Cancer, influenced by genetics and the environment, involves anoikis, a cell death mechanism upon extracellular matrix detachment crucial for metastasis. Understanding this relationship is key for therapy. We analyze cancer and anoikis trends using bibliometrics.

A search was conducted from Web of Science Core, PubMed, Scopus and non-English databases such as the CNKI (inception- 21 December 2024). Data analysis employed Microsoft Excel, VOSviewer, CiteSpace, R software, and the online platform (https://bibliometric.com/).

2510 publications were retrieved, with a significant increase in the last decade. China led, the University of Texas system was productive, and the Oncogene Journal was popular. Breast, and colorectal cancers were frequently studied. Among them, representative tumor-related mechanisms were identified, commonalities such as (EMT, ECM, autophagy) and respective specific mechanisms were summarized.

This bibliometric analysis highlights rapid advances in anoikis research in cancer, emphasizing EMT and FAK pathways' translational potential, guiding targeted therapies, and improving cancer treatment outcomes.

Tumor metastasis is an important reason for the poor prognosis and high mortality in cancer patients. As major component of stromal cells in tumor microenvironment, cancer-associated fibroblasts (CAFs) secreted various factors to promote tumor metastasis. Studies have indicated that endogenous direct current electric field (dcEF) around tumor tissue induced directional migration of cancer cells. However, the regulatory effect of CAFs on cancer migration under dcEF stimulation is still unknown. In this study, a two-layers polydimethylsiloxane (PDMS)-based microfluidic chip was fabricated. The introduction of concave structures achieved the non-contacted co-culture of different cell types, and parallel channels in the chip provided stable and homogeneous dcEF. Cells electrotactic response was evaluated under co-culture circumstance. The results showed that CAFs exhibited directional migration towards anode under dcEF stimulation, while A549 cells had a trend of directional migration towards cathode. The co-existence of CAFs and dcEF significantly enhanced the motility and cathodal migration of A549 cells, suggesting synergistic influences of chemotaxis from CAFs and electrotaxis from dcEF stimulation. Moreover, we demonstrated that lung normal fibroblasts acquired CAFs properties after stimulated by dcEF, characterizing by increasing gene expression of α-SMA and IL-6. Overall, Our device and study provide new insight for tumor electrotaxis in complex microenvironment.

Rotator cuff injuries present significant clinical challenges, often resulting in chronic pain and functional impairment. In this study, we examined the effects of hyperlipidemia (HYP), a systemic metabolic condition, on tendon health. Histological analysis of infraspinatus tendons from hyperlipidemic swine revealed well-organized extracellular matrix (ECM) structures, comparable to those in non-hyperlipidemic (NONHYP) animals, suggesting ECM reorganization. Upstream SIGNOR3.0 analysis demonstrated that tumor necrosis factor receptor-associated factor 6 (TRAF6) activates transcription factor Yin Yang 1 (YY1) via kinase signaling, underscoring its role in tendon ECM remodeling. Hence, we futher examined the role of YY1, which is a critical regulator of collagen synthesis identified through network analysis. Although TRAF6 levels remained unchanged in HYP conditions, increased YY1 expression correlated with elevated COL1 gene expression. Additionally, twist-related protein 1 (TWIST1) emerged as another key molecule, existing in both homo- and heterodimer forms in NON-HYP conditions, but only as a heterodimer in HYP. YY1 enhanced COL1 transcription in the hyperlipidemic environment, while TWIST1 heterodimer formation facilitated collagen crosslinking. Notably, increased YY1 expression inhibited MMP3, resulting in the inactivity of MMP1, MMP8, and MMP9, thereby preserving collagen levels. These findings highlight the complex molecular interactions involving transcriptional regulation by YY1 and post-translational regulation by the TWIST1 heterodimer, essential for the deposition of mature collagen fibrils and driving tendon remodeling in hyperlipidemic conditions. This study offers valuable insights for the change of tendon health condition in hyperlipidemia disease or tendon pathology.

The current study explored the molecular interaction between Vitamin D3 (Vit D3) and pepsin using multi-spectroscopic, molecular dynamic simulation (MDS), and molecular docking. The fluorescence emission spectra discovered Vit D3 interacted with pepsin in a static quenching manner due to the formation of the steady-state complex. Thermodynamic data revealed the spontaneous binding of Vit D3 on pepsin. The formation of the Pepsin-Vit D3 complex was also validated by circular dichroism (CD) spectroscopy. The fluorescence and CD spectroscopy results revealed Vit D3 altered the tertiary and secondary structure of pepsin, respectively. Meanwhile, FTIR spectroscopy results revealed a hypochromic shift in the amide I and II peaks. Kinetic parameters showed Vit D3 inhibited the activity of pepsin by the uncompetitive process. Applied spectroscopic methods disclosed that Vit D3 binding to pepsin caused microenvironmental modifications around the aromatic residues of protein and changed its structure and function. Moreover, MD simulation and molecular docking were done to analyze the formation of Pepsin-Vit D3 complexes. Molecular docking findings demonstrated the interaction of Vit D3 with pepsin mainly involved van der Waals forces and hydrogen bonds that were in good agreement with the fluorescence results. Finally, MDS findings including RMSD, RMSF, and RG confirmed all the experimental data.

Collagen is the most abundant protein in mammals, significantly contributing to cancer progression. Cells express two primary well-conserved collagen receptors, integrins and discoidin domain receptors (DDRs), which bind collagen on distinct sites, suggesting that cancer cells must integrate both signals to decide their fate. The crosstalk between integrins and DDRs mediated by collagen binding produces dynamic, integrated signals that control tumor progression, therapeutic resistance, and cancer cell heterogeneity. This review will discuss the dynamic interplay among collagen, integrins, and DDRs in ECM remodeling during cancer progression and these receptors' crosstalk. In addition, we explored current and future directions for ECM receptor-targeted therapies, including nanotechnologies and precision medicine, to improve therapeutic outcomes by establishing a proper balance between integrins and DDRs in cancer.

In recent years, RNA transcriptome sequencing technology has been continuously evolving, ranging from single-cell transcriptomics to spatial transcriptomics. Although these technologies are all based on RNA sequencing, each sequencing technology has its own unique characteristics, and there is an urgent need to develop an algorithmic toolkit that integrates both sequencing techniques. To address this, we have developed OmniClust, a toolkit based on single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics data. OmniClust employs deep learning algorithms for feature learning and clustering of spatial transcriptomics data, while utilizing machine learning algorithms for clustering scRNA-seq data. OmniClust was tested on 12 spatial transcriptomics benchmark datasets, demonstrating high clustering accuracy across multiple clustering evaluation metrics. It was also evaluated on four scRNA-seq benchmark datasets, achieving high clustering accuracy based on various clustering evaluation metrics. Furthermore, we applied OmniClust to downstream analyses of spatial transcriptomics and single-cell RNA breast cancer data, showcasing its potential to uncover and interpret the biological significance of cancer transcriptome data. In summary, OmniClust is a clustering tool designed for both single-cell transcriptomics and spatial transcriptomics data, demonstrating outstanding performance.

Oxidative stress and chronic inflammation are important drivers in the pathogenesis and progression of many chronic diseases, such as cancers of the breast, kidney, lung, and others, autoimmune diseases (rheumatoid arthritis), cardiovascular diseases (hypertension, atherosclerosis, arrhythmia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), mental disorders (depression, schizophrenia, bipolar disorder), gastrointestinal disorders (inflammatory bowel disease, colorectal cancer), and other disorders. With the increasing demand for less toxic and more tolerable therapies, flavonoids have the potential to effectively modulate the responsiveness to conventional therapy and radiotherapy. Flavonoids are polyphenolic compounds found in fruits, vegetables, grains, and plant-derived beverages. Six of the twelve structurally different flavonoid subgroups are of dietary significance and include anthocyanidins (e.g. pelargonidin, cyanidin), flavan-3-ols (e.g. epicatechin, epigallocatechin), flavonols (e.g. quercetin, kaempferol), flavones (e.g. luteolin, baicalein), flavanones (e.g. hesperetin, naringenin), and isoflavones (daidzein, genistein). The health benefits of flavonoids are related to their structural characteristics, such as the number and position of hydroxyl groups and the presence of C2C3 double bonds, which predetermine their ability to chelate metal ions, terminate ROS (e.g. hydroxyl radicals formed by the Fenton reaction), and interact with biological targets to trigger a biological response. Based on these structural characteristics, flavonoids can exert both antioxidant or prooxidant properties, modulate the activity of ROS-scavenging enzymes and the expression and activation of proinflammatory cytokines (e.g., interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)), induce apoptosis and autophagy, and target key signaling pathways, such as the nuclear factor erythroid 2-related factor 2 (Nrf2) and Bcl-2 family of proteins. This review aims to briefly discuss the mutually interconnected aspects of oxidative and inflammatory mechanisms, such as lipid peroxidation, protein oxidation, DNA damage, and the mechanism and resolution of inflammation. The major part of this article discusses the role of flavonoids in alleviating oxidative stress and inflammation, two common components of many human diseases. The results of epidemiological studies on flavonoids are also presented.

Metastasis, the leading cause of cancer-related deaths, underscores the critical need to understand its regulatory mechanisms to improve prevention and treatment strategies for late-stage tumors. Hematogenous dissemination is a key route of metastasis. However, as the gatekeeper of vessels, the role of pericytes in hematogenous metastasis remains largely unknown. In this review, we comprehensively explore the contributions of pericytes throughout the metastatic cascade, particularly their functions that extend beyond influencing tumor angiogenesis. Pericytes should not be perceived as passive bystanders, but rather as active participants in various stages of the metastatic cascade. Pericytes-targeted therapy may provide novel insights for preventing and treating advanced-stage tumor.

T cells are crucial effector cells in the endogenous defense against cancer, yet the clinical impact of their quantity, diversity, and dynamics remains underexplored. Here, we investigate the clinical relevance of the T cell receptor (TCR) repertoire in patients with bladder cancer. In advanced-stage disease, low pre-treatment peripheral TCR diversity is associated with worse overall survival (p = 0.024), particularly when coupled with low circulating T cell fractions (p = 0.00049). These low-diversity repertoires are dominated by hyper-expanded clones that persist throughout treatment. Further longitudinal analysis reveals reductions in TCR diversity after treatment, indicating adverse effects on the immune system. In early-stage disease, immunotherapy increases TCR diversity in patients with good outcomes. Furthermore, single-cell sequencing identifies most hyper-expanded clones as cytotoxic T cells, while non-expanded clones are predominantly naive T cells. Overall, this highlights TCR diversity as a promising biomarker, offering opportunities for tailored oncological treatments to enhance clinical outcomes.

The extracellular matrix (ECM) protein Beta-Ig H3 (βigH3, also known as transforming growth factor β induced protein (TGFBI)) is related to poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). Proteolytic cleavage of βigH3 has been shown to result in release of the N-terminal fragment covering amino acid 1 to 137, but whether the degradation of βigH3 is associated to prognosis has yet to be determined. In this study we developed an ELISA targeting a collagenase generated fragment of βigH3 (cβigH3) in human serum to use the fragment as a biomarker reflecting degradation of βigH3. We demonstrated that the assay was specific to the cleaved fragment (cβigH3) and confirmed the generation of cβigH3 from degradation of fibroblast generated matrices. Moreover, higher levels of cβigH3 were released upon degradation of matrices produced by TGF-β stimulated pancreatic fibroblast compared to matrices produced by pancreatic fibroblast without TGF-β stimulation, indicating an association of the biomarker with degradation of fibrotic matrix. To evaluate the clinical relevance, we first measured cβigH3 in a cohort of 220 patients with different types of cancer with detectable levels for all 11 cancer types. We then measured the cβigH3 biomarker in pre-treatment serum from a cohort of 469 patients with locally advanced or metastatic PDAC and found that high levels of cβigH3 were associated with longer overall survival independently of age, disease stage, performance status, carbohydrate antigen 19-9 (CA19-9), and the tumor fibrosis biomarker PRO-C3 as compared to patients with high levels of cβigH3 (HR 0.78, 95% CI: 0.0.61-0.98, p = 0.04). In conclusion, cβigH3 reflects proteolytic degradation of βigH3 and shows potential as an independent prognostic biomarker for patients with advanced PDAC.

Breast cancer is one of the most common malignancies with a poor five-year survival rate with metastatic disease among women. It has well been documented that leucine-rich repeat-containing (LRRC) family of proteins are remarkably and aberrantly dysregulated across diverse cancer types. Notably, leucine-rich repeat-containing 56 (LRRC56) was found upregulated in metastatic breast cancer, and plays a crucial role for the movement of cilia via intraflagellar transport 88 (IFT88). However, the role for LRRC56 in breast cancer progression and regulation of IFT88 and associated pathways in metastatic progression of breast cancer has not been defined. Via in vitro functional assessments, we found that LRRC56 pivotally influences the proliferative, migratory and invasive capabilities of cancer cells. Further, via in-vivo assessments, we demonstrated that downregulation of LRRC56 effectively inhibits the growth of breast cancer xenograft tumors and their metastasis to the lungs. Mechanistically, we found that LRRC56 interacts with IFT88 to regulate yes-associated protein 1 (YAP1) expression via modulating the Ras homolog family member A (RhoA)/ Rho-associated protein kinases (ROCKs) signaling pathway. LRRC56 also regulates the expression of integrins and several other key molecules including MMP2, MMP9, FAK, as well as markers of epithelial-mesenchymal transition such as E-cadherin and N-cadherin. In summary, our results demonstrate that overexpression of LRRC56 promotes breast cancer progression via upregulating IFT88/YAP1-RhoA/ROCKs pathway, reprogramming extracellular matrix, and enhancing epithelial-mesenchymal transition. These findings highlight a critical role of LRRC56 in promoting breast cancer progression, suggesting that targeting of LRRC56 may offer a promising strategy for treating metastatic breast cancer.

Metastasis is one of the main reasons for cancer treatment failure. Unfortunately, most treatment approaches inevitably damage the extracellular matrix (ECM) during tumor cell elimination, thereby augmenting the risk of metastasis. Herein, we proposed a "sieging tumor cells" strategy based on ferric coordination polymers (FeCPs), which involved anchoring tumor cells through ECM consolidation and selectively eliminating them in the tumor regions. Due to the weak coordination interactions and amorphous structure of FeCPs, the acidic tumor microenvironment facilitated their disintegration, releasing salicylic acid (SA), 2,5-dihydroxyterephthalic acid (DHTA) and Fe3+ ions. The released SA inhibited heparinase activity to consolidate the ECM, while Fe-mediated chemodynamic therapy (CDT) was enhanced by DHTA due to its fast electron transport behavior, ultimately inhibiting tumor growth and metastasis. The results from the orthotopic 4T1 breast tumor model indicated that lung metastasis was reduced by about 90%, and the survival rate improved by 70% after FeCP treatment. Overall, this "sieging tumor cells" strategy provides an emerging approach for the treatment of malignant tumors by consolidating the ECM in combination with self-enhanced CDT.

Many cancer therapies fail in clinical trials despite showing potent efficacy in preclinical studies. One of the key reasons is the adopted preclinical models cannot recapitulate the complex tumor microenvironment (TME) and reflect the heterogeneity and patient specificity in human cancer. Cancer-on-a-chip (CoC) microphysiological systems can closely mimic the complex anatomical features and microenvironment interactions in an actual tumor, enabling more accurate disease modeling and therapy testing. This review article concisely summarizes and highlights the state-of-the-art progresses in CoC development for modeling critical TME compartments including the tumor vasculature, stromal and immune niche, as well as its applications in therapying screening. Current dilemma in cancer therapy development demonstrates that future preclinical models should reflect patient specific pathophysiology and heterogeneity with high accuracy and enable high-throughput screening for anticancer drug discovery and development. Therefore, CoC should be evolved as well. We explore future directions and discuss the pathway to develop the next generation of CoC models for precision cancer medicine, such as patient-derived chip, organoids-on-a-chip, and multi-organs-on-a-chip with high fidelity. We also discuss how the integration of sensors and microenvironmental control modules can provide a more comprehensive investigation of disease mechanisms and therapies. Next, we outline the roadmap of future standardization and translation of CoC technology toward real-world applications in pharmaceutical development and clinical settings for precision cancer medicine and the practical challenges and ethical concerns. Finally, we overview how applying advanced artificial intelligence tools and computational models could exploit CoC-derived data and augment the analytical ability of CoC.

One of the key challenges in defeating advanced tumors is the ability of cancer cells to evade the selective pressure imposed by chemotherapy, targeted therapies, immunotherapy and cellular therapies. Both genetic and epigenetic alterations contribute to the development of resistance, allowing cancer cells to survive initially effective treatments. In this narration, we explore how genetic and epigenetic regulatory mechanisms influence the state of tumor cells and their responsiveness to different therapeutic strategies. We further propose that an altered balance between cell growth and cell death is a fundamental driver of drug resistance. Cell death programs exist in various forms, shaped by cell type, triggering factors, and microenvironmental conditions. These processes are governed by temporal and spatial constraints and appear to be more heterogeneous than previously understood. To capture the intricate interplay between death-inducing signals and survival mechanisms, we introduce the concept of Death-ision. This framework highlights the dynamic nature of cell death regulation, determining whether specific cancer cell clones evade or succumb to therapy. Building on this understanding offers promising strategies to counteract resistant clones and enhance therapeutic efficacy. For instance, combining DNMT inhibitors with immune checkpoint blockade may counteract YAP1-driven resistance or the use of transcriptional CDK inhibitors could prevent or overcome chemotherapy resistance. Death-ision aims to provide a deeper understanding of the diversity and evolution of cell death programs, not only at diagnosis but also throughout disease progression and treatment adaptation.

Neoadjuvant anti-PD-1 immunotherapy combined with chemotherapy has shown promising pathologic responses in various cancers, including oral squamous cell carcinoma (OSCC). However, the pathologic response of lymph node (LN) metastases remains poorly understood. This study aims to systematically evaluate the pathologic response rates (pRR) of LN metastases in patients with OSCC and identify potential targets to improve therapeutic outcomes.

We assessed the pRRs of LN metastases and matched primary tumors (PT) in patients with OSCC enrolled in a randomized, two-arm, phase II clinical trial (NCT04649476). Single-cell and spatial transcriptomics and multiplex IHC were performed to analyze the tumor microenvironment and identify potential therapeutic targets in LN metastases. A neoadjuvant orthotopic OSCC mouse model was established to evaluate the therapeutic potential of these targets.

We observed significant heterogeneity in pathologic regression of LN metastases, with lower pRRs compared with PTs. pRRs in LN metastases were correlated with overall and disease-free survival in patients with OSCC. We identified an abundance of macrophages in LN metastases exhibiting an unfolded protein response and activated protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling. These macrophages contributed to an extracellular matrix-enriched microenvironment through interactions with fibroblasts, which hindered T cell-mediated cytotoxicity. Pharmacologic inhibition of the PERK pathway significantly enhanced anti-PD-1 therapy in LN metastases and PTs in the mouse model.

Our study confirms that the pathologic response of LN metastases in patients with OSCC undergoing neoadjuvant immunotherapy or immunochemotherapy is inferior to that of PTs. It suggests that targeting the PERK pathway in macrophages could be a potential strategy to enhance treatment outcomes.

Overcoming the physical barrier of the extracellular matrix (ECM) surrounding tumors is a critical challenge in achieving effective immune checkpoint blockade (ICB). The dense ECM impedes the infiltration of immune checkpoint inhibitors (ICIs) and cytotoxic T lymphocytes (CTLs) into tumor tissues. To address this, we design a nanocomplex incorporating a reactive oxygen species (ROS)-responsive nitric oxide (NO) prodrug around TANNylated αPD-L1. Within the tumor microenvironment (TME), this nanocomplex accumulates and selectively releases NO in response to ROS. The released NO activates matrix metalloproteinases (MMPs) in the ECM, leading to collagen degradation. Following this, the pH-responsive release of αPD-L1 in the deeper tumor regions ensures effective delivery, allowing CTLs to penetrate the tumor more efficiently by bypassing the ECM barrier, thereby enhancing immunotherapy. Overall, this study applies a nanocomplex capable of releasing NO and αPD-L1 in the tumor to a solid tumor model, successfully inhibiting tumor growth by altering the immunosuppressive environment through improved penetration.

Cell therapy with tumor-infiltrating lymphocytes (TILs) has yielded durable responses for multiple cancer types, but the causes of therapeutic resistance remain largely unknown. Here multidimensional analysis was performed on time-serial tumor and blood in a lung cancer TIL therapy trial. Using T cell receptor sequencing on both functionally expanded T cells and neoantigen-loaded tetramer-sorted T cells, we identified tumor antigen-specific T cell receptors. We then mapped clones into individual transcriptomes and found that tumor-reactive clonotypes expressed a dysfunctional program and lacked stem-like features among patients who lacked clinical benefit. Tracking tumor-reactive clonotypes over time, decay of antigen-reactive peripheral T cell clonotypes was associated with the emergence of progressive disease. Further, subclonal neoantigens previously targeted by infused T cells were subsequently absent within tumors at progression, suggesting potential adaptive resistance. Our findings suggest that targeting clonal antigens and circumventing dysfunctional states may be important for conferring clinical responses to TIL therapy.

The tumor microenvironment (TME) refers to the complex ecological system surrounding tumor cells, which is intimately associated with regulating tumor cell growth, invasive behavior, and metastatic capacity. Hence, in situ imaging of related bioactivity with resolution in the TME is critical for early cancer detection and accurate diagnosis. In recent years, fluorescence imaging technology has become a widely used tool in TME research due to its non-invasive nature, high spatiotemporal resolution, and capability for real-time monitoring. Among these advancements, signal probes designed based on functional nucleic acids (FNAs) provide a promising and innovative toolkit for targeted imaging analysis of the TME.

This review provides a comprehensive discussion on the construction of FNA-based biosensors and their advancements in TME monitoring. In this review, we initially provide a systematic summary of the current targeting strategies of FNA-based biosensors for visual monitoring of the TME, focusing on targeting cell surface and extracellular matrix components. Subsequently, we further explore the application of FNA-based biosensors in monitoring the TME. These biosensors have successfully achieved the monitoring of key parameters, bioactive molecules and other tumor markers in the tumor microenvironment due to their excellent molecular recognition ability and high sensitivity. Finally, we discuss some of the challenges currently faced in the field. In response to these challenges, we propose potential research directions and look forward to the future development prospects of this field.

Unlike previous reviews of biosensors based on FNAs for imaging tumor markers in the TME, this work is the first to review how such biosensors can be anchored in the TME. With continued efforts and advancements, we believe an increasing number of FNA-based fluorescence imaging probes will be utilized for TME imaging. This progress will significantly enhance our understanding of disease pathogenesis and progression, thereby offering substantial potential in biosensing and imaging analysis.

Cancer is a leading cause of death globally, with resistance to therapy representing a major obstacle to effective treatment. The tumor microenvironment (TME), comprising a complex network to cellular and non-cellular components including cancer-associated fibroblasts, immune cells, the extracellular matrix and region of hypoxia, is integral to cancer progression and therapeutic resistance. This review delves into the multifaceted interactions within the TME that contribute to tumor growth, survival and immune evasion. Key elements such as the role of cancer- associated fibroblasts in remodeling the extracellular matrix and promoting angiogenesis, the influence of immune cells such as tumor-associated macrophages in creating an immunosuppressive milieu and the impact of hypoxia conditions on metabolic adaptation and therapy resistance are thoroughly examined. This review evaluates current and emerging TME-targeted therapeutic strategies, including inhibitors of extracellular matrix components, modulators of immune cell activity and approached to alleviate hypoxia. Combination therapies that integrate TME-targeted agents with conventional treatments such as chemotherapy and immunotherapy are also discussed for their potential to enhance treatment efficacy and circumvent resistance mechanisms. By synthesising recent advances in TME research and therapeutic innovation, this paper aims to underscore the importance of TME in cancer therapy and highlight promising avenues for improving patient outcomes through targeted intervention.

The mammary gland is a dynamic organ with diverse cell populations that maintain glandular homeostasis, particularly during lactation. However, the cellular architecture and molecular mechanisms underlying lactational remodeling in the sheep mammary gland remain incompletely understood. Given similarities in mammary stromal structure, sheep serve as a valuable model for studying lactational changes relevant to the human breast, which experiences collagen loss and sagging during lactation. Utilizing single-cell transcriptomics (scRNA-seq), we mapped the sheep mammary gland's cellular landscape at postpartum days 60 and 150, identifying seven major cell types, including six distinct epithelial clusters. These clusters revealed differentiation among luminal progenitors, hormone-sensing, and myoepithelial cells across peak and late lactation stages. Transcriptomic analysis highlighted pivotal roles for epithelial integrity and ECM remodeling, with myoepithelial cells centrally involved in these processes. We observed significant collagen remodeling driven by fibroblast-epithelial crosstalk and ECM reorganization during late lactation. Comparative analysis with human mammary epithelial cells showed conserved basal and myoepithelial cell populations, while luminal cells diverged across species. This study provides insights into lactation biology and ECM remodeling, offering a framework to inform future studies on lactational adaptation and its implications for human health.

The Bcl-2 family member BAD is a candidate disease modulator because it stimulates apoptosis in a cell context basis and inhibits cell migration during normal mammary gland morphogenesis. This activity depends on 3 key regulatory serines (S75, 99, 118) in the unphosphorylated state. Given that developmental programs are often hijacked in cancer, we hypothesized that BAD would impede breast cancer progression. We generated breast cancer mouse models representing loss-of-function or phosphorylation deficient mutations (PyMT-Bad-/- and PyMT-Bad3SA/3SA, respectively). Preventing BAD phosphorylation significantly decreased breast cancer progression and metastasis. The knock-out phenocopied the control PyMT-Bad+/+ suggesting that phosphorylated BAD protein was inert. Thus, the BAD3SA mutation unmasked latent anti-tumor activity. Indeed, transcriptomics showed PyMT-Bad3SA/3SA activated multiple anti-tumor programs including apoptosis, inflammation, cellular differentiation, and diminished cell migration. This anti-tumor effect associated with clinical survival of breast cancer patients whose tumors had high levels of unphosphorylated BAD. Kinase screens identified ERK as the major BAD kinase in breast cells, and ERK inhibition impeded tumoroid invasion. Our data suggest that unphosphorylated BAD modulates anti-tumor pathways that contribute to excellent patient prognosis. Thus, targeting ERK to dephosphorylate BAD may be an exciting therapeutic opportunity in the future.

Previously considered "housekeeping" genes, small nucleolar RNAs (snoRNAs) are increasingly understood to have wide-ranging functions in cancer, yet their role in metastasis has been less well studied. Here, we identify the snoRNA Snord67 as a regulator of lymph node (LN) metastasis in breast cancer. Snord67 expression is enriched in LN metastases in an immune-competent mouse model of female breast cancer. In an orthotopic breast cancer model, loss of Snord67 decreases LN metastasis. In a model of lymphatic metastasis, Snord67 loss decreases LN tumor growth and distant metastases. In breast cancer cell lines, Snord67 knockout results in loss of targeted 2'-O-methylation on U6 small nuclear RNA, as well as widespread changes in splicing. Together, these results demonstrate that Snord67 regulates splicing and promotes the growth of LN metastases and subsequent spread to distant metastases. SnoRNA-guided modifications of the spliceosome and regulation of splicing may represent a potentially targetable pathway in cancer.

Platelets, traditionally regarded as passive mediators of hemostasis, are now recognized as pivotal regulators in the tumor microenvironment, establishing metabolic feedback loops with tumor and immune cells. Tumor-derived signals trigger platelet activation, which induces rapid metabolic reprogramming, particularly glycolysis, to support activation-dependent functions such as granule secretion, morphological changes, and aggregation. Beyond self-regulation, platelets influence the metabolic processes of adjacent cells. Through direct mitochondrial transfer, platelets reprogram tumor and immune cells, promoting oxidative phosphorylation. Additionally, platelet-derived cytokines, granules, and extracellular vesicles drive metabolic alterations in immune cells, fostering suppressive phenotypes that facilitate tumor progression. This review examines three critical aspects: (1) the distinctive metabolic features of platelets, particularly under tumor-induced activation; (2) the metabolic crosstalk between activated platelets and other cellular components; and (3) the therapeutic potential of targeting platelet metabolism to disrupt tumor-promoting networks. By elucidating platelet metabolism, this review highlights its essential role in tumor biology and its therapeutic implications.

The engraftment of haematopoietic stem and progenitor cells (HSPCs), particularly in cord-blood transplants, remains challenging. Here we report the role of the corticotropin-releasing hormone (CRH) in enhancing the homing and engraftment of human-cord-blood HSPCs in bone marrow through mechanical remodelling. By using microfluidics, intravital two-photon imaging and long-term-engraftment assays, we show that treatment with CRH substantially enhances HSPC adhesion, motility and mechanical remodelling, ultimately leading to improved bone-marrow homing and engraftment in immunodeficient mice. CRH induces Ras homologue gene family member A (RhoA)-dependent nuclear translocation of the yes-associated protein (YAP), which upregulates the expression of genes encoding extracellular-matrix proteins (notably, thrombospondin-2 (THBS2)). This process guides the mechanical remodelling of HSPCs via modulation of the actin cytoskeleton and the extracellular matrix, with THBS2 interacting with the integrin αvβ3 and coordinating the nuclear translocation of YAP upon CRH/CRH-receptor-1 (CRH/CRHR1) signalling. Overall, the CRH/CRHR1/RhoA/YAP/THBS2/αvβ3 axis has a central role in modulating HSPC behaviour via a mechanical feedback loop involving THBS2, αvβ3, the actin cytoskeleton and YAP signalling. Our findings may suggest avenues for optimizing the transplantation of HSPCs.

As one of the most crucial immune cells in the tumor microenvironment (TME), regulating tumor-associated macrophages (TAMs) is vital for enhancing antitumor immunity. Here, an injectable carbon dots (CDs)-linked egg white hydrogel was developed, termed TAMs Transform Factory (TTF-L-C), to spatiotemporally manipulate TAMs. The fabricated CDs significantly promoted macrophage migration. Notably, TTF-L-C achieved macrophage spatial enrichment through CDs-induced directional recruitment with molecular Ctnnd1 upregulation. Subsequently, the recruited macrophages were locoregionally reprogrammed within TTF-L-C, as well as blocking the upregulated PD-L1. Finally, through multi-stage regulation at spatial, cellular, and molecular levels, TTF-L-C released immune-activated M1 macrophages to the tumor site as it degraded. Moreover, TTF-L-C promoted dendritic cell (DCs) maturation and further boosted T cell activation, thereby reshaping the tumor-suppressive TME. Through peritumoral injection, TTF-L-C enhanced tumor immunotherapy in both subcutaneous and recurrent 4T1 tumor models with satisfactory biosafety. Therefore, TTF-L-C is proposed to become a safe and powerful platform for various biomedical applications.

Keratins, as essential components of intermediate filaments in epithelial cells, play a crucial role in maintaining cell structure and function. In various malignant epithelial tumors, abnormal keratin expression is frequently observed and serves not only as a diagnostic marker but also closely correlates with tumor progression. Extensive research has demonstrated that keratins are pivotal in multiple stages of tumor metastasis, including responding to mechanical forces, evading the immune system, reprogramming metabolism, promoting angiogenesis, and resisting apoptosis. Here we emphasize that keratins significantly enhance the migratory and invasive capabilities of tumor cells, making them critical drivers of tumor metastasis. These findings highlight the importance of targeting keratins as a strategic approach to combat tumor metastasis, thereby advancing our understanding of their role in cancer progression and offering new therapeutic opportunities.

Tumor organoid models have emerged as valuable 3D in vitro systems to study cancer behavior in a physiologically relevant environment. The composition and architecture of the extracellular matrix (ECM) play critical roles in tumor organoid culture by influencing the tumor microenvironment and tumor behavior. Traditional matrices such as Matrigel and collagen, have been widely used, but their batch-to-batch variability and limited tunability hinder their reproducibility and broader applications. To address these challenges, researchers have turned to synthetic/engineered matrices and biopolymer-based matrices, which offer precise tunability, reproducibility, and chemically defined compositions. However, these matrices also present challenges of their own. In this review, we explore the significance of ECMs in tumor organoid culture, discuss the limitations of commonly used matrices, and highlight recent advancements in engineered/synthetic matrices for improved tumor organoid modeling.

The tumor microenvironment (TME) is the combination of cells and factors that promotes tumor progression, and cancer-associated fibroblasts (CAFs) are a key component within TME. CAF originates from various stromal cells and is activated by factors such as transforming growth factor-beta (TGF-β) secreted by tumor cells, favoring chemoresistance and metastasis. Recent publications have underlined plasticity and heterogeneity and their strong contribution to the reactive stroma within the TME. Our study aimed to replicate the TME's structure by creating a 3D in vitro model of ovarian cancer (OC). By incorporating diverse tumor and stromal cells, we simulated a physiologically relevant environment for studying CAF-like cell behavior within tumor spheroids in a context-dependent manner. CAF-like cells were generated by exposing human dermal fibroblasts to OC cell line conditioned media in the presence or absence of TGF-β. Herein, we found that different stimuli induce the generation of heterogeneous populations of CAF-like cells. Notably, we observed the ability of CAF-like cells to shape the intratumoral architecture and to contribute to functional changes in tumor cell behavior. This study highlights the importance of precise assessment of CAF for potential therapeutic interventions and further provides a reliable model for investigating novel therapeutic targets in OC.

Peritoneal metastasis is a critical step in the progression of gastric cancer (GC), yet its underlying mechanisms remain poorly understood. Here, we identify FERMT2, a member of the Kindlin protein family, as a key regulator of anoikis resistance (AR) and peritoneal metastasis in GC. FERMT2 expression increases in a suspension-time-dependent manner and is associated with higher pathological grade, advanced clinical stage, and poorer prognosis. Functional studies in vitro and in vivo demonstrate that FERMT2 promotes AR and facilitates peritoneal metastasis. Mechanistically, FERMT2 suppresses the ubiquitination of SOX2, thereby enhancing its stability and up-regulating FN1 transcription. Furthermore, we report that TGFβ-RI expression also increases in a suspension-time-dependent manner, forming a positive feedback loop with FERMT2 via TGFβ-1/TGFβ-RI signaling. This feedback loop drives extracellular fibronectin matrix deposition, strengthens cell-matrix interactions, and supports AR. These findings establish FERMT2 as a pivotal mediator of peritoneal metastasis in GC, offering insights into its potential as a therapeutic target.

Brain metastases remain a major clinical challenge due to their high resistance to conventional and targeted therapies. Cancer-associated fibroblasts are the most common cellular component of the brain metastases tumor microenvironment. They significantly impact the tumor microenvironment because they promote cancer cell invasion, enhance metastasis, boost immune evasion, and contribute to drug resistance. We searched the PubMed and Google Scholar databases and included 99 studies to summarize the present review. Based on the searched articles, the present review emphasizes that biomarkers including PDGFR-β, α-SMA, and collagen I can identify metastatic brain cancer-associated fibroblasts, which lead to a poor prognosis and recurrence. In addition, cancer-associated fibroblasts can cause resistance to therapy by modifying the extracellular matrix (e.g., collagen I, fibronectin), secreting growth factors (e.g., TGF-β, HGF, IL-6), causing immunological evasion (e.g., Tregs, MDSCs), secreting exosomes (e.g., miRNAs), metabolic reprogramming, stemness induction, and plasticity. We also describe the molecular mechanisms by which cancer-associated fibroblasts confer drug resistance in brain metastases, such as extracellular matrix restoration, immunological evasion, metabolic reprogramming, etc. We also cover prospective therapeutic options for overcoming medication resistance, such as cancer-associated fibroblasts depletion, paracrine signaling blockage, metabolic inhibitors, and cancer-associated fibroblasts-targeted immunotherapies. Targeting cancer-associated fibroblasts in addition to existing medications may improve cancer treatment efficacy and survival rates for individuals with brain metastases. However, more research is required to better understand their role in metastatic brain tumors.

Biochemical signals in native tissue microenvironments instruct cell behavior during many biological processes ranging from developmental morphogenesis and tissue regeneration to tumor metastasis and disease progression. The detection and characterization of these signals using spatial and highly resolved quantitative methods have revealed their existence as matricellular proteins in the matrisome, some of which are bound to the extracellular matrix while others are freely diffusing. Including these biochemical signals in engineered biomaterials can impart enhanced functionality and native-like complexity, ultimately benefiting efforts to understand, model, and treat various diseases. In this review, we discuss advances in characterizing, mimicking, and harnessing biochemical signals in developing advanced engineered biomaterials. An overview of the diverse forms in which these biochemical signals exist and their effects on intracellular signal transduction is also provided. Finally, we highlight the application of biochemically complex biomaterials in the three broadly defined areas of tissue regeneration, immunoengineering, and organoid morphogenesis.

Despite the advances in detection, diagnosis, and treatments, cancer remains a lethal disease, claiming the lives of more than 600,000 people in the United States alone in 2024. To accelerate the development of new therapeutic strategies with improved responses, significant efforts have been made to develop microfabricated in vitro models of tumor microenvironments (TMEs) that address the limitations of animal-based cancer models. These models incorporate several advanced tissue engineering techniques to better reflect the organ- and patient-specific TMEs. Additionally, microfabricated models integrated with next-generation single-cell omics technologies provide unprecedented insights into patient's cellular and molecular heterogeneity and complexity. This review provides an overview of the recent understanding of cancer development and outlines the key TME elements that can be captured in microfabricated models to enhance their physiological relevance. We highlight the recent advances in microfabricated cancer models that reflect the unique characteristics of their organs of origin or sites of dissemination.

The heterogeneity of tumors significantly impacts on colorectal cancer (CRC) progression. However, the influence of this heterogeneity on the spatial architecture of CRC remains largely unknown.

Spatial transcriptomic (ST) analysis of AOM/DSS-induced colorectal cancer (CRC), integrated with single-cell RNA sequencing, generated a comprehensive spatial atlas of CRC. Pseudotime trajectory, stemness evaluation, and cell-cell communication analyses explored how CD44+ tumor cells at the leading edge remodel the tumor microenvironment (TME). In vitro experiments and immunofluorescence staining of clinical samples validated pleiotrophin (PTN) signaling in promoting cancer-associated fibroblasts (CAFs) phenotypic transition and CRC progression.

Our findings revealed a distinctive layered ring-like structure within CRC tissues, where CD44+ tumor cells exhibiting high stemness were positioned at the tumor's leading edge. Inflammatory CAFs (iCAFs)-like, myofibroblastic CAFs (myCAFs)-like cells and pro-tumorigenic neutrophils primarily located at the tumor edge, in proximity to CD44+ tumor cells. CD44+ tumor cells then triggered the phenotypic transition of CAFs into iCAF-like and myCAF-like cells through PTN signaling.

Our results provide distinctive insights into how tumor heterogeneity reshapes the TME at the leading edge of tumor, thereby promoting CRC progression.

The interplay between cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) mediates progress, metastasis, and therapy resistance. However, strategy of targeting ECM remodeling to enhance chemosensitivity in ovarian cancer remains elusive. Here, a 22-gene matrisome signature predicts chemotherapy response and survival in ovarian cancer. The dense, collagen-rich ECM secreted by CAFs harbors more M2 tumor-associated macrophages (TAMs) than the looser ECM based on single cell RNA-seq (scRNA-seq) of ovarian cancer, suggesting the promising approach of targeting collagen to remodel ECM. An integrated analysis identifies collagen type I alpha 1 chain (COL1A1) as a major component of the ECM that contributes to chemoresistance and poor prognosis, highlighting its potential as a therapeutic target. Halofuginone (HF), a clinically active derivative of febrifugine, is identified as a COL1A1-targeting natural compound by screening the Encyclopedia of Traditional Chinese Medicine (ETCM). Mechanistically, HF inhibits COL1A1 production via the mTOR-eIF2α-ATF4 axis in CAFs. Notably, HF disrupts collagen deposition and promotes CD8+ T cell infiltration, partially via M2-M1 macrophage polarization to enhance chemosensitivity. Overall, the findings suggest that HF combined with chemotherapy is a promising and effective treatment for ovarian cancer.

The components of the extracellular matrix (ECM) are dynamic, and they mediate mechanical signals that modulate cellular behaviors. Disruption of the ECM can induce the migration and invasion of cancer cells via specific signaling pathways and cytokines. Metastasis is a leading cause of high mortality in malignancies, and early intervention can improve survival rates. However, breast cancer is frequently diagnosed subsequent to metastasis, resulting in poor prognosis and distant metastasis poses substantial hurdles in therapy. In breast cancer, there is notable tissue remodeling of ECM proteins, with several identified as essential components for metastasis. Moreover, specific ECM molecules, receptors, enzymes, and various signaling pathways play crucial roles in breast cancer metastasis, drug treatment, and resistance. The in-depth consideration of these elements could provide potential therapeutic targets to enhance the survival rates and quality of life for breast cancer patients. This review explores the mechanisms by which alterations in the ECM contribute to breast cancer metastasis and discusses current clinical applications targeting ECM in breast cancer treatment, offering valuable perspectives for future ECM-based therapies.

Upper tract urothelial carcinoma (UTUC) presents aggressive features and a tumor microenvironment with T cell depletion. However, the role of tumor-associated neutrophils in UTUC remains unclear. This study aimed to investigate how UTUC tumor-derived factors modulate neutrophils and their impact on T cell immune responses. Our findings demonstrate that UTUC secreted tumor-derived factors, with apolipoprotein A1 (Apo-A1) being the predominant factor, which upregulated arginase-1 expression in neutrophils. STAT3 activation was responsible for the upregulation of arginase-1 in neutrophils. Blocking the interactions between Apo-A1 and its receptors reduced arginase-1 expression in neutrophils treated with tumor tissue culture supernatant (TTCS). Moreover, both CD4+ T and CD8+ T cell proliferation were inhibited by neutrophils treated with Apo-A1 or TTCS. Importantly, blocking Apo-A1 signaling in neutrophils reversed the inhibitory effects on T cells. In UTUC patients, the neutrophil-to-lymphocyte ratio was higher than that in healthy subjects. The expression of arginase-1 in neutrophils and the level of Apo-A1 within UTUC tumors were negatively correlated with tumor-infiltrating CD4+ T cells. Additionally, neutrophils from UTUC patients showed increased expression of arginase-1 and exhibited inhibitory effects of T cell functions. These findings suggest that UTUC orchestrates an immune-suppressive microenvironment through Apo-A1-mediated upregulation of arginase-1 in neutrophils, ultimately leading to the inhibition of T cell proliferation.