Target In Cancer Research Articles

Cell division cyclin 25C knockdown inhibits hepatocellular carcinoma development by inducing endoplasmic reticulum stress

BACKGROUND Cell division cyclin 25C (CDC25C ) is a protein that plays a critical role in the cell cycle, specifically in the transition from the G2 phase to the M phase. Recent research has shown that CDC25C could be a potential therapeutic target for cancers, particularly for hepatocellular carcinoma (HCC). However, the specific regulatory mechanisms underlying the role of CDC25C in HCC tumorigenesis and development remain incompletely understood. AIM To explore the impact of CDC25C on cell proliferation and apoptosis, as well as its regulatory mechanisms in HCC development. METHODS Hepa1-6 and B16 cells were transduced with a lentiviral vector containing shRNA interference sequences (LV-CDC25C shRNA) to knock down CDC25C . Subsequently, a xenograft mouse model was established by subcutaneously injecting transduced Hepa1-6 cells into C57BL/6 mice to assess the effects of CDC25C knockdown on HCC development in vivo . Cell proliferation and migration were evaluated using a Cell Counting Kit-8 cell proliferation assays and wound healing assays, respectively. The expression of endoplasmic reticulum (ER) stress-related molecules (glucose-regulated protein 78, X-box binding protein-1, and C/EBP homologous protein) was measured in both cells and subcutaneous xenografts using quantitative real-time PCR (qRT-PCR) and western blotting. Additionally, apoptosis was investigated using flow cytometry, qRT-PCR, and western blotting. RESULTS CDC25C was stably suppressed in Hepa1-6 and B16 cells through LV-CDC25C shRNA transduction. A xenograft model with CDC25C knockdown was successfully established and that downregulation of CDC25C expression significantly inhibited HCC growth in mice. CDC25C knockdown not only inhibited cell proliferation and migration but also significantly increased the ER stress response, ultimately promoting ER stress-induced apoptosis in HCC cells. CONCLUSION The regulatory mechanism of CDC25C in HCC development may involve the activation of ER stress and the ER stress-induced apoptosis signaling pathway.

Tryptophan fuels MYC-dependent liver tumorigenesis through indole 3-pyruvate synthesis

Cancer cells exhibit distinct metabolic activities and nutritional dependencies compared to normal cells. Thus, characterization of nutrient demands by individual tumor types may identify specific vulnerabilities that can be manipulated to target the destruction of cancer cells. We find that MYC-driven liver tumors rely on augmented tryptophan (Trp) uptake, yet Trp utilization to generate metabolites in the kynurenine (Kyn) pathway is reduced. Depriving MYC-driven tumors of Trp through a No-Trp diet not only prevents tumor growth but also restores the transcriptional profile of normal liver cells. Despite Trp starvation, protein synthesis remains unhindered in liver cancer cells. We define a crucial role for the Trp-derived metabolite indole 3-pyruvate (I3P) in liver tumor growth. I3P supplementation effectively restores the growth of liver cancer cells starved of Trp. These findings suggest that I3P is a potential therapeutic target in MYC-driven cancers. Developing methods to target this metabolite represents a potential avenue for liver cancer treatment.

Aspartame carcinogenic potential revealed through network toxicology and molecular docking insights

The research employed network toxicology and molecular docking techniques to systematically examine the potential carcinogenic effects and mechanisms of aspartame (l-α-aspartyl-l-phenylalanine methyl ester). Aspartame, a commonly used synthetic sweetener, is widely applied in foods and beverages globally. In recent years, its safety issues, particularly the potential carcinogenic risk, have garnered widespread attention. The study first constructed an interaction network map of aspartame with gastric cancer targets using network toxicology methods and identified key targets and pathways. Preliminary validation was conducted through microarray data analysis and survival analysis, and molecular docking techniques were employed to further examine the binding affinity and modes of action of aspartame with key proteins. The findings suggest that aspartame has the potential to impact various cancer-related proteins, potentially raising the likelihood of cellular carcinogenesis by interfering with biomolecular function. Furthermore, the study found that the action patterns and pathways of aspartame-related targets are like the mechanisms of known carcinogenic pathways, further supporting the scientific hypothesis of its potential carcinogenicity. However, given the complexity of the in vivo environment, we also emphasize the necessity of validating these molecular-level findings in actual biological systems. The study introduces a fresh scientific method for evaluating the safety of food enhancers and provides a theoretical foundation for shaping public health regulations.

Integrative analyses identified gap junction beta‐2 as a prognostic biomarker and therapeutic target for breast cancer

AbstractBackgroundIncreasing evidence has shown that connexins are involved in the regulation of tumor development, immune escape, and drug resistance. This study investigated the gene expression patterns, prognostic values, and potential mechanisms of connexins in breast cancer.MethodsWe conducted a comprehensive analysis of connexins using public gene and protein expression databases and clinical samples from our institution. Connexin mRNA expressions in breast cancer and matched normal tissues were compared, and multiomics studies were performed.ResultsGap junction beta‐2 mRNA was overexpressed in breast cancers of different pathological types and molecular subtypes, and its high expression was associated with poor prognosis. The tumor membrane of the gap junction beta‐2 mutated group was positive, and the corresponding protein was expressed. Somatic mutation and copy number variation of gap junction beta‐2 are rare in breast cancer. The gap junction beta‐2 transcription level in the p110α subunit of the phosphoinositide 3‐kinase mutant subgroup was higher than that in the wild‐type subgroup. Gap junction beta‐2 was associated with the phosphoinositide 3‐kinase‐Akt signaling pathway, extracellular matrix–receptor interaction, focal adhesion, and proteoglycans in cancer. Furthermore, gap junction beta‐2 overexpression may be associated with phosphoinositide 3‐kinase and histone deacetylase inhibitor resistance, and its expression level correlated with infiltrating CD8+ T cells, macrophages, neutrophils, and dendritic cells.ConclusionsGap junction beta‐2 may be a promising therapeutic target for targeted therapy and immunotherapy and may be used to predict breast cancer prognosis.

HHLA2 deficiency inhibits pancreatic cancer progression and THP-1 macrophage M2 polarization via EGFR/MAPK/ERK and mTOR/AKT pathway

BackgroundHuman endogenous retrovirus subfamily H long terminal repeat associating protein 2, (HHLA2), a member of B7 family, exhibits heightened expression in various malignant tumors. However, the exact functions of HHLA2 in pancreatic cancer (PC) remain incompletely elucidated.MethodsWe initially conducted an analysis of the B7 family members’ expression pattern in pancreatic tumor samples and adjacent normal tissues using The Cancer Genome Atlas (TCGA) database. Subsequently, immunohistochemistry, RT-qPCR and western blot methods were used to assess HHLA2 expression levels in PC tissues and cell lines. Furthermore, after silencing HHLA2 in PC cell lines, cell migration and proliferation of PC cells were detected by wound healing and CCK-8 assays, and cell invasion of PC cells was detected by transwell assays. We also investigated the regulation of epithelial-mesenchymal transition (EMT) markers and levels of EGFR, MEK, ERK1/2, mTOR and AKT via western blot analysis. Finally, the correlation between HHLA2 expression and immune infiltration was further explored.ResultsSilencing of HHLA2 resulted in the inhibition of PC cell proliferation, migration and invasion, potentially through the suppression of the EGFR/MAPK/ERK and mTOR/AKT signaling pathway. Additionally, silencing HHLA2 led to the inhibition of M2-type polarization of tumor associated macrophages (TAMs).ConclusionThe knockdown of HHLA2 was observed to inhibit the migration and invasion of PC cells through the regulation of the EMT process and EGFR/MAPK/ERK and mTOR/AKT pathway. Furthermore, silencing HHLA2 was found to modulate M2 polarization of TAMs. These finding suggest that HHLA2 could be a promising therapeutic target for Pancreatic cancer.

Global research landscape and trends of cancer stem cells from 1997 to 2023: A bibliometric analysis.

Cancer stem cells (CSCs) are a subset of cells with self-renewal ability and tumor generating potential. Accumulated evidence has revealed that CSCs were shown to contribute to tumorigenesis, metastasis, recurrence and resistance to chemoradiotherapy. Therefore, CSCs were regarded as promising therapeutic targets in cancer. This study is the first to reveal the development process, research hotspots, and trends of entire CSCs research field through bibliometric methods. All relevant publications on CSCs with more than 100 citations (notable papers) and the 100 most cited papers (top papers) during 1997 to 2023 were extracted and analyzed. Cancer research published the largest number of papers (184 papers). The USA accounted for the most publications (1326 papers). Rich, JN was the author with the most publications (56 papers) and the highest M-index (3.111). The most contributive institution was the University of Texas System (164 papers). Before 2007, research mainly focused on the definition and recognition of CSCs. Between 2007 and 2016, with the emergence of the terms such as "sonic hedgehog," "metabolism," "oxidative phosphorylation," and "epithelial mesenchymal transition," research began to shift toward exploring the mechanisms of CSCs. In 2016, the focus transitioned to the tumor microenvironment and the ecological niches. The analysis of papers published in major journals since 2021 showed that "transcription," "inhibition," and "chemoresistance" emerged as new focused issues. In general, the research focus has gradually shifted from basic biology to clinical transformation. "Tumor microenvironment" and "chemo-resistance" should be given more attention in the future.

An Improved PDE6D Inhibitor Combines with Sildenafil To Inhibit KRAS Mutant Cancer Cell Growth.

The trafficking chaperone PDE6D (or PDEδ) was proposed as a surrogate target for K-Ras, leading to the development of a series of inhibitors that block its prenyl binding pocket. These inhibitors suffered from low solubility and suspected off-target effects, preventing their clinical development. Here, we developed a highly soluble, low nanomolar PDE6D inhibitor (PDE6Di), Deltaflexin3, which has the lowest off-target activity as compared to three prominent reference compounds. Deltaflexin3 reduces Ras signaling and selectively decreases the growth of KRAS mutant and PDE6D-dependent cancer cells. We further show that PKG2-mediated phosphorylation of Ser181 lowers K-Ras binding to PDE6D. Thus, Deltaflexin3 combines with the approved PKG2 activator Sildenafil to more potently inhibit PDE6D/K-Ras binding, cancer cell proliferation, and microtumor growth. As observed previously, inhibition of Ras trafficking, signaling, and cancer cell proliferation remained overall modest. Our results suggest reevaluating PDE6D as a K-Ras surrogate target in cancer.

Abstract B009: Targeting bladder cancer-macrophage interactions by SPARC peptides

Abstract Bladder cancer is one of the privileged cancers treated with two modalities of immune therapeutics: intravesical Bacille Calmette-Guérin (BCG) for non-muscle invasive disease and immune checkpoint inhibitors for advanced metastatic muscle invasive disease. However, recurrence, intolerance and adverse events are encountered in both modalities with limited second and third line treatment options. Clinical data indicated that pretreatment infiltration of bladder tumors with tumor associated macrophages (TAMs) is associated with BCG failure, resistance to standard of care chemo- and immune-therapy and poor disease outcome. Preclinical studies indicated that macrophage infiltration is the forerunner of carcinogen-induced preneoplastic bladder lesions and progresses throughout overt neoplastic and metastatic disease. Thus, TAMs represent a plausible therapeutic target for bladder cancer. Capitalizing on our earlier report that SPARC, as tumor suppressor of BCa, we developed peptides mapping the biologically active domains of SPARC and investigated their direct effect on tumor cell malignant phenotype. In tandem, we determined the effect of SPARC-peptides on macrophage differentiation, polarization, and anti-tumor effects. We identified a potent inhibitory effect of our peptides on a panel of bladder cancer cell survival and invasiveness in 2D and 3D cultures. Using macrophage cell lines as well as bone marrow-derived myeloid cells, we found these peptides induced an M1 phenotype in response to cytokine stimulation, with enhanced phagocytic activity and macrophage-induced tumor cell killing in vitro. Moreover, SPARC-peptides inhibited macrophage polarization to M2 phenotype. Our data strongly suggest that SPARC-peptides are promising therapeutic candidates for bladder cancer. Citation Format: Mariam Diab, Neveen Said. Targeting bladder cancer-macrophage interactions by SPARC peptides [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B009.

Hypoxia-induced NOS1 as a therapeutic target in hypercholesterolemia-related colorectal cancer

BackgroundIt is well established that hypercholesterolemia increases the risk of atherosclerosis, especially because it reduces the availability of nitric oxide (NO). However, the relationship between hypercholesterolemia and NO in regulating colorectal cancer development and progression remains unknown.MethodsWe conducted bioinformatics analysis, qRT-PCR, ChIP-qPCR assays, luciferase report assays, clonogenic survival assays, and multiple mouse models to investigate the function and mechanism of hypercholesterolemia in regulating NO signaling. Additionally, NOS inhibitors were used to evaluate the potential of therapeutic strategy in anti-tumor response.ResultsHere, we show that oxidized low-density lipoprotein (oxLDL) cholesterol and its receptor LOX-1 are essential for hypercholesterolemia-induced colorectal tumorigenesis. Mechanically, the oxLDL promotes the oxidant stress-dependent induction of hypoxia signaling to transcriptionally up-regulate NO synthase (NOS) especially NOS1 expression in colorectal cancer (CRC) cells. More importantly, our results suggested that selective inhibition of NOS1 with its specific inhibitor Nω-Propyl-L-arginine is a suitable therapeutic strategy for hypercholesterolemia-related CRC with both efficacy and toxicity reduction.ConclusionsOur findings established that hypercholesterolemia induces the oxidant stress-dependent induction of hypoxia signaling to transcriptionally up-regulate NOS1 expression in CRC cells, and the clinically applicable NOS1 inhibitor Nω-Propyl-L-arginine represents an effective therapeutic strategy for hypercholesterolemia-related CRC.

Abstract A026: PIN1 isomerase promotes the initiation and progression of bladder cancer through SREBP2-mediated cholesterol biosynthesis pathway

Abstract Bladder cancer, one of the most commonly diagnosed cancers worldwide, is associated with high morbidity, mortality, and a poor prognosis. The PIN1 phospho-dependent prolyl isomerase is frequently overexpressed in many human cancer types and affects tumor initiation and progression through disrupting the balance of oncoprotein and tumor suppressor protein signaling. However, the functional pSer/Thr.Pro protein substrates of PIN1 and its effects on downstream signaling in bladder carcinogenesis remain largely unknown. Phenotypically, we discovered that ablation of Pin1 in human/mouse bladder cancer cells and organoids formed from mouse primary urothelial cells resulted in decreased cell proliferation, stemness maintenance, cell invasion, migration, urothelium clearance capacity, and reduced free/total cholesterol levels in vitro. Re-expressing Pin1 in Pin1 knockout cells reversed the defects caused by lack of Pin1. Moreover, in vivo subcutaneous xenograft and allograft transplantation mouse models combined with an orthotopic implantation model were utilized to confirm a positive role for Pin1 in controlling tumor growth and potential metastasis. Therapeutically, a combination of the sulfopin PIN1 inhibitor and the simvastatin HMGCR inhibitor was shown to suppress cell proliferation in vitro and tumor growth in vivo synergistically. Mechanistically, we observed a negative enrichment of SREBP2-driven cholesterol metabolism pathways in PIN1 knockout cells via RNA-sequencing and used a suite of diverse molecular and biochemical approaches to show that PIN1 directly binds to JNK-dependent phosphorylated SREBP2 (Ser455) and vice versa. These results indicate that active cholesterol biosynthesis pathway in bladder cancer cells is regulated by PIN1-mediated isomerization and JNK-mediated phosphorylation of its key transcriptional factor SREBP2. These findings emphasize that PIN1 can act as a regulator and potential therapeutic target in bladder cancer. Citation Format: Xue Wang, Tony Hunter. PIN1 isomerase promotes the initiation and progression of bladder cancer through SREBP2-mediated cholesterol biosynthesis pathway [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A026.

JAM3 promotes cervical cancer metastasis by activating the HIF-1α/VEGFA pathway.

Cervical cancer is the fourth most common cancer and the leading cause of mortality among women worldwide. Tumor metastasis is an important cause of poor prognosis. Determining the exact mechanisms of metastasis and potential targeted therapies is urgently needed. Junctional adhesion molecule 3 (JAM3) is an important member of the TJ tight junction (TJ) family, and its biological function in cervical cancer needs to be further clarified. We found that JAM3 was highly expressed in cervical cancer patients with lymph node metastasis and that high expression of JAM3 promoted cervical cancer cell metastasis both in vitro and in vivo. In addition, overexpression of JAM3 induces epithelial-mesenchymal transition (EMT). Moreover, silencing JAM3 suppressed cervical cancer cell migration and invasion in vitro. Finally, JAM3 overexpression activated the HIF-1α/VEGFA pathway. In conclusion, our results suggested that JAM3 promotes cervical cancer cell migration and invasion by activating the HIF-1α/VEGFA pathway. JAM3 may be a promising biomarker and effective therapeutic target for cervical cancer.

Abstract A001: Urine-based liquid biopsy test for the detection of residual bladder cancer in radical cystectomy patients

Abstract One commonly employed management strategy for muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy followed by radical cystectomy (RC) and urinary diversion. Approximately 35% of patients achieve a pathologic complete response (pCR) when evaluated from RC specimens. RC with urinary diversion is a life-altering operation with high complication rates and therefore determining who are complete responders would improve quality of life and could decrease costs and still achieve a high cure rate via RC avoidance. Unfortunately, current methods cannot accurately identify complete responders. Our lab has developed a urine-based liquid biopsy test in which DNA isolated from urine and germline is isolated and subjected to panel exome sequencing for enumeration of somatic variants. This occurs under the premise that tumor DNA identified (as mutant alleles) is a marker of residual disease while the absence of tumor DNA (meaning the absence of mutant alleles) can indicate a pCR. A 60 gene panel was designed to be used for exonic sequencing of urinary DNA (uDNA) to identify mutations indicative of bladder cancer or therapeutic targets. We have shown that most mutations in tumor tissue (Mt) are detectable as mutations in urine (Mu). We also showed that the presence or absence of residual Mu after completion of chemotherapy strongly associates with residual disease or pCR at the time of RC, respectively. Therefore, this test could be used after neoadjuvant therapy to better identify patients for RC avoidance. We optimized this test by studying pre-analytical factors affecting the yield, purity, and integrity of uDNA and the quality of sequencing data using prospectively collected samples from patients with MIBC. We are also in the process of testing commercial and novel preservatives to optimize DNA integrity, yield, and mutation detection accuracy to enable temporary ambient temperature storage without compromising mutation detection, permitting shipping/centralized testing. Lastly, we are comparing two library preparation approaches. Study of these preanalytical factors has increased the number of Mu that can be detected and were applied to a cohort of patients who underwent bladder sparing curative-intent treatment in a prospective clinical trial. Studies described herein will enable liquid biopsy tests to accurately identify patients with pCR after neoadjuvant therapy and might safely avoid radical cystectomy. Citation Format: Philip H. Abbosh, Henkel Valentine, Rhea Arya. Urine-based liquid biopsy test for the detection of residual bladder cancer in radical cystectomy patients [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A001.

Risk assessment model based on nucleotide metabolism-related genes highlights SLC27A2 as a potential therapeutic target in breast cancer.

Breast cancer (BC) is the most prevalent malignant tumor worldwide among women, with the highest incidence rate. The mechanisms underlying nucleotide metabolism on biological functions in BC remain incompletely elucidated. MATERIALSAND METHODS: We harnessed differentially expressed nucleotide metabolism-related genes from The Cancer Genome Atlas-BRCA, constructing a prognostic risk model through univariate Cox regression and LASSO regression analyses. A validation set and the GSE7390 dataset were used to validate the risk model. Clinical relevance, survival and prognosis, immune infiltration, functional enrichment, and drug sensitivity analyses were conducted. Our findings identified four signature genes (DCTPP1, IFNG, SLC27A2, and MYH3) as nucleotide metabolism-related prognostic genes. Subsequently, patients were stratified into high- and low-risk groups, revealing the risk model's independence as a prognostic factor. Nomogram calibration underscored superior prediction accuracy. Gene Set Variation Analysis (GSVA) uncovered activated pathways in low-risk cohorts and mobilized pathways in high-risk cohorts. Distinctions in immune cells were noted between risk cohorts. Subsequent experiments validated that reducing SLC27A2 expression in BC cell lines or using the SLC27A2 inhibitor, Lipofermata, effectively inhibited tumor growth. We pinpointed four nucleotide metabolism-related prognostic genes, demonstrating promising accuracy as a risk prediction tool for patients with BC. SLC27A2 appears to be a potential therapeutic target for BC among these genes.

Retraction: Knockdown of TRIM65 inhibits lung cancer cell proliferation, migration and invasion: A therapeutic target in human lung cancer.

Retraction: Knockdown of TRIM65 inhibits lung cancer cell proliferation, migration and invasion: A therapeutic target in human lung cancer.

A humanized trivalent Nectin-4-targeting nanobody drug conjugate displays potent antitumor activity in gastric cancer

BackgroundGastric cancer represents a highly lethal malignancy with an elevated mortality rate among cancer patients, coupled with a suboptimal postoperative survival prognosis. Nectin-4, an overexpressed oncological target for various cancers, has been exploited to create antibody-drug conjugates (ADCs) to treat solid tumors. However, there is limited research on Nectin-4 ADCs specifically for gastric cancer, and conventional immunoglobulin G (IgG)-based ADCs frequently encounter binding site barriers. Based on the excellent tumor penetration capabilities inherent in nanobodies (Nbs), we developed Nectin-4-targeting Nb drug conjugates (NDCs) for the treatment of gastric cancer.ResultsAn immunized phage display library was established and employed for the selection of Nectin-4-specific Nbs using phage display technology. Subsequently, these Nbs were engineered into homodimers to enhance Nb affinity. To prolong in vivo half-life and reduce immunogenicity, we fused an Nb targeting human serum albumin (HSA), resulting in the development of trivalent humanized Nbs. Further, we site-specifically conjugated a monomethyl auristatin E (MMAE) at the C-terminus of the trivalent Nbs, creating Nectin-4 NDC (huNb26/Nb26-Nbh-MMAE) with a drug-to-antibody ratio (DAR) of 1. Nectin-4 NDC demonstrated excellent in vitro cell-binding activities and cytotoxic efficacy against cells with high Nectin-4 expression. Subsequent administration of Nectin-4 NDC to mice bearing NCI-N87 human gastric cancer xenografts demonstrated rapid tissue penetration and high tumor uptake through in vivo imaging. Moreover, Nectin-4 NDC exhibited noteworthy dose-dependent anti-tumor efficacy in in vivo studies.ConclusionWe have engineered a Nectin-4 NDC with elevated affinity and effective tumor uptake, further establishing its potential as a therapeutic agent for gastric cancer.Graphical abstract

Current scenario of fused pyrimidines with in vivo anticancer therapeutic potential.

Cancer, characterized by uncontrolled cell growth and metastasis, is responsible for nearly one in six deaths and represents a severe threat to public health worldwide. Chemotherapy can substantially improve the quality of life and survival of patients with cancer, but anticancer chemotherapeutics are associated with a range of adverse effects. Moreover, almost all currently available anticancer chemotherapeutics could develop drug resistance over a period of time of application in cancer patients and ultimately lead to cancer relapse and death in 90% of patients, creating an urgent need to develop new anticancer agents. Fused pyrimidines trait the inextricable part of DNA and RNA and are vital in numerous biological processes. Fused pyrimidines can act on various biological cancer targets and have the potential to address drug resistance. In addition, more than 20 fused pyrimidines have already been approved for clinical treatment of different cancers and occupy a prominent place in the current therapeutic arsenal, revealing that fused pyrimidines are privileged scaffolds for the development of novel anticancer chemotherapeutics. The purpose of this review is to summarize the current scenario of fused pyrimidines with in vivo anticancer therapeutic potential along with their acute toxicity, metabolic profiles as well as pharmacokinetic properties, toxicity and mechanisms of action developed from 2020 to the present to facilitate further rational exploitation of more effective candidates.

Identifying Key Regulatory Genes in Drug Resistance Acquisition: Modeling Pseudotime Trajectories of Breast Cancer Single-Cell Transcriptome

Single-cell RNA-sequencing (scRNA-seq) technology has provided significant insights into cancer drug resistance at the single-cell level. However, understanding dynamic cell transitions at the molecular systems level remains limited, requiring a systems biology approach. We present an approach that combines mathematical modeling with a pseudotime analysis using time-series scRNA-seq data obtained from the breast cancer cell line MCF-7 treated with tamoxifen. Our single-cell analysis identified five distinct subpopulations, including tamoxifen-sensitive and -resistant groups. Using a single-gene mathematical model, we discovered approximately 560–680 genes out of 6000 exhibiting multistable expression states in each subpopulation, including key estrogen-receptor-positive breast cancer cell survival genes, such as RPS6KB1. A bifurcation analysis elucidated their regulatory mechanisms, and we mapped these genes into a molecular network associated with cell survival and metastasis-related pathways. Our modeling approach comprehensively identifies key regulatory genes for drug resistance acquisition, enhancing our understanding of potential drug targets in breast cancer.

To explore the mechanism of Yigong San anti-gastric cancer and immune regulation.

Yigong San (YGS) is a representative prescription for the treatment of digestive disorders, which has been used in clinic for more than 1000 years. However, the mechanism of its anti-gastric cancer and regulate immunity are still remains unclear. To explore the mechanism of YGS anti-gastric cancer and immune regulation. Firstly, collect the active ingredients and targets of YGS, and the differentially expressed genes of gastric cancer. Secondly, constructed a protein-protein interaction network between the targets of drugs and diseases, and screened hub genes. Then the clinical relevance, mutation and repair, tumor microenvironment and drug sensitivity of the hub gene were analyzed. Finally, molecular docking was used to verify the binding ability of YGS active ingredient and hub genes. Firstly, obtained 55 common targets of gastric cancer and YGS. The Kyoto Encyclopedia of Genes and Genomes screened the microtubule-associated protein kinase signaling axis as the key pathway and IL6, EGFR, MMP2, MMP9 and TGFB1 as the hub genes. The 5 hub genes were involved in gastric carcinogenesis, staging, typing and prognosis, and their mutations promote gastric cancer progression. Finally, molecular docking results confirmed that the components of YGS can effectively bind to therapeutic targets. YGS has the effect of anti-gastric cancer and immune regulation.

DNA Reaction Circuits to Establish Designated Biological Functions in Multicellular Community.

In multicellular organisms, individual cells are coordinated through complex communication networks to accomplish various physiological tasks. Aiming to establish new biological functions in the multicellular community, we used DNA as the building block to develop a cascade of nongenetic reaction circuits to establish a dynamic cell-cell communication network. Utilizing membrane-anchored amphiphilic DNA tetrahedra (TDN) as the nanoscaffold, reaction circuits were incorporated into three unrelated cells in order to uniquely regulate their sense-and-response behaviors. As a proof-of-concept, this step enabled these cells to simulate significant biological events involved in T cell-mediated anticancer immunity. Such events included cancer-associated antigen recognition and the presentation of antigen-presenting cells (APCs), APC-facilitated T cell activation and dissociation, and T cell-mediated cancer targeting and killing. By combining the excellent programmability and molecular recognition ability of DNA, our cell-surface reaction circuits hold promise for mimicking and manipulating many biological processes.

Deciphering the potential role of PGRN in regulating CD8+ T cell antitumor immunity

A key factor contributing to resistance in immune checkpoint blockade (ICB) therapies is CD8+ T-cell tolerance in the tumor microenvironment (TME), partly resulting from upregulating coinhibitory receptors. Here, we describe the role of PGRN as a coinhibitory molecule that modulates the antitumor response of CD8+ T cells, thus presenting a novel immunosuppressive target for lung cancer. The in vivo subcutaneous transplanted lung cancer model showed that PGRN expression was elevated on CD8+ T cells that infiltrated transplanted lung cancers. Furthermore, PGRN deficiency was found to specifically encourage the infiltration of CD8+ T cells, enhance their proliferation, migration, and activation, and resist apoptosis, ultimately inhibiting tumor growth. This was achieved by PGRN knockout, increasing the production of T cell chemokine CCL3, which boosts the antitumor immune response induced by CD8+ T cells. Critically, the PD-L1 inhibitor exhibited a synergistic effect in enhancing the antitumor response in PGRN–/– mice. In summary, our findings highlight the significance of PGRN as a novel target for boosting CD8+ T cells antitumor immunity and its potential to overcome the resistance in ICB therapy.