Inhibit Tumor Cell Research Articles

FTO-mediated DSP m6A demethylation promotes an aggressive subtype of growth hormone-secreting pituitary neuroendocrine tumors

BackgroundGrowth hormone-secreting pituitary neuroendocrine tumors can be pathologically classified into densely granulated (DGGH) and sparsely granulated types (SGGH). SGGH is more aggressive and associated with a poorer prognosis. While epigenetic regulation is vital in tumorigenesis and progression, the role of N6-methyladenosine (m6A) in aggressive behavior has yet to be elucidated.MethodsWe performed m6A-sequencing on tumor samples from 8 DGGH and 8 SGGH patients, complemented by a suite of assays including ELISA, immuno-histochemistry, -blotting and -fluorescence, qPCR, MeRIP, RIP, and RNA stability experiments, aiming to delineate the influence of m6A on tumor behavior. We further assessed the therapeutic potential of targeted drugs using cell cultures, organoid models, and animal studies.ResultsWe discovered a significant reduction of m6A levels in SGGH compared to DGGH, with an elevated expression of fat mass and obesity-associated protein (FTO), an m6A demethylase, in SGGH subtype. Series of in vivo and in vitro experiments demonstrated that FTO inhibition in tumor cells robustly diminishes hypoxia resistance, attenuates growth hormone secretion, and augments responsiveness to octreotide. Mechanically, FTO-mediated m6A demethylation destabilizes desmoplakin (DSP) mRNA, mediated by the m6A reader FMR1, leading to prohibited desmosome integrity and enhanced tumor hypoxia tolerance. Targeting the FTO-DSP-SSTR2 axis curtailed growth hormone secretion, therefor sensitizing tumors to octreotide therapy.ConclusionOur study reveals the critical role of FTO in the aggressive growth hormone-secreting pituitary neuroendocrine tumors subtype and suggests FTO may represent a new therapeutic target for refractory/persistent SGGH.

Near-Infrared-II Photoactivated Iron(III) Complexes for Highly Efficient RNS and ROS Synergistic Therapy.

Reactive nitrogen species (RNS) are more lethal than reactive oxygen species (ROS), which gives them a very promising future in the field of cancer treatment. However, there are still a few drugs available for RNS generation. In this work, two 5th-order nonlinear optical materials, FB-Fe(III)/SNP@PEG and FB-Fe(II)-FB/SNP@PEG, are synthesized. The outstanding nonlinear optical properties of FB-Fe(III)/SNP@PEG help to achieve generation of bounteous superoxide anions (O2•-) in deep tissues, while sodium nitroprusside (SNP) provides NO in the body, both of which are prerequisites for RNS generation. Meanwhile, type I and type II ROS were also generated under irradiation of a 1600 nm laser. Based on the synergistic effect of ROS and RNS, FB-Fe(III)/SNP@PEG induced mitochondrial damage and DNA fragmentation and inhibited tumor cells through apoptosis, possessing better therapeutic effects than FB-Fe(II)-FB/SNP@PEG. This work put forward an innovative strategy to achieve the cooperative release of RNS and ROS in deep tissues, which provides insights and ideas for applying nonlinear optical materials to RNS therapy.

Abstract B042: Dissection of the T cell infiltrate in mouse pancreatic tumors reveals a diverse tumor-reactive T cell repertoire targeting neoantigens and tumor-associated antigens

Abstract Although pancreatic cancer is generally refractory to immune checkpoint blockade (ICB), recent studies of tumor-infiltrating T cells in human tumor samples demonstrated the presence of in vivo expanded, tumor-reactive T cell receptor (TCR) clonotypes. Here, we explored the T cell repertoire in ICB-refractory murine pancreatic cancer models by combining single-cell transcriptomics with functional TCR characterization. Our initial studies in an orthotopic, transplantable model revealed a remarkable diversity of tumor-reactive TCR clonotypes that could be distinguished from bystander T cells based on gene expression signatures. We identified TCRs exclusively reactive against the tumor of origin, TCRs that also react against an independently derived pancreatic tumor line, and TCRs broadly reactive to tumor cells of diverse tissue origin (e.g. MC38), the latter category being predominant. Subsequent studies were performed in an autochthonous mouse model, in which single focal tumors were induced in the pancreas by means of in vivo electroporation of gene constructs encoding mutant Kras and inducing CRISPR/Cas9-mediated inactivation of tumor suppressor genes. We analyzed the T cell repertoire in tumors with different levels of mutational burden by also inactivating DNA damage repair genes. Interestingly, even in mismatch repair-deficient tumors that featured a high mutational load, the anti-tumor T cell response was primarily directed against recurrent tumor-associated antigens (TAAs) rather than ‘private’ mutanome-encoded neoantigens. Several TAA-reactive TCRs also mediated reactivity against non-transformed cells. Immunopeptidome analysis thus far revealed the identity of 5 cognate antigens targeted by the tumor-reactive TCR repertoire: a mutanome-encoded neoantigen, an epitope encoded by an ectopically expressed endogenous retroviral provirus, and three epitopes derived from TAAs: Lon Peptidase 2 (LONP2), ATPase Na+/K+ Transporting Subunit Beta 3 (ATP1B3) and SEC24B, a component of secretory vesicles. Notably, the overexpression of LONP2 and ATP1B3 was found associated with progression of human cancers, whereas silencing was shown to suppress tumor cell growth. Overexpression of SEC24B in cancers has not been reported, but this protein plays an essential role in the secretory pathway of acinar cells. In summary, in-depth analysis of the natural T cell response in murine pancreatic cancer models revealed a diverse tumor-reactive T cell repertoire that is predominantly directed against TAAs, some of which are also expressed in normal somatic cells. These findings underline the importance of uncovering the antigen-specificity of the natural tumor-reactive TCR repertoire, both in mouse models and human tumor samples, to assess its therapeutic potential and safety with regard to personalized immunotherapy. Citation Format: Stefan Zens, Hannes Kehm, Daniel Baumann, Aline Konrad, Zibo Meng, Arnoud H. de Ru, Julian Mochayedi, Francesca Lucato, Angelika B. Riemer, Isabel Poschke, Michael Volkmar, Peter A. van Veelen, Rienk Offringa. Dissection of the T cell infiltrate in mouse pancreatic tumors reveals a diverse tumor-reactive T cell repertoire targeting neoantigens and tumor-associated antigens [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B042.

A biomimetic targeted nanosystem delivering synergistic inhibitors for glioblastoma immune microenvironment reprogramming and treatment

Efficient drug delivery across the blood-brain barrier is imperative for treating glioblastoma (GBM). This study utilized the GBM cell membrane to construct a biomimetic targeted nanosystem (GMNPs@AMD/RAPA) that hierarchically releases the CXCR4 antagonist AMD3100 and the mTOR pathway inhibitor rapamycin (RAPA) for reprogramming the tumor immune microenvironment and suppressing the progression of GBM. By initially inhibiting the CXCL12/CXCR4 axis, the tumor microenvironment (TME) was reprogrammed to enhance the infiltration of cytotoxic T lymphocytes (CTLs) into the TME while suppressing tumor cell survival, proliferation, and angiogenesis. Subsequently, through further cellular uptake and degradation of the nanoparticles, the mTOR pathway inhibitor RAPA was released, further suppressing the tumor progression. This study successfully combined chemotherapy and immunotherapy, achieving effective synergistic therapeutic effects, and suppressing the progression of GBM.

Co-delivery of PROTAC and siRNA via novel liposomes for the treatment of malignant tumors

Targeted elimination of damaged or overexpressed proteins within the tumor serves a pivotal role in regulating cellular function and restraining tumor cell growth. Researchers have been striving to identify safer and more effective methods for protein removal. Here, we propose the synergistic employment of a small molecule degrading agent (PROTAC) and siRNA to attain enhanced protein clearance efficiency and tumor therapeutic effects. Co-delivery liposomes were prepared to facilitate the efficient encapsulation of PROTAC and siRNA. Specifically, the cationic liposome significantly improved the solubility of the insoluble PROTAC (DT2216). The cationic polymer (F-PEI) achieved efficient encapsulation of the nucleic acid drug, thereby promoting endocytosis and enhancing the therapeutic impact of the drug. Both in vivo and in vitro experiments demonstrated remarkable degradation of target proteins and inhibition of tumor cells by the co-delivery system. In conclusion, the co-delivery liposomes furnished a nano-delivery system proficient in effectively encapsulating both hydrophilic and hydrophobic drugs, thereby presenting a novel strategy for targeted combination therapy in treating tumors.

Inhibiting the expression of spindle appendix cooled coil protein 1 can suppress tumor cell growth and metastasis and is associated with cancer immune cells in esophageal squamous cell carcinoma.

Inhibiting the expression of spindle appendix cooled coil protein 1 (SPDL1) can slow down disease progression and is related to poor prognosis in patients with esophageal cancer. However, the specific roles and molecular mechanisms of SPDL1 in esophageal squamous cell carcinoma (ESCC) have not been explored yet. The current study aimed to investigate the expression levels of SPDL1 in ESCC via transcriptome analysis using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. Moreover, the biological roles, molecular mechanisms, and protein networks involved in SPDL1 were identified using machine learning and bioinformatics. The cell counting kit-8 assay, EdU staining, and transwell assay were used to investigate the effects of inhibiting SPDL1 expression on ESCC cell proliferation, migration, and invasion. Finally, the correlation between the SPDL1 expression and cancer immune infiltrating cells was evaluated by analyzing data from the TCGA database. Results showed that SPDL1 was overexpressed in the ESCC tissues. The SPDL1 expression was related to age in patients with ESCC. The SPDL1 co-expressed genes included those involved in cell division, cell cycle, DNA repair and replication, cell aging, and other processes. The high-risk scores of SPDL1-related long non-coding RNAs were significantly correlated with overall survival and cancer progression in patients with ESCC (P < 0.05). Inhibiting the SPDL1 expression was effective in suppressing the proliferation, migration, and invasion of ESCC TE-1 cells (P < 0.05). The overexpression of SPDL1 was positively correlated with the levels of Th2 and T-helper cells, and was negatively correlated with the levels of plasmacytoid dendritic cells and mast cells. In conclusion, SPDL1 was overexpressed in ESCC and was associated with immune cells. Further, inhibiting the SPDL1 expression could effectively slow down cancer cell growth and migration. SPDL1 is a promising biomarker for treating patients with ESCC.

Extracellular vesicles derived from mesenchymal stem cells suppress breast cancer progression by inhibiting angiogenesis.

Previous studies have highlighted the antitumor effects of mesenchymal stem cell‑derived extracellular vesicles (MSC‑EVs), positioning them as a promising therapeutic avenue for cancer treatment. However, some researchers have proposed a bidirectional influence of MSC‑EVs on tumors, determined by the specific tissue origin of the MSCs and the types of tumors involved. The present study aimed to elucidate the effects of human placenta MSC‑derived extracellular vesicles (hPMSC‑EVs) on the malignant behavior of a mouse breast cancer model of 4T1 cells in vitro and in vivo. The findings revealed that hPMSC‑EVs significantly inhibited the proliferation, migration and colony formation of cultured 4T1 mouse breast cancer cells without inducing apoptosis. Exposure to conditioned medium from 4T1 cells pretreated with hPMSC‑EVs resulted in decreased angiogenic activity, accompanied by the downregulation of angiogenesis‑promoting genes in human umbilical vein endothelial cells. In murine xenograft models derived from the 4T1 cell line, local administration of hPMSC‑EVs substantially hindered tumor growth. Further results revealed that hPMSC‑EVs inhibited angiogenesis in vivo, as reflected by the use of a vascular growth factor receptor 2‑Fluc transgenic mouse model. In summary, the results confirmed that hPMSC‑EVs negatively modulated breast cancer growth by suppressing tumor cell proliferation and migration via an indirect antiangiogenic mechanism. These results underscored the therapeutic potential of EVs, suggesting a promising avenue for alternative anticancer treatments in the future.

Modulating glucose metabolism and relieving hypoxia for enhanced Chemo/Photoimmunotherapy with photosensitizing enzymatic nanodrugs

Photoimmunotherapy by photodynamic therapy (PDT) induces immunogenic cell death (ICD), providing anti-tumor treatment in a safe, precise, minimally invasive way. However, PDT-demanded massive oxygen consumption exacerbates the hypoxia and creates an acidic tumor microenvironment (TME), leading to an anaerobic glycolysis and immune escape condition. In this study, a natural anti-tumor resveratrol (RSV) nanodrug was introduced via Fe3+ coordination flash nanoprecipitation (cFNP) for enhanced aqueous solubility to specifically downregulate the expression of Pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA), reduce the glucose resorption and lactate production, tipping the cellular balance from anaerobic glycolysis to oxidative phosphorylation (OXPHOS). RSV enhances the immunotherapy by suppressing tumor cell glycolysis and active the apoptotic cell death as well. Meanwhile, structural linker Fe3+ could also effectively catalyze the endogenous H2O2 in the tumor cells to generate oxygen in situ and relieve the hypoxic microenvironment, enhancing the PDT efficacy. This strategy can effectively modulate glucose metabolism and relieve hypoxia by Fe/RSV/ZnPc nanodrugs to greatly promote the synergistic chemo/photoimmunotherapy, providing a promising strategy to tackle the formulation of multi-therapeutic nanodrugs for clinical cancer therapy.

Mechanisms of Yiai Fuzheng formula in the treatment of triple-negative breast cancer based on UPLC-Q-Orbitrap-HRMS, network pharmacology, and experimental validation

Ethnopharmacological relevanceYiai Fuzheng formula (YAFZF), as a Traditional Chinese Medicine (TCM) prescription, has been used widely at Zhongnan Hospital of Wuhan University for its therapeutic effects and high safety on triple-negative breast cancer (TNBC). ObjectiveIn this study, we employed ultra-high-performance liquid chromatography-quadrupole/orbitrap high-resolution mass spectrometry (UPLC-Q-Orbitrap-HRMS), network pharmacology, and experimental validation to elucidate the underlying action mechanism of YAFZF in the treatment of TNBC. MethodsThe key active ingredients in YAFZF were analyzed using UPLC-Q-Orbitrap-HRMS, and then the potential components, target genes and signalling pathways of YAFZF were predicted using the network pharmacological method. We then used molecular docking to visualize the combination characteristics between major active components and macromolecules in the crucial pathway. In vitro experiments were conducted to investigate the inhibitory effects of YAFZF treatment on the cell viability, invasion, and migration of 4T1 and MDA-MB-231 cells. The xenograft TNBC models were constructed using female Balb/c mice, and their body weights, tumour volumes, and weights were monitored during YAFZF treatment. Quantitative real-time PCR (qRT-PCR), Hematoxylin-eosin (HE), immunohistochemistry (IHC) staining, Western blot (WB), and terminal deoxynucleotidyl transferase (TdT)-dUTP nick-end labeling (TUNEL) staining were used for further experimental validation. ResultsBased on UPLC-Q-Orbitrap-HRMS and network pharmacology analysis, 6 major bioactive components and 153 intersecting genes were obtained for YAFZF against TNBC. Functional enrichment analysis identified that the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signalling pathway might be the mechanism of action of YAFZF in the treatment of TNBC. Molecular docking results suggested that the main active compounds in YAFZF had strong binding energies with the proteins in the PI3K/Akt pathway. In vitro experiments showed that YAFZF inhibited the cell viability, invasion, and migration abilities of TNBC cells. Animal experiments confirmed that YAFZF treatment suppressed tumour cell proliferation and increased apoptotic cells. PCR, HE, WB, and IHC results indicated that YAFZF could suppress xenograft tumour metastases by inhibiting the PI3K/AKT/mTOR pathway regulating the epithelial-mesenchymal transition (EMT) process. ConclusionYAFZF therapy showed its potential for reducing proliferation, invasion, and migration abilities, increasing apoptosis of TNBC cells. Furthermore, YAFZF treated TNBC by inhibiting xenograft tumour distant metastases via the regulation of EMT by the PI3K/Akt/mTOR pathway, suggesting that it may be useful as an adjuvant treatment.

A multifunctional nutrient transfer nanoCRISPR scaffold induces metabolic remodeling to fuel cancer immunotherapy

Tumor cells are major consumers of glutamine and glucose in the tumor microenvironment (TME), causing nutrient deficiency of immune cells, leading to immune escape and resistance to immunotherapy. However, pharmacological modulation would cause metabolic inhibition in both immune cells and tumor cells. Herein, a multifunctional nutrient transfer nanoCRISPR scaffold (FUEL) is fabricated to realize “nutrient transfer” from tumor cells to immune cells and remodel the metabolism in the TME, thus fueling cancer immunotherapy. FUEL is endowed with characteristics of enhanced blood circulation, specific tumor cell targeting, effective lysosomal escape, cascaded reactive-oxygen-species (ROS)-responsiveness, and ASCT2/GLUT1 dual gene knockout. Consequently, FUEL can restrict nutrient uptake of tumor cells thoroughly, increase glucose and glutamine in the TME remarkably to satisfy metabolic demands of immune cells, and reduce immunosuppressive metabolites concurrently. Metabolomics data shows that energy metabolism and biosynthesis are reduced in tumor cells but enhanced in immune cells. FUEL remarkably impedes the growth, metastasis, and recurrence of solid tumors in mice, further shows stronger anti-tumor immune responses and enhanced tumor inhibition in combination with anti-PD-L1 antibody. Overall, this nutrient transfer strategy enables a “one arrow aiming at three eagles” effect that induces a cascade amplification of antitumor immune responses for the maximized tumor therapy efficacy.

Illuminating the fight against breast cancer: Preparation and visualized photothermal therapy of hyaluronic acid coated ZIF-8 loading with indocyanine green and cryptotanshinone for triple-negative breast cancer

Triple-negative breast cancer (TNBC) is characterized by higher recurrence rate and mortality. Thermally-mediated ablation via photothermal therapy (PTT) demonstrates considerable promise for the eradication of breast cancer. Nonetheless, the efficacy of PTT is impeded by the thermal tolerance of tumor cells, which is attributed to the augmented expression of heat shock proteins (HSPs). These proteins, which function as ATP-dependent molecular chaperones, confer protection to cancer cells against the cytotoxic heat generated during PTT. Glycolysis is an important way for breast cancer cells to produce ATP, which can promote the occurrence and development of lung metastasis of breast cancer. Therefore, inhibiting glycolysis may diminish the expression of HSPs, curtail the growth of breast cancer, and prevent its metastasis. Glycolytic metabolism plays a pivotal role in the ATP biosynthesis within breast cancer cells, facilitating the progression and dissemination of pulmonary metastases. Consequently, targeting glycolysis presents a strategic approach to HSP expression, the proliferation of breast cancer, and impede its metastatic spread. Herein, we designed an indocyanine green (ICG) and cryptotanshinone (CTS) loaded hyaluronic acid (HA) coated Zeolitic Imidazolate Framework-8 (ZIF-8) drug delivery system. The drug delivery system had excellent photothermal properties, which could reach temperature sufficient for photothermal ablation of tumor cells. (ICG + CTS)@HA-ZIF-8 also showed pH-responsive drug release, enhancing the sustained release of ICG and CTS to extend their systemic circulation duration. Moreover, the HA modification of ZIF-8 served to augment its targeting capabilities both in vitro and in vivo, leveraging the enhanced permeation and retention (EPR) effect, as well as active tumor targeting via the CD44 receptor pathway, resulting in a higher drug concentration and a better therapeutic effect in tumor. (ICG + CTS)@HA-ZIF-8 could downregulate the expression of glycolysis-related protein pyruvate kinase-M2 (PKM2), thereby inhibiting the glycolysis process, further suppressing tumor cell energy metabolism, downregulating the expression of HSPs, overcoming tumor cell heat resistance, and improving PTT effect. It exhibited a notable suppressive impact on both the proliferation and migration of breast cancer cells, potentially offering innovative insights for the visualized PTT in breast cancer treatment.

Development of cantharidin/baicalin co-delivery system based on mitochondrial targeting strategy for enhanced hepatocellular carcinoma therapy

Cantharidin (CTD) as a treatment for primary liver cancer are well known, and although structural alteration and nano-delivery are efficient in diminishing toxicity, its urinary and digestive toxicity has hindered its clinical application. Based on the synergistic effect of CTD and baicalin (BA) on proliferation inhibition of liver tumor cells, the highly expressed folic acid (FA) receptor of liver cancer cell membrane and the high negative membrane potential of tumor cell mitochondria, we synthesized CHEMS-FRFK and prepared a dual-ligand modified co-delivery liposomes (FA/FRFK-CTD/BA-Lips). Liposomes were spherical particles with uniform particle size, high encapsulation rate, good stability and no hemolysis. The results confirmed that FA/FRFK-CTD/BA-Lips had good targeting to mitochondria of tumor cells, and its target effect on mitochondria of HepG2 was better than that of Huh-7 cells. Compared with CTD, the cytotoxicity of liposomes on HepG2 is 7.0 times higher, while the cytotoxic effect on normal liver cells Thle-2 is 2.1 times lower. It may be related to increasing clathrin-mediated endocytosis, inhibiting tumor cell migration, arresting cell cycle in G1/G0 phase, and promoting mitochondria-mediated endogenous Bcl-2/Caspase 3 apoptosis pathway. Meanwhile, FA/FRFK-CTD/BA-Lips could alter the pharmacokinetic behavior of CTD and BA by increasing concentrations in vivo, slowing release and excretion, good anti-tumor with no obvious toxicity, and successfully delivered CTD/BA to liver tissue, tumor cells and mitochondria. Therefore, FA/FRFK-CTD/BA-Lips, as a delivery system targeting the mitochondria of liver cancer cells, has promising development potential, and could provide a new strategy for solving the problem of CTD toxicity and the treatment of hepatocellular carcinoma.

A platelet-related signature for predicting the prognosis and immunotherapy benefit in bladder cancer based on machine learning combinations.

Bladder cancer carries a large societal burden, with over 570,000 newly diagnosed cases and 210,000 deaths globally each year. Platelets play vital functions in tumor progression and therapy benefits. We aimed to construct a platelet-related signature (PRS) for the clinical outcome of bladder cancer cases. Ten machine learning techniques were used in the integrative operations to build PRS using the datasets from The Cancer Genome Atlas (TCGA), gene series expression (GSE)13507, GSE31684, GSE32894 and GSE48276. A number of immunotherapy datasets and prediction scores, including GSE91061, GSE78220, and IMvigor210, were utilized to assess how well the PRS predicted the benefit of immunotherapy. Vitro experiment was performed to verify the role of α1C-tubulin (TUBA1C) in bladder cancer. Enet (alpha =0.4) algorithm-based PRS had the highest average C-index of 0.73 and it was suggested as the optimal PRS. PRS acted as an independent risk factor for bladder cancer and patients with high PRS score portended a worse overall survival rate, with the area under the curve of 1-, 3- and 5-year operating characteristic curve being 0.754, 0.779 and 0.806 in TCGA dataset. A higher level of immune-activated cells, cytolytic function and T cell co-stimulation was found in the low PRS score group. Low PRS score demonstrated a higher tumor mutation burden score and programmed cell death protein 1 & cytotoxic T-lymphocyte associated protein 4 immunophenoscore, lower tumor immune dysfunction and exclusion score, intratumor heterogeneity score and immune escape score in bladder cancer, suggesting the PRS as an indicator for predicting immunotherapy benefits. Vitro experiment showed that TUBA1C was upregulated in bladder cancer and knockdown of TUBA1C obviously suppressed tumor cell proliferation. The present study developed an ideal PRS for bladder cancer, which may be used as a predictor of prognosis, a risk classification system, and a therapy guide.

Single-cell transcriptomic sequencing analysis of mechanistic insights into the IFN-γ signaling pathway in different tumor cells.

This study aimed to investigate the relationship between the interferon-gamma (IFN-γ) pathway in different tumor microenvironments (TME) and patients' prognosis, as well as the regulatory mechanisms of this pathway in tumor cells. Using RNA-seq data from the TCGA database, we analyzed the predictive value of the IFN-γ pathway across various tumors. We employed a univariate Cox regression model to assess the prognostic significance of IFN-γ signaling in different tumor types. Additionally, we analyzed single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database to examine the distribution characteristics of the IFN-γ pathway and explore its regulatory mechanisms, highlighting how IFN-γ influenced cellular interactions within the TME. Our analysis revealed a significant association between the IFN-γ pathway and adverse prognosis in pan-cancer tissues (P < 0.001). Interestingly, this correlation varied regarding positive and negative regulation across different tumor types. Through a detailed examination of scRNA-seq data, we found that the IFN-γ pathway exerted substantial regulatory effects on stromal and immune cells. In contrast, its expression and regulatory patterns in tumor cells exhibited diversity and heterogeneity. Further analysis indicated that the IFN-γ pathway not only enhanced the immunogenicity of tumor cells but also inhibited their proliferation. Cell-cell interaction analysis confirmed the pivotal role of the IFN-γ pathway within the overall regulatory network. Moreover, we identified HMGB2 (high mobility group box 2) in T cells as a potential key regulator of tumor cell proliferation. The IFN-γ pathway exhibited a dual function by both suppressing tumor cell proliferation and enhancing their immunogenicity, positioning it as a pivotal target for refined cancer diagnosis and cancer strategies.

Scinderin is a potential prognostic biomarker and correlated with immunological regulation: from pan-cancer analysis to liver hepatocellular carcinoma.

This study aimed to systematically dissect the role of Scinderin (SCIN) in tumorigenesis. Bioinformatics techniques were employed based on cancer data from TCGA, ENCORI, HPA, GEPIA2, UALCAN, Kaplan-Meier plotter, TIMER, TISIDB, cBioPortal, HCCDB, GeneMANIA and LinkedOmics database. Experiments in vitro and in vivo were conducted to dissect the role of SCIN in liver hepatocellular carcinoma (LIHC). Significantly differential expression of SCIN was found in nine types of cancers, including LIHC. Through pan-cancer analysis, the correlations between SCIN expression with prognosis and immune cell infiltration were proven, especially in LIHC, ovarian serous cystadenocarcinoma and lung adenocarcinoma. The highest frequency of alteration in SCIN (6.81%) was seen in patients with uterine corpus endometrial carcinoma, in which "mutation" was the predominant type, with a frequency of about 5.29%; meanwhile, S673F and S381Y were the two most frequent mutation sites. Furthermore, the abnormal expression of SCIN exhibited a strong relationship with immune cell subtypes, immune checkpoint genes, tumor mutation burden, microsatellite instability, neoantigen, molecular subtypes, mismatch repair signatures and DNA methyl-transferase in different cancer types. Through comparative analysis, we discovered that SCIN was dramatically up-regulated in LIHC, and associated with poor survival. Experiments in vitro and in vivo suggested the knockdown of SCIN could suppress tumor cell proliferation and improve the survival rate partly in animal models. This study reveals SCIN may be a promising biomarker for prognosis and treatment in certain cancers, especially in LIHC.

Advances of Fundamental Research on Traditional Chinese Medicine in Regulation of Tumor-associated Macrophages for the Prevention and Treatment of Lung Cancer Metastasis

Lung cancer is the leading cause of cancer-related deaths worldwide, with metastasis being the primary cause of mortality in lung cancer patients, and its prevention and control efficacy remain limited. In recent years, immunotherapy has emerged as a promising direction for overcoming the bottleneck of metastasis. Macrophages, as essential components of innate immunity, participate in the entire process of tumor initiation and progression. Tumor-associated macrophages (TAMs) represent the most abundant immune population in the tumor microenvironment (TME), displaying both anti-tumor M1-like and pro-tumor M2-like phenotypes. The latter promotes tumor invasion and metastasis, angiogenesis, lymphangiogenesis, immune suppression, and reactivation of dormant disseminated tumor cells (DTCs), thereby facilitating tumor metastasis. In recent years, traditional Chinese medicine (TCM) has shown significant efficacy in inhibiting tumor metastasis and has been extensively validated. It exerts anti-tumor effects by reducing the recruitment of TAMs, inhibiting M2-like polarization, and modulating cytokines and proteins in the TME. This paper reviews the relationship between TAMs and lung cancer metastasis, elucidates the targets and mechanisms of TCM in regulating TAMs to prevent and treat lung cancer metastasis, aiming to provide insights into lung cancer prevention and treatment. .

Blocking smoothened cholesterylation: A strategy for overcoming drug resistance in cancer

In this issue of Cell Chemical Biology, Liu etal.1 report the identification of Q29, a synthetic diterpenoid that blocks covalent cholesterol modification of smoothened (SMO) and inhibits hedgehog signaling. Q29 is capable of suppressing tumor cell growth, both invitro and invivo, and overcoming resistance to SMO inhibitors.

Yadanziolide A Inhibits Proliferation and Induces Apoptosis of Hepatocellular Carcinoma via JAK-STAT Pathway: A Preclinical Study.

Liver cancer is a significant global health concern, prompting the search for innovative therapeutic solutions. Yadanziolide A (Y-A), a natural derivative of Brucea javanica, has emerged as a promising candidate for cancer treatment; however, its efficacy and underlying mechanisms in liver cancer remain incompletely understood. In this study, we conducted a comprehensive evaluation of Y-A's effects on liver cancer cells using a range of in vitro assays and an orthotopic liver cancer mouse model. Our findings reveal that Y-A exerts dose-dependent cytotoxic effects on liver cancer cells, significantly inhibiting proliferation, migration, and invasion at concentrations ≥ 0.1 μM. Furthermore, Y-A induces apoptosis, as evidenced by increased apoptotic cell populations and apoptosome formation. In vivo studies confirm that Y-A inhibits tumor growth and reduces liver damage in mouse models. Mechanistically, Y-A targets the TNF-α/STAT3 pathway, inhibiting STAT3 and JAK2 phosphorylation, thereby activating apoptotic pathways and suppressing tumor cell growth. These results suggest that Y-A has promising anticancer activity and potential utility in liver cancer therapy.

Focal adhesion kinase signaling - tumor vulnerabilities and clinical opportunities.

Focal adhesion kinase (FAK; encoded by PTK2) was discovered over 30 years ago as a cytoplasmic protein tyrosine kinase that is localized to cell adhesion sites, where it is activated by integrin receptor binding to extracellular matrix proteins. FAK is ubiquitously expressed and functions as a signaling scaffold for a variety of proteins at adhesions and in the cell cytoplasm, and with transcription factors in the nucleus. FAK expression and intrinsic activity are essential for mouse development, with molecular connections to cell motility, cell survival and gene expression. Notably, elevated FAK tyrosine phosphorylation is common in tumors, including pancreatic and ovarian cancers, where it is associated with decreased survival. Small molecule and orally available FAK inhibitors show on-target inhibition in tumor and stromal cells with effects on chemotherapy resistance, stromal fibrosis and tumor microenvironment immune function. Herein, we discuss recent insights regarding mechanisms of FAK activation and signaling, its roles as a cytoplasmic and nuclear scaffold, and the tumor-intrinsic and -extrinsic effects of FAK inhibitors. We also discuss results from ongoing and advanced clinical trials targeting FAK in low- and high-grade serous ovarian cancers, where FAK acts as a master regulator of drug resistance. Although FAK is not known to be mutationally activated, preventing FAK activity has revealed multiple tumor vulnerabilities that support expanding clinical combinatorial targeting possibilities.

Total triterpenoids from apple peels exert pronounced anti-breast-cancer activity in vivo and in vitro.

Apples are among the most nutritionally valuable fruits and have a history of use in traditional Chinese medicine. Triterpenoids, the primary bioactive compounds found in apples, demonstrate significant antitumor activity. Following enrichment and optimization, the total content of major triterpenoids in total triterpenoids from apple peels (ATT) reached 5.76 g kg-1. The growth of MDA-MB-231 xenograft tumors was significantly inhibited after treatment with ATT. Network pharmacology analysis conclusively identified a close association between the antitumor effect of ATT and the phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) signaling pathway. Experimental validation using MDA-MB-231 cells and a xenograft nude mouse model confirmed that ATT suppressed tumor cell proliferation effectively by modulating the PI3K-Akt signaling pathway, which was consistent with the findings from network pharmacology. The total triterpenoids from apple peels also induced cell apoptosis by mediating the PI3K-Akt signaling pathway. The total triterpenoids from apple peels can inhibit tumor cell proliferation and induce cell apoptosis effectively through the PI3K-Akt signaling pathway, suggesting that ATT holds promise as a prospective therapeutic agent for breast cancer treatment. © 2024 Society of Chemical Industry.