Tumor Research Articles

Ferroptosis-related gene signature for predicting prognosis and identifying potential therapeutic drug in EGFR wild-type lung adenocarcinoma

Epidermal growth factor receptor wild type lung adenocarcinoma (EGFRWT LUAD) still has limited treatment options and unsatisfactory clinical outcomes. Ferroptosis, as a form of cell death, has been reported to play a dual role in regulating tumor cell survival. In this study, we constructed a 3-ferroptosis-gene signature, FeSig, and verified its accuracy and efficacy in predicting EGFRWT LUAD prognosis at both the RNA and protein levels. Patients with higher FeSig scores were found to have worse clinical outcomes. Additionally, we explored the relationship between FeSig and tumor microenvironment, revealing that enhanced interactions between fibroblasts and tumor cells in FeSighigh patients causing tumor resistance to ferroptosis. To address this challenge, we screened potential drugs from NCI-60 (The US National Cancer Institute 60 human tumour cell line anticancer drug screen) and Connectivity map database, ultimately identifying 6-mercatopurine (6-MP) as a promising candidate. Both in vitro and in vivo experiments demonstrated its efficacy in treating FeSighigh EGFRWT LUAD tumor models. In summary, we develop a novel FeSig for predicting prognosis and guiding drug application.

INVESTIGASI KADAR HEMOGLOBIN PASIEN CANCER PAYUDARA PRE DAN POST KEMOTERAPI

Anemia refers to a decrease in serum hemoglobin concentration to pathological levels where hemoglobin level in women is <12 g/dl and in men <14 g/dl. More than 40% of cancer patients undergoing chemotherapy are subjected to anemia. As chemotherapy drugs are unable to distinguish between normal and neoplastic cells, their destructive nature results in a reduced number of red blood cells through the hemolysis process. The principles of chemotherapy are required to maintain a number of normal cells to avoid unintended side effects. This study aimed to investigate the hemoglobin levels before and after chemotherapy. The method of this study was qualitative, using a case study approach. The study sample consisted of three individuals, and the hemoglobin levels were assessed using the EasyTouch hemoglobinometer. The data were processed using Colaizzi’s analysis method: reading, meaning formulation, and theming. The results of this study were presented in three themes: (1) anemia occurred due to oxidative stress, (2) a decrease in the number of red blood cells caused by lysis; and (3) PRC transfusion as a way to overcome anemia. It can be concluded that a decrease in the number of red blood cells is inevitable. Therefore, patients are advised to get sufficient rest, increase their intake of nutritious food, and consume iron vitamins.

Tissue microarray analyses of the essential DNA repair factors ATM, DNA-PKcs and Ku80 in head and neck squamous cell carcinoma

BackgroundHead and neck squamous cell carcinoma (HNSCC) negative for Human Papillomavirus (HPV) has remained a difficult to treat entity, whereas tumors positive for HPV are characterized by radiosensitivity and favorable patient outcome. On the cellular level, radiosensitivity is largely governed by the tumor cells` ability to repair radiation-induced DNA double-strand breaks (DSBs), but no biomarker is established that could guide clinical decision making. Therefore, we tested the impact of the expression levels of ATM, the central kinase of the DNA damage response as well as DNA-PKcs and Ku80, two major factors in the main DSB repair pathway non-homologous end joining (NHEJ).MethodsA tissue microarray of a single center HNSCC cohort was stained for ATM, DNA-PKcs and Ku80 and the expression scored based on staining intensity and the percentages of tumor cells stained. Scores were correlated with clinicopathological parameters and survival.ResultsSamples from 427 HNSCC patients yielded interpretable stainings and were scored following an established algorithm. The majority of tumors showed strong expression of both NHEJ factors, whereas the expression of ATM varied more. The expression scores of ATM and DNA-PKcs were not associated with patient survival. For HPV-negative HNSCC, the minority of tumors without strong Ku80 expression trended towards superior survival when treatment included radiotherapy. Focusing stronger on staining intensity to define the subgroup with lowest and therefore potentially insufficient expression levels in the HPV-negative subgroup, we observed significantly better overall survival for patients treated with radiotherapy but not with surgery alone.ConclusionsOur data suggest that HPV-negative HNSCC with particularly low Ku80 expression represent a highly radiosensitive subpopulation. Confirmation in independent cohorts is required.

A Multifunctional Exosome with Dual Homeostasis Disruption Augments cGAS-STING-Mediated Tumor Immunotherapy by Boosting Ferroptosis.

Ferroptosis has shown great potential in activating antitumor immunity. However, the cunning tumor cells can evade ferroptosis by increasing the efflux of iron and promoting the production of the reductant glutathione to mitigate oxidative stress. Herein, a multifunctional exosome loaded with manganese-doped iron oxide nanoparticles (MnIO), GW4869, and l-buthionine sulfoximine (BSO) is developed to disrupt the iron metabolism homeostasis and redox homeostasis to enhance tumor immunotherapy. The efficient transport of MnIO by exosomes and the inhibition of iron exocytosis by GW4869 led to a high retention of up to 29.57% ID/g for iron in the tumors. Such a high retention of iron, in combination with the BSO-induced disruption of the redox homeostasis, effectively promotes the ferroptosis of tumor cells. Consequently, the multifunctional exosomes that noticeably enhance ferroptosis by dual homeostasis disruption provoke the cGAS-STING-based antitumor immune response and effectively suppress tumor growth and lung metastasis in orthotopic breast cancer.

Fibrolytic vaccination against ADAM12 reduces desmoplasia in preclinical pancreatic adenocarcinomas.

A hallmark feature of pancreatic ductal adenocarcinoma (PDAC) is massive intratumoral fibrosis, designated as desmoplasia. Desmoplasia is characterized by the expansion of cancer-associated fibroblasts (CAFs) and a massive increase in extracellular matrix (ECM). During fibrogenesis, distinct genes become reactivated specifically in fibroblasts, e.g., the disintegrin metalloprotease, ADAM12. Previous studies have shown that immunotherapeutic ablation of ADAM12+ cells reduces fibrosis in various organs. In preclinical mouse models of PDAC, we observe ADAM12 expression in CAFs as well as in tumor cells but not in healthy mouse pancreas. Therefore, we tested prophylactic and therapeutic vaccination against ADAM12 in murine PDAC and observed delayed tumor growth along with a reduction in CAFs and tumor desmoplasia. This is furthermore associated with vascular normalization and alleviated tumor hypoxia. The ADAM12 vaccine induces a redistribution of CD8+ T cells within the tumor and cytotoxic responses against ADAM12+ cells. In summary, vaccination against the endogenous fibroblast target ADAM12 effectively depletes CAFs, reduces desmoplasia and delays the growth of murine PDACs. These results provide proof-of-principle for the development of vaccination-based immunotherapies to treat tumor desmoplasia.

The Role of Heat Shock Factor 1 in Preserving Proteomic Integrity During Copper-Induced Cellular Toxicity

Copper is crucial for many physiological processes across mammalian cells, including energy metabolism, neurotransmitter synthesis, and antioxidant defense mechanisms. However, excessive copper levels can lead to cellular toxicity and “cuproptosis”, a form of programmed cell death characterized by the accumulation of copper within mitochondria. Tumor cells are less sensitive to this toxicity than normal cells, the mechanism for which remains unclear. We address this important issue by exploring the role of heat shock factor 1 (HSF1), a transcription factor that is highly expressed across several types of cancer and has a crucial role in tumor survival, in protecting against copper-mediated cytotoxicity. Using pancreatic ductal adenocarcinoma cells, we show that excessive copper triggers a proteotoxic stress response (PSR), activating HSF1 and that overexpressing HSF1 diminishes intracellular copper accumulation and prevents excessive copper-induced cell death and amyloid fibrils formation, highlighting HSF1′s role in preserving proteasomal integrity. Copper treatment decreases the lipoylation of dihydrolipoamide S-acetyltransferase (DLAT), an enzyme necessary for cuproptosis, induces DLAT oligomerization, and induces insoluble DLAT formation, which is suppressed by overexpressing HSF1, in addition to enhancing the interaction between HSF1 and DLAT. Our findings uncover how HSF1 protects against copper-induced damage in cancer cells and thus represents a novel therapeutic target for enhancing copper-mediated cancer cell death.

Self-supply of hydrogen peroxide by a bimetal-based nanocatalytic platform to enhance chemodynamic therapy for tumor treatment.

The Tumor Microenvironment (TME) is characterized by low pH, hypoxia, and overexpression of glutathione (GSH). Owing to the complexity of tumor pathogenesis and the heterogeneity of the TME, achieving satisfactory efficacy with a single treatment method is difficult, which significantly impedes tumor treatment. In this study, composite nanoparticles of calcium-copper/alginate-hyaluronic acid (CaO2-CuO2@SA/HA NC) with pH and GSH responsiveness were prepared for the first time through a one-step synthesis using hyaluronic acid (HA) as a targeting ligand. Nanoparticles loaded with H2O2 can enhance the ChemoDynamic Therapy (CDT) effects. Simultaneously, Cu2+ can generate oxygen in the TME and alleviate hypoxia in tumor tissue. Cu2+ and H2O2 undergo the Fenton reaction to produce cytotoxic hydroxyl radicals and Ca2+ ions, which enhance the localization and clearance of nanoparticles in tumor cells. Additionally, HA and sodium alginate (SA) were utilized to improve the targeting and biocompatibility of the nanoparticles. FTIR, XRD, DLS, SEM, TEM, and other analytical methods were used to investigate their physical and chemical properties. The results indicate that the CaO2-CuO2@SA/HA NC prepared using a one-step method had a particle size of 220 nm, a narrow particle size distribution, and a uniform morphology. The hydrogen peroxide self-supplied nanodrug delivery system exhibited excellent pH-responsive release performance and glutathione-responsive •OH release ability while also reducing the level of reactive oxide species (ROS) quenching. In vitro cell experiments, no obvious side effects on normal tissues were observed; however, the inhibition rate of malignant tumors HepG2 and DU145 exceeded 50%. The preparation of CaO2-CuO2@SA/HA NC nanoparticles, which can achieve both chemokinetic therapy and ion interference therapy, has demonstrated significant potential for clinical applications in cancer therapy.

Polyclonal-to-monoclonal transition in colorectal precancerous evolution.

Unravelling the origin and evolution of precancerous lesions is crucial for effectively preventing malignant transformation, yet our current knowledge remains limited1-3. Here we used a base editor-enabled DNA barcoding system4 to comprehensively map single-cell phylogenies in mouse models of intestinal tumorigenesis induced by inflammation or loss of the Apc gene. Through quantitative analysis of high-resolution phylogenies including 260,922 single cells from normal, inflamed and neoplastic intestinal tissues, we identified tens of independent celllineages undergoing parallel clonal expansions within each lesion. We also found polyclonal origins of human sporadic colorectal polyps through bulk whole-exome sequencing and single-gland whole-genome sequencing. Genomic and clinical data support a model of polyclonal-to-monoclonal transition, with monoclonal lesions representing a more advanced stage. Single-cell RNA sequencing revealed extensive intercellular interactions in early polyclonal lesions, but there was significant loss of interactions during monoclonal transition. Therefore, our data suggest that colorectal precancer is often founded by many different lineages and highlight their cooperative interactions in the earliest stages of cancer formation. These findings provide insights into opportunities for earlier intervention in colorectal cancer.

Antiproliferative and biochemical evaluation of rose extracts: impact on tumor and normal skin cells

Rose petals (Rosa L.) are rich sources of phenolic compounds, including anthocyanins. Anthocyanins and anthocyanidins are associated with multiple health benefits due to their antioxidant properties. In this study, eighteen rose cultivars were comparatively analyzed to determine their total polyphenol and flavonoid content, as well as their antioxidant activity using the 2,2-diphenylpicrylhydrazyl (DPPH) radical scavenging method. The extracts were purified using Amberlite XAD-7 and Sephadex LH-20 columns to obtain anthocyanin-rich fractions. Individual anthocyanins were separated and identified using high-performance liquid chromatography coupled with electrospray ionization mass spectrometry (HPLC-ESI-MS). The three cultivars with the highest anthocyanin content were further examined for cytotoxic effects on cell cultures at various extract concentrations (200-1000 µg/mL) using two skin cell lines: a melanoma cell line (A375) and a normal skin cell line (Hs27). The HPLC-MS analysis identified nine different anthocyanin compounds, with the total anthocyanin content in the rose cultivars varying from 12.42 to 331.95 mg of cyanidin-3-glucoside equivalent/100g of fresh weight. The total polyphenol and total flavonoid contents ranged from 289 to 2703 mg gallic acid equivalent/100g fresh weight and 102 to 603 mg catechin equivalent/100g fresh weight, respectively. Antioxidant activity ranged from 450 to 1304 µmol trolox equivalent/g fresh weight. A significant correlation was observed between antioxidant activity and the content of anthocyanins (R = 0.875, p < 0.001), flavonoids (R = 0.982, p < 0.001), and polyphenols (R = 0.991, p < 0.001). Furthermore, principal component analysis, along with dendrograms and heatmaps, illustrated the relationships among these key compounds and their association with antioxidant activity. The MTT assay showed a substantial suppression of A375 cancer skin cells, while simultaneously exhibiting cell proliferation in Hs27 normal skin cells in a concentration-dependent manner. Altogether, results suggest that the anthocyanins from these rose cultivars could be considered as a promising agent for adjuvant treatment of skin melanoma.

Comprehensive multi-omics analysis identifies chromatin regulator-related signatures and TFF1 as a therapeutic target in lung adenocarcinoma through a 429-combination machine learning approach

IntroductionLung cancer is a leading cause of cancer-related deaths, with its incidence continuing to rise. Chromatin remodeling, a crucial process in gene expression regulation, plays a significant role in the development and progression of malignant tumors. However, the role of chromatin regulators (CRs) in lung adenocarcinoma (LUAD) remains underexplored.MethodsThis study developed a chromatin regulator-related signature (CRRS) using a 429-combination machine learning approach to predict survival outcomes in LUAD patients. The CRRS model was validated across multiple independent datasets. We also investigated the impact of CRRS on the immune microenvironment, focusing on immune cell infiltration. To identify potential therapeutic targets, TFF1, a chromatin regulator, was knocked down using siRNA in LUAD cells. We assessed its impact through apoptosis analysis, proliferation assays, and in vivo tumor growth studies. Additional validation was performed using Ki67 expression and TUNEL assays.ResultsThe CRRS accurately predicted survival outcomes and was shown to modulate immune cell infiltration in the tumor microenvironment. High-risk patients demonstrated increased activity in cell cycle regulation and DNA repair pathways, along with distinct mutation profiles and immune responses compared to low-risk patients. TFF1 emerged as a key therapeutic target. Knockdown of TFF1 significantly inhibited LUAD cell proliferation, induced apoptosis, and suppressed in vivo tumor growth. Ki67 and TUNEL assays confirmed the role of TFF1 in regulating tumor growth and cell death.DiscussionThese findings highlight the potential of chromatin regulators in prognostic modeling and immune modulation in LUAD. TFF1 was identified as a promising therapeutic target, suggesting that targeting TFF1 could provide new treatment strategies. Further research is warranted to explore its full potential and therapeutic applicability.

Oncolytic viruses: a potential breakthrough immunotherapy for multiple myeloma patients

Oncolytic virotherapy represents an innovative and promising approach for the treatment of cancer, including multiple myeloma (MM), a currently incurable plasma cell (PC) neoplasm. Despite the advances that new therapies, particularly immunotherapy, have been made, relapses still occur in MM patients, highlighting the medical need for new treatment options. Oncolytic viruses (OVs) preferentially infect and destroy cancer cells, exerting a direct and/or indirect cytopathic effect, combined with a modulation of the tumor microenvironment leading to an activation of the immune system. Both naturally occurring and genetically modified viruses have demonstrated significant preclinical effects against MM cells. Currently, the OVs genetically modified measles virus strains, reovirus, and vesicular stomatitis virus are employed in clinical trials for MM. Nevertheless, significant challenges remain, including the efficiency of the virus delivery to the tumor, overcoming antiviral immune responses, and the specificity of the virus for MM cells. Different strategies are being explored to optimize OV therapy, including combining it with standard treatments and targeted therapies to enhance efficacy. This review will provide a comprehensive analysis of the mechanism of action of the different OVs, and preclinical and clinical evidence, focusing on the role of oncolytic virotherapy as a new possible immunotherapeutic approach also in combination with the current therapeutic armamentarium and underlying the future directions in the context of MM treatments.

Tellurium-Doped Bioactive Glass Induces Ferroptosis in Osteosarcoma Cells Regardless of FSP1

Human osteosarcoma (OS) is a rare tumor predominantly affecting long bones and characterized by a poor prognosis. Currently, the first line of intervention consists of the surgical resection of primary tumors combined with radiotherapy and chemotherapy, with a profound impact on the patient’s life. Since the surgical removal of OS frequently results in a large resection of bones, the use of biomaterials to sustain the stability of the remaining tissue and to stimulate bone regeneration is challenging. Moreover, residual neoplastic cells might be responsible for tumor recurrence. Here, we explored the potential of tellurium-ion-doped bioactive glass as a novel therapeutic intervention to both eradicate residual malignant cells and promote bone regeneration. Bioactive glass (BAG) has been extensively studied and employed in the field of regenerative medicine due to its osseointegration properties and ability to improve bone tissue regeneration. We found that the incorporation of tellurium (Te) in BAG selectively kills OS cells through ferroptosis while preserving the viability of hBMSCs and stimulating their osteodifferentiation. However, the mechanism of Te toxicity is still unclear: (i) Te-BAG generates lipid-ROS through LOXs activity but not iron overload; (ii) Te-dependent ferroptosis is mediated by GPX4 down-regulation; and (iii) the anti-ferroptotic activity of FSP1 is abrogated, whose expression confers the resistance of OS to the canonical induction of ferroptosis. Overall, our data show that Te-doped bioglass could represent an interesting biomaterial with both pro-ferroptotic activity towards residual cancer cells and pro-osteoregenerative activity.

Forimtamig, a novel GPRC5D-targeting T-cell bispecific antibody with a 2+1 format, for the treatment of multiple myeloma.

Despite several approved therapies, multiple myeloma (MM) remains an incurable disease with high unmet medical need. "Off-the-shelf" T-cell bispecific antibodies (TCBs) targeting BCMA and GPRC5D have demonstrated high objective response rates (ORR) in heavily pre-treated MM patients, however, primary resistance, short duration of response and relapse driven by antigen shift frequently occurs. Although GPRC5D represents the most selective target in MM, recent findings indicate antigen loss occurs more frequently than with BCMA. Thus, anti-GPRC5D immunotherapies must hit hard during a short period of time to kill as many myeloma cells as possible. Here, we characterize forimtamig, a novel GPRC5D-targeting TCB with 2+1 format, using preclinical models of MM. Bivalent binding of forimtamig to the N-terminus of GPRC5D confers higher affinity as compared to classical 1+1 TCB formats correlating with formation of more stable immunological synapses and higher potency in tumor cell killing and T cell activation. Using an orthotopic mouse model of MM, forimtamig recruited T effector cells to the bone marrow and induced rapid tumor killing even after the introduction of step-up dosing to mitigate cytokine release. Combination of forimtamig with standard-of-care (SoC) agents including anti-CD38 antibodies, immunomodulatory drugs and proteasome inhibitors improved depth and duration of response. The combination of forimtamig with novel therapeutic agents including BCMA-TCB and Cereblon E3 Ligase Modulatory Drugs (CELMoDs) was potent and prevented occurrence of GPRC5D-negative tumor relapse. Forimtamig is currently being evaluated in Phase 1 clinical trials in relapsed and refractory myeloma (RRMM) patients for monotherapy and in combination treatments. NCT04557150.

Mycosis fungoides - differentiation from inflammation and detection of circulating tumor cells with the EuroClonality-NGS assay.

Mycosis fungoides (MF) is a rare malignancy characterized by the presence of circulating tumor cells (CTCs) in a subgroup of patients. Reliably distinguishing MF from inflammatory skin conditions (IF) is a challenging task. This study aimed to evaluate the potential benefits of next-generation sequencing (NGS)-based T-cell receptor (TR) rearrangement repertoire analysis for detecting clonal rearrangements in MF and IF. Skin biopsies and blood samples from 33 MF patients (diagnosed according to WHO-EORTC criteria) and 10 IF patients were analyzed using TRB- and TRG-NGS. 27/33 MF patients were early-stage IA (n=19), IB (n=8), and six had advanced stages (IIB, n=5; IIIA, n=1). Analysis applying the standard abundance thresholds identified at least one clonal rearrangement in the skin DNA of 32/33 MF (97%) and 9/10 IF cases (90%). To enhance specificity, an abundance- and distribution-based approach was applied, considering only rearrangements that significantly stood out from the physiological background as clonal (MF 29/33, IF 1/10), allowing for a highly sensitive (88%) and specific (90%) discrimination between MF and IF. CTCs were detected in 11/24 (46%) early-stage and 3/5 (60%) late-stage MF patients. NGS-based TR repertoire analysis is a highly sensitive and specific method for the differential diagnosis of early-stage MF compared to IF, and for the sensitive molecular detection of CTCs.

A single-cell perspective on immunotherapy for pancreatic cancer: from microenvironment analysis to therapeutic strategy innovation

Pancreatic cancer remains one of the most lethal malignancies, with conventional treatment options providing limited efficacy. Recent advancements in immunotherapy have offered new hope, yet the unique tumor microenvironment (TME) of pancreatic cancer poses significant challenges to its successful application. This review explores the transformative impact of single-cell technology on the understanding and treatment of pancreatic cancer. By enabling high-resolution analysis of cellular heterogeneity within the TME, single-cell approaches have elucidated the complex interplay between various immune and tumor cell populations. These insights have led to the identification of predictive biomarkers and the development of innovative, personalized immunotherapeutic strategies. The review discusses the role of single-cell technology in dissecting the intricate immune landscape of pancreatic cancer, highlighting the discovery of T cell exhaustion profiles and macrophage polarization states that influence treatment response. Moreover, it outlines the potential of single-cell data in guiding the selection of immunotherapy drugs and optimizing treatment plans. The review also addresses the challenges and prospects of translating these single-cell-based innovations into clinical practice, emphasizing the need for interdisciplinary research and the integration of artificial intelligence to overcome current limitations. Ultimately, the review underscores the promise of single-cell technology in driving therapeutic strategy innovation and improving patient outcomes in the battle against pancreatic cancer.

Mechanisms of extracellular vesicle uptake and implications for the design of cancer therapeutics.

The translation of pre-clinical anti-cancer therapies to regulatory approval has been promising, but slower than hoped. While innovative and effective treatments continue to achieve or seek approval, setbacks are often attributed to a lack of efficacy, failure to achieve clinical endpoints, and dose-limiting toxicities. Successful efforts have been characterized by the development of therapeutics designed to specifically deliver optimal and effective dosing to tumour cells while minimizing off-target toxicity. Much effort has been devoted to the rational design and application of synthetic nanoparticles to serve as targeted therapeutic delivery vehicles. Several challenges to the successful application of this modality as delivery vehicles include the induction of a protracted immune response that results in their rapid systemic clearance, manufacturing cost, lack of stability, and their biocompatibility. Extracellular vesicles (EVs) are a heterogeneous class of endogenous biologically produced lipid bilayer nanoparticles that mediate intercellular communication by carrying bioactive macromolecules capable of modifying cellular phenotypes to local and distant cells. By genetic, chemical, or metabolic methods, extracellular vesicles (EVs) can be engineered to display targeting moieties on their surface while transporting specific cargo to modulate pathological processes following uptake by target cell populations. This review will survey the types of EVs, their composition and cargoes, strategies employed to increase their targeting, uptake, and cargo release, and their potential as targeted anti-cancer therapeutic delivery vehicles.

The IP3R inhibitor desmethylxestospongin B reduces tumor cell migration, invasion and metastasis by impairing lysosome acidification and β1-integrin recycling.

Cancer is the second leading cause of death worldwide. >90 % of cancer-related deaths are due to metastasis, a process that depends on the ability of cancer cells to leave the primary tumor, migrate, and colonize different tissues. Inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ signaling plays an essential role in maintaining the homeostasis of cancer cells and the sustained proliferation. Desmethylxestospongin B (dmXeB) is a specific inhibitor of the IP3R that selectively arrests cell proliferation and promotes cancer cell death at high concentrations. However, whether migration, invasion and metastasis can be affected by this drug is unknown. Here, by using the highly metastatic triple negative breast cancer (TNBC) cell line MDA-MB-231, we demonstrate that a prolonged inhibition of IP3R-mediated Ca2+ signals with dmXeB significantly reduces cell migration and invasion in vitro and metastasis in vivo. We found that this phenomenon was independent of the bioenergetic control of IP3R over the mitochondria and AMPK activation. Furthermore, employing a tandem LC3-GFP-mcherry assay, we found that prolonged inhibition of IP3R with dmXeB leads to diminished autophagic flux. This reduction can be attributed to impaired lysosomal acidification, as evidenced by assessments using DQ-BSA and pHrodo. Since cell migration requires appropriate assembly and disassembly of focal adhesions, along with the internalization and recycling of integrins via autophagy, we explored the dependency of integrin recycling from autophagosomes, finding that IP3R inhibition with dmXeB impaired the recycling of β1-integrins, which accumulated within autophagosomes. Our findings reveal an unexpected effect of IP3R inhibition with dmXeB in cancer cells that could represent a novel therapeutic strategy for the treatment of cancer metastasis.

Heterogeneous nuclear ribonucleoprotein K is a potential target for enhancing the chemosensitivity of nasopharyngeal carcinoma.

The resistance of tumor cells to chemotherapy drugs is a critical determinant in the recurrence and metastasis of nasopharyngeal carcinoma (NPC). Therefore, it is crucial to identify effective biotargets that can enhance the sensitivity of NPC cells to chemotherapy drugs. Heterogeneous nuclear ribonucleoprotein K (hnRNPK) plays a central role in regulating chemotherapy resistance across various tumor types. However, its specific function in NPC cells remains unclear. This study reveals that hnRNPK is overexpressed in NPC tissues while weakly expressed in normal nasopharyngeal tissues. The expression level of hnRNPK is negatively associated with NPC patient survival. Importantly, hnRNPK is a key inducer of chemotherapy resistance in NPC, as evidenced by the significant increase in NPC cell sensitivity to cisplatin following hnRNPK knockdown. Mechanistically, hnRNPK induces chemotherapy resistance in NPC cells by suppressing the activation of the Akt/caspase 3 pathway. In NPC tumor-bearing mice, hnRNPK knockdown enhances the efficacy of cisplatin chemotherapy. Consequently, this work identifies a potential target for enhancing the sensitivity of NPC cells to chemotherapy.

Patient-Derived Melanoma Immune-Tumoroids as a Platform for Precise High throughput Drug Screening.

In vitro models are crucial in cancer research, but they must truthfully mimic in vivo tumors for clinical relevance. The development of unprecedent melanoma quadruple multicellular tumoroids (MCTs) is proposed comprising tumor cells, keratinocytes, fibroblasts, and monocytes that replicate tumor architecture, tumor microenvironment, and secretome behavior. These MCTs of 300µm in diameter secreted keratin and collagen, showing complexity proportional to their cell combinations. Further, closely resembled in vivo tumors in terms of cells organization, growth, progression, and immune behavior. Drug screening using these MCTs demonstrated their potential as patient-derived platforms for precision medicine. These findings highlight the true value of MCTs for studying melanoma biology and testing therapeutic interventions with greater precision and relevance to human disease.

Five Unreported Ketone Compounds—Penicrustones A–E—From the Endophytic Fungus Penicillium crustosum

Five unreported ketone compounds—penicrustones A–E—were isolated from the solid fermentation of the endophytic fungus Penicillium crustosum. Their structures were elucidated on the basis of extensive spectroscopic analysis. Their absolute configurations were determined via ECD calculations and single-crystal X-Ray crystallography. All compounds were evaluated for their antimicrobial and antitumor activities. Compounds 4 and 5 showed moderate inhibitory effects on Micrococcus luteus, with MIC values of 12.5 and 25.0 μg/mL, respectively. In addition to this, compound 4 also showed cytotoxicity on tumor cell lines KTC-1 and Hela, with IC50 values of 4.28 and 4.64 μg/mL, respectively.