Nuclear medicine has revolutionized disease diagnosis and treatment, particularly in oncology, by enabling precise imaging and targeted therapies using radiopharmaceuticals. Recently, Gallium-68 (68Ga) has emerged as a powerful positron emission tomography (PET) imaging agent, with a growing role in theranostics when paired with 177Lu for cancer treatment. The ability to obtain 68Ga from 68Ge/68Ga generators, along with its favorable radiochemical and pharmacokinetic properties, has driven an increasing number of clinical applications, which culminated with the approvals of 68Ga-DOTA-TOC and 68Ga-DOTA-TATE for the treatment of neuroendocrine tumors, and 68Ga-PSMA-11 for prostate cancer over the past decade. This review provides a comprehensive overview of 68Ga radiochemistry, chelators, and key compounds in clinical trials, highlighting the potential of this radionuclide in precision oncology.

Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment (TME) and play a crucial role in tumor progression. The biological properties of tumors, such as drug resistance, vascularization, immunosuppression, and metastasis are closely associated with CAFs. During tumor development, CAFs contribute to tumor progression by remodeling the extracellular matrix (ECM), inhibiting immune cell function, promoting angiogenesis, and facilitating tumor cell growth, invasion, and metastasis. Studies have shown that CAFs can promote endothelial cell proliferation by directly secreting cytokines such as vascular endothelial growth factor (VEGF) and fibroblast Growth Factor (FGF), as well as through exosomes. CAFs also secrete the chemokine stromal cell-derived factor 1 (SDF-1) to recruit endothelial progenitor cells (EPCs) into the peripheral blood and guide their migration to the tumor periphery. Additionally, CAFs can induce tumor cells to transform into "endothelial cells" that participate in vascular wall formation. However, the precise mechanisms remain to be further investigated. Due to their widespread presence in various solid tumors and their tumor-promoting function, CAFs are emerging as therapeutic targets. In this review, we summarize the specific mechanisms through which CAFs promote angiogenesis and outline current therapeutic strategies targeting CAF-induced vascularization, ongoing clinical trials targeting CAFs, and discuss potential future treatment approaches. We hope this will contribute to the advancement of CAF-targeted tumor treatment strategies.

Hepatocellular carcinoma (HCC) stands as one of the most prevalent and deadliest malignancies on a global scale. Its complex pathogenesis arises from multifactorial etiologies, including viral infections, metabolic syndromes, and environmental carcinogens, all of which drive genetic and molecular aberrations in hepatocytes. This intricate condition is associated with multiple causative factors, resulting in the abnormal activation of various cellular and molecular pathways. Given that HCC frequently manifests within the context of a compromised or cirrhotic liver, coupled with the tendency of late-stage diagnoses, the overall prognosis tends to be unfavorable. Systemic therapy, especially conventional cytotoxic drugs, generally proves ineffective. Despite advancements in therapeutic interventions, conventional treatments such as chemotherapy often exhibit limited efficacy and substantial systemic toxicity. In this context, nanomedicine, particularly lipid-based nanoparticles (LNPs), has emerged as a promising strategy for enhancing drug delivery specificity and reducing adverse effects. This review provides a comprehensive overview of the molecular and metabolic underpinnings of HCC. Furthermore, we explored the role of lipid-based nano-formulations including liposomes, solid lipid nanoparticles, and nanostructured lipid carriers in targeted drug delivery for HCC. We have highlighted recent advances in LNP-based delivery approaches, FDA-approved drugs, and surface modification strategies to improve liver-specific delivery and therapeutic efficacy. It will provide a comprehensive summary of various treatment strategies, recent clinical advances, receptor-targeting strategies and the role of lipid composition in cellular uptake. The review concludes with a critical assessment of existing challenges and future prospects in nanomedicines-driven HCC therapy.

Receptor-mediated targeted drug delivery has emerged as a pivotal strategy in cancer therapy, offering precision and specificity in combating malignant diseases while minimizing systemic toxicity. This review explores the multifaceted role of receptors in cancer biology, emphasizing their contributions to cancer progression, metastasis, and their potential as therapeutic targets. Ligand-based targeting approaches highlight the utility of small molecules, peptides, and antibodies, as well as the development of novel targeting ligands. A critical focus is placed on engineering receptor-targeted nanoparticles and advanced drug delivery systems. Innovations in dual-targeting strategies and the targeted delivery to the tumour microenvironment (TME) and metastatic niches are discussed, underscoring their potential to enhance therapeutic efficacy. Additionally, receptor-targeted imaging is reviewed for its dual role in diagnosis and real-time treatment monitoring. To address the challenges of side effects and off-target toxicity, strategies that minimize these risks while targeting overexpressed receptors in solid tumours are explored. Finally, the review outlines future directions in receptor-targeted cancer therapy, emphasizing the need for interdisciplinary research to refine these strategies further. This comprehensive analysis aims to provide a roadmap for advancing receptor-based therapeutic approaches, ultimately improving outcomes for cancer patients.

A series of LCA-aromatic amino acid conjugates were synthesized and tested for their inhibitory effects on N-glycan specific ST6GAL1 and O-glycan specific ST3GAL1. The LCA-amino acid conjugates with phenyl and indole moieties showed enhanced inhibitory activity and selectivity towards the N-glycan-specific ST6GAL1, with the indole-containing compound 4e exhibiting the highest activity (IC50 = 20.0 ± 0.5 μM). In addition, compound 4e exhibited the highest antimetastatic potential, effectively inhibiting MDA-MB-231 cell migration at non-cytotoxic concentrations. Compound 4e also suppressed tumor growth and metastasis in vivo, attributing to its potential to disrupt integrins sialylation. The conjugate has also demonstrated excellent antiangiogenetic properties in vitro and ex vivo, owing to its ability to downregulate the VEGF/VEGFR2/Akt pathway. Taken together, these findings prove the practicality of employing LCA as a scaffold and aromatic amino acid conjugation in the discovery of novel, potent, and selective ST inhibitors necessary to address abnormal cell surface α-2,6-N-sialylation.

Ischemia-reperfusion (I/R) injury is associated with a variety of retinal diseases, resulting in loss of the number of ganglion cells (RGCs), retinal structural disorders, and retinal dysfunction. The Reelin protein is an important regulator of neuronal migration and synaptogenesis, and the Reln signaling pathway plays an essential role in regulating the targeted projection of RGC dendrites and neuronal survival, which has not been reported in retinal I/R injury. The aim of this study was to investigate the expression, role and mechanism of Reln in retinal I/R injury. By establishing Reln-CreERT2 mTmG transgenic mice, it was observed that the expression of Reln initially decreased and then increased after retinal I/R injury. After supplementing exogenous Reelin protein and adeno-associated virus (AAV)-targeted regulation of Reln in vivo, morphological and functional experiments demonstrated its effectiveness in protecting RGCs survival, maintaining morphological integrity of the retina, and inhibiting post-injury retinal dysfunction. Furthermore, integrin β1 (Itgb1) was identified as the main receptor through which Reelin exerts neuroprotective effects while regulating retinal I/R injury repair through the Dab1-PI3K-Akt pathway. These findings provide evidence supporting Reln pathway's role in maintaining retinal homeostasis and facilitating injury repair. Moreover, these findings have significant implications for identifying new targets for preventing and treating various retinal diseases.

Advances in narrowband imaging (NBI) have revealed that squamous epithelial lesions form alongside changes in squamous epithelial cells and intrapapillary capillary loops (IPCLs) in the head and neck. However, the molecular interactions between squamous epithelial cells and endothelial cells (ECs) that promote IPCL proliferation are unclear. This study aimed to identify the mechanisms of cooperation between parenchymal squamous cells and stromal IPCLs during the formation of head and neck squamous cell carcinoma (SCC). We investigated ligand-receptor interactions between squamous epithelial and endothelial cells of IPCLs using Visium analysis on frozen, formalin-fixed and paraffin-embedded (FFPE) tissues from hypopharyngeal squamous epithelial lesions. We examined the protein expression in hypopharyngeal superficial squamous epithelial lesions using immunohistochemistry and immunofluorescence. mRNA expression levels of these genes in SCC and non-tumor tissues were analyzed using RT-qPCR. Phenotypic changes were analyzed by inducing candidate genes into SCC cell lines via a lentivirus system. Visium analysis revealed that Fibronectin 1 (FN1) acted as a ligand in endothelial cells, Cellular communication network factor 1 (CCN1) as a ligand in SCC cells, and Integrin subunit alpha V (ITGAV) as a receptor for both FN1 and CCN1. The expression of these three candidates increased in low-grade dysplasia, an early stage of neoplastic lesions, and was significantly higher in invasive SCCs, except for CCN1. When ITGAV was introduced into SCC cell lines (FaDu and Detroit 562) and HaCaT cells treated with FN1, the cells showed increased proliferation ability. SCC develops via ligand-receptor molecular interactions between squamous epithelial and vascular endothelial cells in IPCLs.

Deciphering the processes through which cancer cells overcome stress, escape a repressive microenvironment and metastasize remains a challenge. Autophagy has been demonstrated to regulate cancer metastasis and C-terminal binding protein (CtBP) has been previously implicated in promoting metastasis in breast cancer. Here we identify the formation of a complex between CtBP and tripartite-motif-containing protein 28 (TRIM28) in the nucleus. Interestingly, this complex regulates the stability of both proteins, as the removal of either partner leads to degradation of the other. Furthermore, the stability of this complex in the nucleus inhibits autophagy through two independent mechanisms. Firstly, the formation of the complex sequesters TRIM28 in the nucleus, preventing its involvement in and its degradation through autophagy. Secondly, this complex participates in the suppression of PTEN expression and leads to inhibition of Unc-51-like kinase 1-mediated autophagy through activation of the protein kinase B-mammalian target of rapamycin pathway. Using mammary gland-specific CtBP-knockout mice, we demonstrate that repression of autophagy by the CtBP-TRIM28 complex modulates luminal duct formation. In breast cancer models, CtBP-TRIM28-dependent inhibition of cellular autophagy also promotes malignant metastasis. Therefore, our study reveals similarities between the mechanisms driving tumor progression and those involved in normal mammary gland development, potentially helping to pave the way toward targeted intervention in breast cancer metastasis.

While CD49d (α4 integrin) is an established prognostic marker in chronic lymphocytic leukaemia (CLL) and is associated with aggressive disease, its impact on T-cell biology remains poorly understood. Compared to healthy donors, CLL patients exhibited significantly elevated CD49d expression in both CD4+ and CD8+ T cells (p < 0.001) as detected by flow cytometry, which was also confirmed by the single-cell RNA sequencing (scRNA-seq) (p < 0.001). Differentially expressed genes in CD49d+ T (both CD8+ and CD4+ T cells) versus CD49d- T cells identified in CLL patients were enriched in cellular senescence pathways, while this phenomenon is absent in healthy individuals. Functional validation demonstrated that CD49d+ T cells displayed elevated senescence-associated markers (e.g. interferon-gamma, granzyme B) and a shift towards memory phenotypes, correlating with immunosuppressive signatures. This discovery suggests that targeting CD49d-dependent senescence pathways may reverse T-cell dysfunction in CLL immunotherapy.

Triptolide (TP) is a promising anti-tumor candidate derived from the herb Tripterygium wilfordii, but its poor water solubility and multi-organ toxicity limit its application. Here, we developed novel nanoparticles (TP-SP@NPs) modified with dextran sulfate and RGD peptide for double-targeted delivery of TP to both tumor cells and pro-tumor macrophages in pancreatic cancer treatment. TP-SP@NPs exhibited suitable particle size (about 98 nm), good stability and controlled release performance. TP-SP@NPs showed high cellular uptake in Pan02 cells and M2 macrophages through αvβ3 integrin-RGD interaction and SR-A-DS interaction, effectively inhibiting tumor growth by triggering apoptosis of these cells. In Pan02 tumor-bearing mice, TP-SP@NPs specifically accumulated at the tumor site and efficiently decreased the number of M2 macrophages, thereby exerting better curative effect on pancreatic cancer and lower systemic toxicity as compared with TP. As a result, TP-SP@NPs had achieved selective anti-tumor effect, good biosafety and great promise in clinical application.

Glioblastoma, the most aggressive type of primary brain tumor, is marked by high invasiveness and metastasis, posing significant challenges in treatment. Fucoxanthin, a carotenoid derived from brown macroalgae, has demonstrated therapeutic potential in cancer therapy; however, its precise mechanisms of action remain unclear. In this study, we explored the inhibitory effects of fucoxanthin on integrin-mediated adhesion and migration in human glioma U-87 MG cells, shedding light on its potential antimetastatic properties. Our data indicated that fucoxanthin at 1 μM did not affect cell viability but inhibited integrin-mediated adhesion of human glioma U-87 MG cells to fibronectin, a key extracellular matrix (ECM) ligand for integrins, without affecting adhesion to poly-l-lysine, a nonintegrin ligand, indicating its selective impact on integrin-mediated adhesion. Fucoxanthin treatment significantly reduced the size and number of focal adhesions (FA), which play a central role in cell adhesion and migration. In addition, fucoxanthin significantly impaired U-87 MG cell migratory capacity, including a reduced accumulated migration distance and velocity, determined by time-lapse videomicroscopy. Further, fucoxanthin remarkably inhibited integrin engagement-mediated actin polymerization, Vav3 phosphorylation, and the downstream activation of Rac1, FAK, and paxillin, further supporting its role in disrupting integrin signaling and cytoskeletal remodeling. Additionally, complementary experiments utilizing protein binding assays, competitive ELISA, CETSA, DARTS, and MST collectively confirmed the direct interaction between fucoxanthin and β1 integrin as well as reduced ligand affinity of β1 integrin for fibronectin. The theoretical model of molecular docking and the dynamics simulation align with our experimental findings, providing a plausible mechanism by which fucoxanthin competitively inhibits the binding of β1 integrin to fibronectin. In summary, our study highlights fucoxanthin as a promising therapeutic agent that impairs integrin-mediated adhesion and migration in glioblastoma cells by directly targeting β1 integrin and disrupting integrin signaling pathways. These findings offer valuable insights into the potential of fucoxanthin as an antimetastatic agent in glioblastoma treatment.

Corneal neovascularization (CoNV) is a leading cause of visual impairment worldwide. However, CoNV remains challenging to cure clinically because of the limitations of current drugs. New and more effective therapeutic formulations for CoNV treatment are therefore urgently needed. Antisense oligonucleotide drugs hold great promise for the treatment of neovascular diseases, and ionizable cationic lipid nanoparticles (icLNPs) have shown excellent performance for nucleic acid delivery, with high encapsulation, good cellular uptake, and effective endosomal escape. In the present study, we identified integrin β1 (Itgb1) as a key gene involved in angiogenesis and revealed the significant upregulation of Flt1 in vascular endothelial cells and pericytes in CoNV using single-cell sequencing. Itgb1 knockdown significantly inhibited the proliferation and migration of vascular endothelial cells and CoNV in mice. Based on these findings, we developed Itgb1-small interfering RNA (siRNA)-loaded icLNPs, and conjugated anti-Flt1 peptide to their surface to improve CoNV targeting. Furthermore, because lipid nanoparticles reportedly trigger immune responses by upregulating pro-inflammatory cytokine expression, which may promote neovascularization, we modified triptolide (a compound with anti-inflammatory properties) into the icLNPs. The triptolide-modified, anti-Flt1 peptide-conjugated, and Itgb1-siRNA-loaded icLNPs (Itgb1-siRNA@TPL) effectively inhibited the proliferation and migration of vascular endothelial cells in vitro and CoNV in mice after eye drop administration. These effects occurred via downregulation of the PI3K/AKT and NF-κB signaling pathways. Finally, the biosafety of Itgb1-siRNA@TPL was tested, and the results revealed that it was not toxic to the cornea or major organs and had no impact on corneal epithelial healing. In conclusion, Itgb1-siRNA@TPL represent a novel, noninvasive, and effective approach for the treatment of CoNV.

Bone metastases and pathological fractures significantly impact the prognosis and quality of life in cancer patients. However, clinical and radiological features alone have been shown to fail to predict skeletal related events of a bone metastasis (SREs).

This study focuses on key molecular players including Matrix Metalloproteinases (MMPs), Integrins, Bone Morphogenetic Proteins (BMPs), Parathormone-related Protein (PTHrP).

The RANK/RANKL/Osteoprotegerin (OPG) pathway, and N-terminal peptide (NTx), involved in the metastatic process and bone integrity disruption. Elevated levels of these molecules have been pointed out as potential biomarkers for predicting SREs, but they have been poorly investigated. Moreover, batimastat, marimastat, tanomastat, andecaliximab, and HIV protease targeting MMPs; Volociximab/M200, cilengitide, abituzumab, and FAK inhibitors targeting integrins; LDN193189, DMH1, and ISLR modulators targeting BMPs; and PTH (7-33)-CBD targeting PTHrP have shown promising results antagonizing these molecules, but no effect on preventing and managing metastatic fractures has been assessed yet.

This paper underscores the importance of advanced molecular biology and transcriptomics in identifying novel therapeutic targets. The integration of these biomarkers with clinical and radiological assessments using artificial intelligence tools could revolutionize the diagnostics and treatment strategies for patients with bone metastases.

Quercetin is a natural flavonoid found in many plants which has various pharmacological activities including antitumor effect. However, the poor water solubility and bioavailability limit the potential benefits of quercetin for patients. Thus, modifying quercetin structure and developing actively targeted drug delivery systems are extremely important for tumor precision therapy. Herein, polymer-drug conjugates dextran-quercetin (D-Q) and cRGD-dextran (R-D) were synthesized by grafting quercetin and polypeptide cRGDfk (Arg-Gly-Asp-(D-Phe)-Lys) to dextran. Then cRGD-modified dextran-quercetin polymer micelles (R-D-Q) were constructed by self-assembling of D-Q and R-D. R-D-Q micelles possessed appropriate particle size (133.4 nm), nearly neutral potential (8.14 mV) and excellent drug-loading efficiency (13.1 %) and achieved higher cytotoxicity, apoptosis induction and penetration to human breast cancer MCF-7 cells than the micelles unmodified with cRGD, which were ascribed to cRGD-integrin mediated transcytosis. R-D-Q micelles effectively suppressed tumor growth in tumor-bearing mice by delivering more quercetin throughout the tumor tissue. And R-D-Q micelles could promote the apoptosis of tumor cells by activating p38 and JNK signal pathways and suppressing ERK signal pathway. In addition, R-D-Q micelles had no damage to normal tissues of mice at therapeutic dose. These results indicate promising prospects for R-D-Q micelles as an effective drug delivery system against tumor.

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. The French CRC screening campaign is based on fecal immunochemical tests (FIT), confirmed by colonoscopy, an invasive procedure with a poor participation rate. This study aimed to compare the expression of circulating exosomal proteins (MMP14, β1-Integrin subunit, β3-Integrin subunit, and α1(I) Collagen chain) in patients with CRC or adenomas.

A total of 71 patients were recruited, including 24 controls (normal colonoscopy), 11 patients with adenoma, and 36 with CRC. Plasmatic exosomal protein expression was measured by western blot analysis and reported to either protein or exosome content.

The three groups were comparable regarding clinical characteristics. A significant difference was observed for MMP14 relative expression (p = 0.0007), MMP14 expression reported to exosomal protein content (p = 0.0003), and MMP14 expression reported to exosome content (p = 0.0005). These three parameters were significantly higher in patients with adenoma vs. control patients (p = 0.0013, p = 0.0004, and p = 0.0003, respectively). Only MMP14 relative intensity was significantly higher in the CRC group vs. the control group (p = 0.0018).

Exosomal MMP14 is a promising early diagnostic biomarker for CRC and adenoma. These preliminary results warrant confirmation in larger studies using quantitative measurements such as ELISA or flow cytometry.

Tumorigenesis ensues within a heterogeneous tissue microenvironment that promotes malignant transformation, metastasis and treatment resistance. A major feature of the tumor microenvironment is the heterogeneous population of cancer-associated fibroblasts and myeloid cells that stiffen the extracellular matrix. The heterogeneously stiffened extracellular matrix in turn activates cellular mechanotransduction and creates a hypoxic and metabolically hostile microenvironment. The stiffened extracellular matrix and elevated mechanosignaling also drive tumor aggression by fostering tumor cell growth, survival, and invasion, compromising antitumor immunity, expanding cancer stem cell frequency, and increasing mutational burden, which promote intratumor heterogeneity. Delineating the molecular mechanisms whereby tissue mechanics regulate these phenotypes should help to clarify the basis for tumor heterogeneity and cancer aggression and identify novel therapeutic targets that could improve patient outcome. Here, we discuss the role of the extracellular matrix in driving cancer aggression through its impact on tumor heterogeneity.

Integrins consist of 24 species, each with unique tissue expression profiles and distinct biological functions. The β subunit of integrin interacts with the FERM-folded head domain of talin through an NPxY/F motif, triggering integrin activation. Although this motif is conserved across most integrin-β subunits, the precise molecular mechanism governing talin's selective recognition of different integrin-β subunits remains unclear. We identify two distinct configurations of the talin head when interacting with β2 and β3 integrins, providing critical insights into subunit-specific recognition of integrins. Structural studies reveal that mutations at the subdomain interface of the talin head can shift its β2-bound configuration to a β3-bound configuration. This shift enhances β2-integrin affinity, leading to increased lymphocyte function-associated antigen-1 (LFA-1)-mediated natural killer cell activity. Together, our data elucidate the structural basis of talin's role in mediating integrin activation in a subunit-specific manner and advance our understanding of how talin may regulate diverse functions of various integrin species.

The field of mechanobiology has grown in the past decade, but limited studies investigate how the extracellular matrix affects the cell metabolome. The methionine cycle involves the catabolism and regeneration of methionine through the donation and recovery of a single methyl group; this methyl group can methylate DNA, RNA, and proteins to alter gene expression and protein-protein interactions. Through studying cells cultured on fibrous (mimicking healthy extracellular matrice (ECM)) and flat (mimicking severely fibrotic ECM) substrates, we observed an increase in methionine cycle enzyme expression in cells on the flat substrate. We also present how the methionine cycle is modulated by the ECM through transmembrane protein integrin β1. By inhibiting integrin activation through the ligand-mimicking peptide RGD, we observed that the methionine cycle was protected from alteration. The results presented provide insight into possible therapeutic targets for fibrotic diseases and knowledge of mechanisms by which the ECM alters cell processes.

Targeting integrin receptors for MRI represents a novel method in diagnosing glioblastoma. In the present study carbon-encapsulated iron nanoparticles to explore murine glioma tracking based upon specific direct targeting with monoclonal antibodies against the beta-3 subunit (CD61) of the integrin αVβ3 receptor are described.

The carbon arc discharge method was used to synthesize nanoparticles and amidation-type reaction were applied to attach monoclonal antibody (anti-CD61) with acidic group functionalized nanoparticles to lead two types of bioconjugates (Fe@C-CONH-anti-CD61 and Fe@C-(CH2)2-CONH-anti-CD61). The as-synthesized bioconjugates were tested on murine glioma cells (GL261) using MTT, LDH and calcein AM/propidium iodide assays. Relaxometry measurements were performed with a 1.5 T (63 MHz) MRI scanner using both GL261 cells and C57BL/6 mice bearing GL261 tumors.

The results showed that Fe@C-CONH-anti-CD61 and Fe@C-(CH2)2-CONH-anti-CD61 nanoparticles have higher binding affinity towards GL261 cells compared to pristine nanoparticles without antibodies. Studies evidenced that the antibody-decorated nanoparticles did not produce any severe cytotoxic effects on murine glioma cells. Preclinical MRI studies demonstrated that the Fe@C-(CH2)2-CONH-anti-CD61 nanoparticle-based construct specifically targeted murine glioma in animals.

The carbon-encapsulated iron nanoparticles functionalized with monoclonal antibodies recognizing the beta-3 subunit of the integrin αVβ3 receptor can be considered as a potential contrast agent for MRI-based tracking glioblastoma.

Each stage of tumor development is intrinsically linked to the tumor microenvironment (TME), wherein the extracellular matrix (ECM) serves as a vital and abundant component in tumor tissues. The ECM is a non-cellular, three-dimensional macromolecular network scaffold that provides structural support to cells, stores bioactive molecules, and mediates signaling pathways through specific binding to cell surface receptors. Moreover, the ECM in tumor tissues plays a crucial role in impeding drug diffusion and resisting apoptosis induced by conventional anti-cancer therapies that primarily target cancer cells. Therefore, directing attentions towards the tumor ECM can facilitate the identification of novel targets and the development of new therapies. This review aims to summarize the composition, structure, remodeling, and function of tumor ECM, its association with drug resistance, and current targeting strategies, with a specific emphasis on nanoparticles (NPs).

Recent advancements in nanotechnology have significantly advanced nanocarrier-mediated drug delivery systems, promoting therapeutic outcomes in mitigating chronic inflammation and cancer. Nanomaterials offer significant advantages over traditional small-molecule drugs, including a high surface-area-to-volume ratio, tunable structural features, and extended bloodstream circulation time. Chronic inflammation is a well-established mechanism for malignant initiation, progression, and metastasis, promoting the potent strategy for cancer prevention and therapy. Numerous studies revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) have the therapeutic ability to manage disease progression via amolerating angiogenesis and inducing apoptosis. However, prolonged intake of NSAIDs is often limited by adverse side-effects and systemic toxicities. The encapsulation of NSAIDs in a nanocarrier have materialized as a dynamic approach to mitigate the limitations by improving pharmacokinetics and pharmacodynamics, reducing off-target effects, and enhancing the drug stability. This review encompasses recent progress in the development of NSAID-based nanotherapeutics, focusing on pivotal mechanisms underlying nanoparticle-mediated drug delivery, such as improved tumor-specific targeting and strategies to overcome drug resistance. The ability of these nano-cargoes to accommodate anti-inflammatory strategies with advanced drug delivery platforms is critically evaluated. This review also highlights the transformative potential of NSAID-encapsulated nanoparticles as a multifaceted therapeutic venue for addressing chronic inflammation and mitigating cancer progression.

TP53, the most frequently mutated gene in human cancer, encodes a transcriptional activator that induces myriad downstream target genes. Despite the importance of p53 in tumor suppression, the specific p53 target genes important for tumor suppression remain unclear. Recent studies have identified the p53-inducible gene Zmat3 as a critical effector of tumor suppression, but many questions remain regarding its p53-dependence, activity across contexts, and mechanism of tumor suppression alone and in cooperation with other p53-inducible genes. To address these questions, we used Tuba-seqUltra somatic genome editing and tumor barcoding in a mouse lung adenocarcinoma model, combinatorial in vivo CRISPR/Cas9 screens, meta-analyses of gene expression and Cancer Dependency Map data, and integrative RNA-sequencing and shotgun proteomic analyses. We established Zmat3 as a core component of p53-mediated tumor suppression and identified Cdkn1a as the most potent cooperating p53-induced gene in tumor suppression. We discovered that ZMAT3/CDKN1A serve as near-universal effectors of p53-mediated tumor suppression that regulate cell division, migration, and extracellular matrix organization. Accordingly, combined Zmat3-Cdkn1a inactivation dramatically enhanced cell proliferation and migration compared to controls, akin to p53 inactivation. Together, our findings place ZMAT3 and CDKN1A as hubs of a p53-induced gene program that opposes tumorigenesis across various cellular and genetic contexts.

Renal cell carcinoma (RCC) is a significant global health concern, and the early diagnosis and accurate staging of clear cell renal cell carcinoma (ccRCC) remain major challenges. [18F]FDG PET/CT is not ideal for diagnosing ccRCC due to the low glucose metabolism potential of cancer cells. Both fibroblast activation protein (FAP) and the angiogenic integrin αvβ3 receptor are closely linked to the pathogenesis and progression of ccRCC. The aim of this study is to evaluate a novel radiopharmaceutical [18F]AlF-NOTA-FAPI-RGD (denoted as [18F]AlF-LNC1007), a dual-targeting heterodimer tracer targeting both FAP and integrin αvβ3, and to compare the diagnostic value of [18F]AlF-LNC1007 with [18F]FDG and [18F]AlF-NOTA-FAPI-04 PET/CT in RCC. Materials and Methods: A total of 35 participants, highly suspected to have RCC, were recruited. [18F]AlF-LNC1007 and [18F]AlF-NOTA-FAPI-04/[18F]FDG scans were performed at least one day apart, and both were completed within one week. The Wilcoxon signed-rank test or paired t-test was used to assess differences in tumor uptake and TBR (tumor-to-background ratio) between [18F]AlF-LNC1007 and the other two imaging agents. The Spearman correlation coefficient was used to evaluate the correlation between tumor uptake and the expression of FAP and αvβ3. Results: The detection rate, sensitivity, and positive predictive value (PPV) of [18F]AlF-LNC1007 for RCC primary lesions were significantly higher than those of [18F]FDG, at 91% vs. 76%, 100% vs. 85%, and 91% vs. 87%, respectively. Obvious advantages were also seen in metastatic lesions at 94% vs. 34%, 94% vs. 29%, and 100% vs. 100%. Compared to [18F]AlF-NOTA-FAPI-04, the corresponding detection rate, sensitivity, and PPV were 98% vs. 90%, 100% vs. 92%, and 98% vs. 98% for primary lesions, and 89% vs. 78%, 89% vs. 93%, and 100% vs. 82% for metastatic lesions. The uptake and TBR of [18F]AlF-LNC1007 in both primary and metastatic lesions were significantly higher than those of [18F]FDG (all P < 0.001). The uptake of [18F]AlF-LNC1007 showed a moderate to high positive correlation with the expression levels of αvβ3 and the combined expression of FAP and αvβ3 (r = 0.756, P = 0.0003; r = 0.678, P = 0.0002) and a low positive correlation with FAP expression alone (r = 0.389, P = 0.014). The uptake of [18F]AlF-NOTA-FAPI-04 showed a low to moderate positive correlation with FAP expression and the combined expression of FAP and αvβ3 (r = 0.570, P = 0.0002; r = 0.408, P = 0.010), and no correlation with αvβ3 expression alone (r = 0.262, P = 0.107). Conclusion: [18F]AlF-LNC1007 demonstrated significantly higher diagnostic efficacies and uptake in primary and metastatic renal cell carcinoma (RCC) compared to FDG PET/CT. Additionally, [18F]AlF-LNC1007 exhibited higher diagnostic efficacies and uptake in primary RCC than [18F]AlF-NOTA-FAPI-04 PET/CT. While these findings suggest potential diagnostic advantages, further studies are needed to fully evaluate its diagnostic efficacy compared to the standard of treatment.

Catalytic DNA circuits have emerged as a powerful tool for high-performance biosensing application; however, the establishment of a safe and efficient in vivo delivery system remains a critical bottleneck. Peptides serve as attractive carriers due to their rich chemical diversity, excellent biocompatibility, high loading capacity, and specific binding ability, making them ideal candidates for the on-demand regulation of DNA circuits-yet remains largely unexplored. In this study, we developed a multifunctional enzyme-responsive peptide (ERP) for the efficient loading and specific intracellular delivery and release of catalytic circuitry probes through a phosphorylation-based charge reversal procedure. This ERP-programmed catalytic DNA circuit enables the precise, spatially controllable in vivo imaging of microRNA (miRNA). The multifunctional cationic peptide formed a stable nanocomplex with anionic DNA cargo via strong electrostatic interactions, thus protecting the DNA probes from degradation in biological environments. Moreover, with the ability to actively targeting tumor cells and facilitate endogenous phosphorylation-guided release of DNA probes, this multifunctional peptide could significantly reduce the nonspecific delivery of probes to healthy tissues, thereby minimizing unwanted off-site signal leakage. By the integration of cell-selective delivery and site-specific stimulation, this endogenously regulated and multiply guaranteed DNA circuit system paves a simple yet effective way for disease diagnosis.

Ovarian cancer is one of the most prevalent malignancies worldwide, with the highest mortality rate among gynecological cancers. This study aims to investigate the molecular mechanisms of SPOCK2 in ovarian cancer progression and metastasis and evaluate its potential as a therapeutic target.

The expression levels of SPOCK2 in ovarian cancer tissues and normal tissues were analyzed using data from The Cancer Genome Atlas (TCGA) and immunohistochemistry experiments. Functional assays, including epithelial-mesenchymal transition (EMT), invasion, and migration assays, were performed in high-grade serous ovarian cancer (HGSOC) cells to explore the role of SPOCK2. The interaction between SPOCK2 and ITGA3 and the subsequent activation of focal adhesion kinase (FAK) signaling were investigated. In vivo experiments were conducted to validate the effects of SPOCK2 knockdown on tumor metastasis and invasiveness.

SPOCK2 expression was significantly upregulated in ovarian cancer tissues compared to normal tissues and was associated with poor prognosis. Functional assays demonstrated that SPOCK2 promotes EMT, invasion, and migration in HGSOC cells by interacting with ITGA3 and activating FAK signaling. In vivo experiments confirmed that SPOCK2 knockdown significantly suppressed tumor metastasis and invasiveness.

This study highlights the critical role of the SPOCK2/ITGA3 axis in driving ovarian cancer progression and provides evidence for SPOCK2 as a potential molecular marker and therapeutic target. These findings offer new insights into the early diagnosis and treatment of ovarian cancer, with significant clinical implications for improving patient outcomes.

Differentiation of fibroblasts into myofibroblasts is necessary for wound healing, but excessive myofibroblast presence and persistence can result in scarring. Treatment for scarring is limited largely due to a lack of comprehensive understanding of how fibroblasts and myofibroblasts differ at the transcript level. The purpose of this study was to characterize transcriptional profiles of injured fibroblasts relative to normal fibroblasts, utilizing fibroblasts from the vocal fold as a model.

Utilizing bulk RNA sequencing technology, we identified differentially expressed genes between four cell lines of normal fibroblasts (cVFF), one line of scarred fibroblasts (sVFF), and four lines of fibroblasts treated with transforming growth factor-beta 1 (TGF-β1), representing an induced-scar phenotype (tVFF). Principal component analysis revealed clustering of normal fibroblasts separate from the clustering of fibroblasts treated with TGF-β1; scarred fibroblasts were more similar to normal fibroblasts than fibroblasts treated with TGF-β1. Enrichment analyses revealed pathways related to cell signaling, receptor-ligand activity, and regulation of cell functions in scarred fibroblasts, pathways related to cell adhesion in normal fibroblasts, and pathways related to ECM binding in fibroblasts treated with TGF-β1. Although transcriptomic profiles between scarred fibroblasts and fibroblasts treated with TGF-β1 were relatively dissimilar, the most highly co-expressed genes were enriched in pathways related to actin cytoskeleton binding, which supports the use of fibroblasts treated with TGF-β1 to represent a scarred cell phenotype.

Transcriptomics of normal fibroblasts differ from myofibroblasts, including from those retrieved from scar and those treated with TGF-β1. Despite large differences in transcriptomics between tVFF and sVFF, tVFF serve as a useful in vitro model of myofibroblasts and highlight key similarities to myofibroblasts extracted from scar pathology, as well as expected differences related to normal fibroblasts from healthy vocal folds.

Glioblastoma is a highly aggressive brain tumor, and the transition from the proneural to mesenchymal subtype is associated with more aggressive and therapy-resistant features. However, the signaling pathways and genes involved in this transition remain largely undefined.

We utilized patient-derived xenograft (PDX) samples of glioblastoma, specifically PDX-L14, which exhibit both negative and overexpressed FOSL1 expression. mRNA expression profiles were assessed by RNA sequencing in these samples, followed by gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Gene Set Enrichment Analysis (GSEA). Validation of the hub genes was performed using qPCR and immunohistochemistry assays.

Differentially expressed genes (DEGs) between FOSL1 overexpression groups were predominantly involved in ferroptosis, immune response, angiogenesis, vascular mimicry, autophagy, epithelial-mesenchymal transition (EMT), cancer cell stemness, temozolomide (TMZ) resistance, and NF-κB signaling. Downregulated DEGs were associated with TMZ resistance, glioma proliferation, RNA processing, and Wnt/β-catenin signaling. Key enrichment pathways, including NF-κB, Want, and BMP, are all critical for maintaining glioma stemness. FOSL1 was found to regulate RNA processing and ubiquitination. Notably, 8 upregulated (ITGA5, SDC1, PHLDB2, TNFRSF8, ADAM8, TLR7, STEAP3, and POU3F2) and 4 downregulated (IFIT1, FBXO16, ARL3, and BEX1) genes were identified, with implications for glioblastoma prognosis.

This transcriptome investigation emphasizes the diverse functions of FOSL1 in different biological processes and signaling networks during the shift from proneural to mesenchymal state in glioblastoma.

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer, driven by either Merkel cell polyomavirus (MCPyV) integration or ultraviolet (UV)-induced mutations. In MCPyV-positive tumors, viral T antigens inactivate tumor suppressors pRb and p53, while virus-negative MCCs harbor UV-induced mutations that activate similar oncogenic pathways. Key signaling cascades, including PI3K/AKT/mTOR and MAPK, support tumor proliferation, survival, and resistance to apoptosis. Histologically, MCC consists of small round blue cells with neuroendocrine features, high mitotic rate, and necrosis. The tumor microenvironment (TME) plays a central role in disease progression and immune escape. It comprises a mix of tumor-associated macrophages, regulatory and cytotoxic T cells, and elevated expression of immune checkpoint molecules such as PD-L1, contributing to an immunosuppressive niche. The extracellular matrix (ECM) within the TME is rich in proteoglycans, collagens, and matrix metalloproteinases (MMPs), facilitating tumor cell adhesion, invasion, and interaction with stromal and immune cells. ECM remodeling and integrin-mediated signaling further promote immune evasion and therapy resistance. Although immune checkpoint inhibitors targeting PD-1/PD-L1 have shown promise in treating MCC, resistance remains a major hurdle. Therapeutic strategies that concurrently target the TME-through inhibition of ECM components, MMPs, or integrin signaling-may enhance immune responses and improve clinical outcomes.

Disintegrins are small non-enzymatic proteins present often at low concentration in the venom of viperid snakes. Isolated disintegrins are known for their lack of toxicity as well as their capacity to antagonize integrin receptors. Integrins are a major family of heterodimeric cell surface receptors that mediate cell-cell and cell-extracellular matrix (ECM) interactions. Integrins regulate key functions in cancer pathology and also tumor development. The aim of this study consisted in the isolation and characterization of disintegrins from rattlesnake new species Crotalus mictlantecuhtli venom. A disintegrin fraction obtained by RP-HPLC and named mictlan-D3, consist in two isoforms of 7439 and 7509 Da with 72 amino acid sequence containing the RGD binding motif. Mictlan-D3 inhibited MDA-MB-231 and HMEC-1 cell adhesion to laminin (LN), fibronectin (FN) and vitronectin (VN), highest inhibition was on MDA-MB-231 cell adhesion to LN by 81 % at 1 μM. The blockade of ⍺Vβ3 integrin was evaluated by wound healing migration assay. Mictlan-D3 inhibited MDA-MB-231 cell migration by 80 % and 38 % after 24 and 72 h of incubation respectively. HMEC-1 cell migration was inhibited by 67.6 % and 27.9 % after 24 and 72 h of incubation. Additionally, mictlan-D3. This work represent the first characterization of disintegrins from the Crotalus mictlantecuhtli venom.

Cancer treatment is among today's most active and challenging research fields. In recent years, significant progress has been made in developing new cancer therapies, including nutraceuticals and natural compounds with anticancer properties. Lactoferrin, a glycoprotein present in mammals, is of significant interest due to its pleiotropic behavior, demonstrating a broad spectrum of biological activities such as antimicrobial, antioxidant, anti-inflammatory, immunomodulatory, and anticancer effects. In this review, we examine the current knowledge of Lf's role in cancer. In addition, it exhibits a synergistic effect along with conventional drugs, potentially enhancing their efficacy and, at the same time, reducing the side effects associated with most traditional therapies. However, it is essential to consider the precise molecular mechanism by which Lf exerts its antitumor activity. Searching interactions with several molecules can provide insight into this mechanism. Additionally, finding lactoferrin receptors can improve the strategies for the specific release of the conjugates. For all these reasons, Lactoferrin becomes a potential therapeutic agent that should be examined in depth.

The extracellular matrix (ECM) of solid tumor constitutes a formidable physical barrier that impedes immune cell infiltration, contributing to immunotherapy resistance. Breast cancer, particularly triple-negative breast cancer (TNBC), is characterized by a collagen-rich tumor microenvironment, which is associated with T cell exclusion and poor therapeutic outcomes. Discoidin domain receptor 2 (DDR2) and integrins, key ECM regulatory receptors on cancer cells, play pivotal role in maintaining this barrier. In this study, we developed a dual-receptor-targeted strategy using metal-organic frameworks (MOFs) to deliver DDR2-specific siRNA (siDDR2) and ITGAV-specific siRNA (siITGAV) to disrupt the ECM barrier. siDDR2 modulates immune infiltration by regulating collagen-cell interactions, while siITGAV suppresses TGF-β1 activation. The MOF@siDDR2+siITGAV complex significantly reduced collagen deposition, enhanced CD8+ T cell infiltration, and downregulated programmed cell death ligand 1 (PD-L1) expression in TNBC. Consequently, this approach markedly inhibited tumor growth. Our findings demonstrate that dual-receptor-targeted MOF-based nanocarriers (MOF@siDDR2+siITGAV) can effectively reprogram the tumor ECM to enhance immune cell access, offering a promising prospect for synergistic cancer immunotherapy. STATEMENT OF SIGNIFICANCE: A dual-receptor-targeted MOF nanocarrier is developed to improve immune accessibility in tumors. Concurrent blockade of DDR2 and ITGAV effectively decreases collagen deposition, increases CD8+ T cell infiltration, and suppresses PD-L1 expression. Modulating the mechanical properties of the extracellular matrix (ECM) to enhance immune accessibility offers an innovative strategy for cancer treatment.

In the presence of cellular mutations and impaired mechanisms of energy transmission to the attached cells and tissues, excess energy is available to upregulate some of the mechanotransduction pathways that maintain cell and tissue structure and function. The ability to transfer applied energy through integrin-mediated pathways, cell ion channels, cell membrane, cytoskeleton-nucleoskeleton connections, cell junctions, and cell-extracellular matrix attachments provides an equilibrium for energy storage, transmission, and dissipation in tissues. Disruption in energy storage, transmission, or dissipation via genetic mutations blocks mechanical communication between cells and tissues and impairs the mechanical energy equilibrium that exists between cells and tissues. This results in local structural changes through altered regulatory pathways, which produce cell clustering, collagen encapsulation, and an epithelial-mesenchymal transition (EMT), leading to increased cellular motility along newly reorganized collagen fibers (fibrosis). The goal of this review is to postulate how changes in energy transfer between cells and the extracellular matrix may alter local energy equilibrium and mechanotransduction pathways. The changes along with cellular mutations lead to cell and ECM changes reported in cancer, which is postulated to modify mechanical equilibria between cells and their ECM. This leads to uncontrolled cancer cellular proliferation and collagen remodeling.

The extracellular matrix (ECM) is a dynamic network providing mechanical and biochemical cues that regulate cellular behavior. ECM stiffness critically influences fibroblasts, the primary ECM producers, particularly in inflammation and fibrosis. This review explores the role of ECM stiffness in fibroblast-driven inflammation and tissue remodeling, focusing on the physicochemical and biological mechanisms involved. Engineered materials, hydrogels, and polydimethylsiloxane (PDMS) are highlighted for replicating tissue-specific stiffness, enabling precise control over cell-matrix interactions. The surface functionalization of substrate materials, including collagen, polydopamine, and fibronectin, enhances bioactivity and fibroblast adhesion. Key mechanotransduction pathways, such as integrin signaling and YAP/TAZ activation, are related to regulating fibroblast behaviors and inflammatory responses. The role of fibroblasts in driving chronic inflammatory diseases emphasizes their therapeutic potentials. Advances in ECM-modifying strategies, including tunable biomaterials and hydrogel-based therapies, are explored for applications in tissue engineering, drug delivery, anti-inflammatory treatments, and diagnostic tools for the accurate diagnosis and prognosis of ECM stiffness-related inflammatory diseases. This review integrates mechanobiology with biomedical innovations, providing a comprehensive prognosis of fibroblast responses to ECM stiffness and outlining future directions for targeted therapies.

Caveolin-1 (CAV1) is a membrane protein that promotes migration, invasion and metastasis of cancer cells when phosphorylated on tyrosine-14 (Y14) by a cell intrinsic mechanism involving the activation of a novel Rab5-Rac1 signaling axis. Moreover, CAV1 expressed in aggressive cancer cells is included into extracellular vesicles (EVs) and such EVs increase the metastatic potential of recipient lower grade cancer cells. However, the relevance of CAV1 Y14 phosphorylation in these extrinsic EV-stimulated events remained to be determined. Here we used B16F10 mouse melanoma cells over-expressing wild-type CAV1, phospho-mimetic CAV1(Y14E) or phospho-null CAV1(Y14F) as models to determine how the EV protein content was affected by Y14 phosphorylation and how these EVs modulated the metastatic potential of recipient B16F10 cells lacking CAV1. EVs from B16F10 cells over-expressing wild-type and CAV1(Y14/E) contain CAV1, and other proteins linked to signaling pathways associated with cell adhesion and migration. CAV1 inclusion in EVs was reduced by the Y14F mutation and global protein composition was also significantly different. Moreover, CAV1 wild-type and CAV1(Y14E) EVs promoted migration, as well as invasion of cells lacking CAV1 [B16F10(Mock) cells]. In addition, β3 integrin was transferred via CAV1(Y14E) EVs to B16F10 (Mock) cells, and treatment with such EVs promoted metastasis of recipient B16F10(Mock) cells. Finally, CAV1(Y14E) EV-enhanced migration, invasion and metastasis of recipient cells was blocked by anti-αVβ3 antibodies. In conclusion, CAV1 phosphorylated on Y14 not only intrinsically promotes migration, invasion and metastasis of cells expressing the protein (in cis), but also favors the inclusion of CAV1 into EVs, as well as the extrinsic acquisition of malignant traits in recipient cells, through integrin transfer (in trans).

The liver is the most common site of metastasis of colorectal cancer (CRC), and colorectal liver metastasis is one of the major causes of CRC-related deaths worldwide. The tumor microenvironment, particularly the extracellular matrix (ECM), plays a critical role in CRC metastasis and chemoresistance. Based on findings from clinical and basic research, this review attempts to offer a complete understanding of the role of the ECM in colorectal liver metastasis and to suggest potential ways for therapeutic intervention. First, the ECMs' role in regulating cancer cell fate is explored. We then discuss the hepatic ECM fingerprint and its influence on the metastatic behavior of CRC cells, highlighting key molecular interactions that promote metastasis. In addition, we examine how changes in the ECM within the metastatic niche contribute to chemoresistance, focusing on ECM remodeling by ECM stiffening and the activation of specific signaling pathways. Understanding these mechanisms is crucial for the development of novel strategies to overcome metastasis and improve outcomes for CRC patients.

Exosomes have emerged as pivotal players in precision oncology, offering innovative solutions to longstanding challenges such as metastasis, therapeutic resistance, and immune evasion. These nanoscale extracellular vesicles facilitate intercellular communication by transferring bioactive molecules that mirror the biological state of their parent cells, positioning them as transformative tools for cancer diagnostics and therapeutics. Recent advancements in exosome engineering, artificial intelligence (AI)-driven analytics, and isolation technologies are breaking barriers in scalability, reproducibility, and clinical application. Bioengineered exosomes are being leveraged for CRISPR-Cas9 delivery, while AI models are enhancing biomarker discovery and liquid biopsy accuracy. Despite these advancements, key obstacles such as heterogeneity in exosome populations and the lack of standardized isolation protocols persist. This review synthesizes pioneering research on exosome biology, molecular engineering, and clinical translation, emphasizing their dual roles as both mediators of tumor progression and tools for intervention. It also explores emerging areas, including microbiome-exosome interactions and the integration of machine learning in exosome-based precision medicine. By bridging innovation with translational strategies, this work charts a forward-looking path for integrating exosomes into next-generation cancer care, setting it apart as a comprehensive guide to overcoming clinical and technological hurdles in this rapidly evolving field.

The tumour microenvironment is the "hotbed" of tumour cells, providing abundant extracellular support for growth and metastasis. However, the tumour microenvironment is not static and is constantly remodelled by a variety of cellular components, including tumour cells, through mechanical, biological and chemical means to promote metastasis. Focal adhesion plays an important role in cell-extracellular matrix adhesion. An in-depth exploration of the role of focal adhesion in tumour metastasis, especially their contribution at the biomechanical level, is an important direction of current research. In this review, we first summarize the assembly of focal adhesions and explore their kinetics in tumour cells. Then, we describe in detail the role of focal adhesion in various stages of tumour metastasis, especially its key functions in cell migration, invasion, and matrix remodelling. Finally, we describe the anti-tumour strategies targeting focal adhesion and the current progress in the development of some inhibitors against focal adhesion proteins. In this paper, we summarize for the first time that focal adhesion play a positive feedback role in pro-tumour metastatic matrix remodelling by summarizing the five processes of focal adhesion assembly in a multidimensional way. It is beneficial for researchers to have a deeper understanding of the role of focal adhesion in the biological behaviour of tumour metastasis and the potential of focal adhesion as a therapeutic target, providing new ideas for the prevention and treatment of metastases.

Esophageal adenocarcinoma (EAC) is a highly lethal cancer of the upper gastrointestinal tract with rising incidence in western populations. To decipher EAC disease progression and therapeutic response, we performed multiomic analyses of a cohort of primary and metastatic EAC tumors, incorporating single-nuclei transcriptomic and chromatin accessibility sequencing, along with spatial profiling. We identified tumor microenvironmental features previously described to associate with therapy response. We identified five malignant cell programs, including undifferentiated, intermediate, differentiated, epithelial-to-mesenchymal transition, and cycling programs, which were associated with differential epigenetic plasticity and clinical outcomes, and for which we inferred candidate transcription factor regulons. Furthermore, we revealed diverse spatial localizations of malignant cells expressing their associated transcriptional programs and predicted their significant interactions with microenvironmental cell types. We validated our findings in three external single-cell RNA-seq and three bulk RNA-seq studies. Altogether, our findings advance the understanding of EAC heterogeneity, disease progression, and therapeutic response.