting migration behavior are explored by tuning the degree of denaturation, assembly states, and cross‐linking conditions of collagen. Results demonstrate that moderate cross‐linking and assembly contribute to the migration processes, while denaturation significantly suppresses migration. Of particular note is the positive correlation of F‐actin expression levels with these phenomena. More importantly, the hydrophilic and hydrophobic properties of the collagen surface also affect the migration process. In summary, the study may provide insights to flexibly tune the migration behavior of cancer cells, which may be promising in inhibiting tumor metastasis.

Circadian regulation of cancer stem cells and the tumor microenvironment during metastasis.

The circadian clock regulates daily rhythms of numerous physiological activities through tightly coordinated modulation of gene expression and biochemical functions. Circadian disruption is associated with enhanced tumor formation and metastasis via dysregulation of key biological processes and modulation of cancer stem cells (CSCs) and their specialized microenvironment. Here, we review how the circadian clock influences CSCs and their local tumor niches in the context of different stages of tumor metastasis. Identifying circadian therapeutic targets could facilitate the development of new treatments that leverage circadian modulation to ablate tumor-resident CSCs, inhibit tumor metastasis and enhance response to current therapies.