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.

Recent research highlighted the contribution of extracellular matrix, and particularly of ADAMTS proteases, in immune regulation. Now, our work with melanoma and mammary tumor models revealed that tumor blockade induced by the lack of Adamts1 led to an increased vascular deposition of its substrate, the basement membrane glycoprotein NIDOGEN-1 (NID1). Significantly, the overexpression of NID1 in the melanoma syngeneic model also blocked tumor progression, disclosing an overlapping phenotype with the absence of Adamts1. These tumors showed important alterations in their immune infiltrates, emphasizing an enhanced presence of antitumorigenic macrophages and a global inflammatory landscape. We corroborated in vitro that full length NID1, but not its fragments, promoted an M1-like macrophage polarization, mainly mediated by the αvβ3 integrin. Significantly, the projection of RNA-seq from our tumor models to two large human melanoma datasets allowed us to discover a new gene signature associated with good prognosis and the abundance of M1-like macrophages. These results support NID1 as a novel tumor suppressor with immunomodulatory properties, and unveil the existence of key oncological drivers in the extracellular scenario.

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.

Fibroinflammation refers to the highly integrated fibrogenic and inflammatory responses mediated by the concerted function of fibroblasts and innate immune cells in response to tissue perturbation. This process underlies the desmoplastic remodelling of the tumour microenvironment and thus plays an important role in tumour initiation, growth and metastasis. More specifically, fibroinflammation alters the biochemical and biomechanical signalling in malignant cells to promote their proliferation and survival and further supports an immunosuppressive microenvironment by polarizing the immune status of tumours. Additionally, the presence of fibroinflammation is often associated with therapeutic resistance. As such, there is increasing interest in targeting this process to normalize the tumour microenvironment and thus enhance the treatment of solid tumours. Herein, we review advances made in unravelling the complexity of cancer-associated fibroinflammation that can inform the rational design of therapies targeting this.

A growing number of studies have shown that in addition to adaptive immune cells such as CD8 + T cells and CD4 + T cells, various other cellular components within prostate cancer (PCa) tumor microenvironment (TME), mainly tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (MDSCs), have been increasingly recognized as important modulators of tumor progression and promising therapeutic targets.

In this review, we aim to delineate the mechanisms by which TAMs, CAFs and MDSCs interact with PCa cells in the TME, summarize the therapeutic advancements targeting these cells and discuss potential new therapeutic avenues.

We searched PubMed for relevant studies published through December 10 2023 on TAMs, CAFs and MDSCs in PCa.

TAMs, CAFs and MDSCs play a critical role in the tumorigenesis, progression, and metastasis of PCa. Moreover, they substantially mediate therapeutic resistance against conventional treatments including anti-androgen therapy, chemotherapy, and immunotherapy. Therapeutic interventions targeting these cellular components have demonstrated promising effects in preclinical models and several clinical trials for PCa, when administrated alone, or combined with other anti-cancer therapies. However, the lack of reliable biomarkers for patient selection and incomplete understanding of the mechanisms underlying the interactions between these cellular components and PCa cells hinder their clinical translation and utility.

New therapeutic strategies targeting TAMs, CAFs, and MDSCs in PCa hold promising prospects. Future research endeavors should focus on a more comprehensive exploration of the specific mechanisms by which these cells contribute to PCa, aiming to identify additional drug targets and conduct more clinical trials to validate the safety and efficacy of these treatment strategies.

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.

Treatment of breast cancer (BC) remains to face clinical challenges due to poor tumor penetration of therapeutic agents, which is a direct consequence of the high content of hyaluronan (HA) within the extracellular matrix (ECM) of tumor tissues. Herein, we reported the synthesis of phototherapy liposomes which integrated hyaluronidase (HAase) conjugated with a matrix metalloproteinase 2 (MMP-2) responsive peptide in their phospholipid membrane, and preloaded with indocyanine green (ICG), CaO2, and L-buthionine sulfoximine (BSO). Under near-infrared (NIR) laser irradiation, the responsive release of HAase and photodynamic therapy (PDT) effect generated by ICG enabled the controlled degradation of HA in the ECM. Moreover, the photothermal effect of ICG inactivated the residual HAase. This sequential cascade of events facilitated the highly efficient penetration of liposomes into tumor and degrades HA into oligosaccharides (oHA) through adjusting NIR laser irradiation intensity and duration. The phototherapy liposomes also alleviated hypoxia and depleted glutathione (GSH) within the tumor microenvironment. Combined treatment with our liposomes and laser irradiation led to a cell survival rate of <20 % for both 4 T1 and MDA-MB-231 cells. In 4 T1 tumor-bearing mice, the liposome group under NIR light irradiation significantly enhanced tumor ablation, achieving an inhibition rate of 64.9 %, demonstrating that the combination of PDT/PTT with oHA improves the therapeutic efficacy. As expected, the generation of oHA reduced the adverse effects triggered by HAase. These phototherapy liposomes, by promoting the penetration of PDT/PTT drugs, offer a promising strategy to enhance the treatment effectiveness for BC.

The extracellular matrix (ECM) plays a critical role in cancer progression by influencing tumor growth, invasion, and metastasis. This review explores the emerging therapeutic strategies that target the ECM as a novel approach in cancer treatment. By disrupting the structural and biochemical interactions within the tumor microenvironment, ECM-targeted therapies aim to inhibit cancer progression and overcome therapeutic resistance. We examine the current state of ECM research, focusing on key components such as collagen, laminin, fibronectin, periostin, and hyaluronic acid, and their roles in tumor biology. Additionally, we discuss the challenges associated with ECM-targeted therapies, including drug delivery, specificity, and potential side effects, while highlighting recent advancements and future directions. This review underscores the potential of ECM-focused strategies to enhance the efficacy of existing treatments and contribute to more effective cancer therapies.

Mechanical forces of the tumor microenvironment change dynamically during key events of tumorigenesis such as invasion and metastasis. These changes in compressive forces often affect the breast cancer cell phenotype. However, it is lesser known how these dynamic mechanical forces in the tumor microenvironment affect the phenotypes of tumor infiltrated leukocytes (TIL) and their subsequent anticancer activities. Here we find, in primary patient-derived explant cultures (PDEC) containing resident TILs, that low compression promotes a change in the original identity of breast cancer cells from luminal to a more mesenchymal and undifferentiated state. These altered tumor cells induce an upregulation of immunosuppressive cytokines such as interleukin-10 (IL-10) and Transforming Growth Factor Beta (TGF-β), as well as polarization of macrophages towards pro-tumor M2(Gc)-type and depletion of CD8+ effector memory T-cells. These immunosuppressive events are mediated by tumor cell derived fibroblast growth factor 2 (FGF2) and prostaglandin E2 (PGE2). We also find that FGF2 rich areas in primary tumors show enrichment in M2-like-macrophages and diminished numbers of CD8 + T and B-cells. Our results suggest that low compressive forces in the tumor microenvironment induce local immunosuppression via FGF2 secretion arising from phenotypic plasticity of tumor cells.

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.

The tumor environment of prostate cancer (PCa) tissues of high Gleason score has been proved to be more immune suppressive and has higher extracellular matrix (ECM) stiffness, but whether ECM mechanical stiffness is the cause of higher ability of invasiveness and immune escape of PCa with high Gleason score remains uncertain. In this study, we showed that higher polyacrylamide hydrogels (PAAG) stiffness resulted in the progression and immune escape of PCa via integrin β1/FAK/YAP axis. The translocation of YAP into cell nucleus to bind to TEAD2 promoted the transcriptional activation of USP8. NBR1 could be ubiquitinated, and then degraded, via interacting with P62/SQSTM1 and through autophagy-lysosome pathway. Increased expression of USP8 promoted the abundance of NBR1 via K63-linked de-ubiquitination and PD-L1 via K48-linked de-ubiquitination in response to high PAAG stiffness. NBR1-mediated selective autophagy accelerated the degradation of MHC-1 of PCa. The USP8 inhibitor presented a potential application value in sensitizing immunotherapy of PCa. Taken together, we identified a USP8-mediated de-ubiquitination mechanism that involves in the process of high PAAG stiffness-mediated high expression of PD-L1 and low expression of MHC-1 of PCa cells, which provided a rationale of immunotherapy sensitization of PCa via USP8 inhibition.

Colorectal cancer (CRC) is the third most common cause of death worldwide and has high mortality and a poor prognosis. Long non-coding RNAs (lncRNAs) are non-coding RNAs longer than 200 nucleotides that play roles in cancer through multiple mechanisms. TMEM51-AS1 is a newly discovered 40,650 bp lncRNA. Our results showed that TMEM51-AS1 expression was significantly downregulated in CRC tissues (fold change = 0.74, P < 0.0001). This finding was confirmed in 20 pairs of CRC carcinoma and paracancerous tissues (fold change = 0.5, P < 0.001). Additionally, TMEM51-AS1 expression was found to be significantly reduced in CRC cell lines compared to normal human intestinal epithelial cells (P < 0.001). Bioinformatic analysis revealed that TMEM51-AS1 expression was associated with immune escape, RNA methylation, and DNA damage and repair. TMEM51-AS1 may also activate energy metabolism pathways to participate in cancer development. Drug sensitivity analysis confirmed that several drugs are more effective in CRC patients with high expression of TMEM51-AS1. In conclusion, our study demonstrates that TMEM51-AS1 can suppress the progression of CRC.

The pericellular matrix (PCM) is the immediate microniche surrounding cells in various tissues, regulating matrix turnover, cell-matrix interactions, and disease. This study elucidates the structure-mechanical properties and mechanobiology of the PCM in fibrocartilage, using the murine meniscus as the model. The fibrocartilage PCM is comprised of thin, randomly oriented collagen fibrils that entrap proteoglycans, contrasting with the densely packed, highly aligned collagen fibers in the bulk extracellular matrix (ECM). Compared to the ECM, the PCM exhibits lower modulus and greater isotropy, but has similar relative viscoelastic properties. In Col5a1+/- menisci, the reduction of collagen V results in thicker, more heterogeneous collagen fibrils, reduced modulus, loss of isotropy and faster viscoelastic relaxation in the PCM. Such altered PCM leads to impaired matrix-to-cell strain transmission, and in turn, disrupts mechanotransduction of meniscal cells, as illustrated by reduced calcium signaling activities and alters expression of matrix genes. In vitro, Col5a1+/- cells produce a weakened PCM with inferior properties and reduced protection of cells against tensile stretch. These findings highlight the PCM as a distinctive microstructure in fibrocartilage mechanobiology, underscoring a pivotal role of collagen V in PCM function. Targeting the PCM or its constituents offers potential for improving meniscus regeneration, osteoarthritis intervention and broader fibrocartilage-related therapies.

The standard treatments for prostate cancer (PCa) include chemotherapy, hormone therapy, targeted therapies based on androgen receptor (AR) and/or gonadotropin-releasing hormone (GnRH) receptor antagonists, and radiation therapy. But PCa therapeutic resistance remains an unsolved challenge, leading to progression to castration-resistant prostate cancer (CRPC). Emerging PCa therapies - including poly(ADP-ribose) polymerase (PARP) inhibitors, AR crosstalk signalling pathway inhibitors, B-cell lymphoma 2 (BCL-2) inhibitors, cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitors, CRISPR/Cas9, epigenetic inhibitors, and nanotechnology-based drug-delivery approaches - provide promising targeted solutions. Targeted protein degradation therapy, particularly AR degradation therapies, effectively inhibits resistance at its source. This review summarises the established and emerging PCa therapies, focusing on discussing their efficacy in terms of PCa resistance with supporting experimental findings and the mechanisms of PCa drug resistance.

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.

Tissue densification is a fundamental biological process involved in development, regeneration, and disease, significantly influencing tissue mechanics and cellular mechanical microenvironments. However, the effects of tissue densification on mechanical properties, the roles of key cytoskeletal components, and their responses to external mechanical stress remain poorly understood. In this study, fibroblast-collagen microtissues were cultured on polydimethylsiloxane (PDMS) microstring scaffolds with different mechanical constraints to generate low- and high-densification microtissues. High-precision indentation force sensor analysis demonstrated that increased densification enhanced microtissue stiffness, accelerated stress relaxation, and elevated energy dissipation. Pharmacological disruption of cytoskeletons revealed the critical role of F-actin in regulating stiffness and viscoelastic resistance in a densification-dependent manner: in high-densification microtissues, F-actin had a greater impact on stiffness and dissipated energy, but a reduced effect on stress relaxation. Furthermore, under 50% strain indentation, high-densification microtissues exhibited irreversible deformation and increased cellular injury. Injured regions showed reduced stiffness, shorter stress relaxation time constants, and higher energy dissipation, indicating structural and cellular damage. These results enhance our understanding of tissue mechanobiology by elucidating the interplay between tissue densification, cytoskeletal mechanics, and injury responses, providing valuable insights for optimizing tissue mechanical microenvironments and improving the mechanical compatibility of biomaterials.

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.

Cancer initiation and early tumour growth are complex processes influenced by multiple cellular and microenvironmental factors. A critical aspect of tumour progression is the dynamic interplay between cancer cells and the extracellular matrix (ECM), which undergoes significant alterations to support malignancy. The loss of cell polarity is an early hallmark of tumour progression, disrupting normal tissue architecture and fostering cancerous transformation. Circumstantially, cancer-associated microRNAs (miRNAs) regulate key oncogenic processes, including ECM remodelling, epithelial-to-mesenchymal transition (EMT), and tumorigenic vascular development, further driving tumour growth. ECM alterations, particularly changes in stiffness and mechanotransduction signals, create a supportive niche for cancer cells, enhancing their survival, proliferation, and invasion. EMT and its subtype, epithelial-to-endothelial transition (EET), contribute to tumour plasticity, promote the generation of cancer stem cells (CSCs), and support tumour vascularisation. Furthermore, processes of vascular development like vasculogenesis and angiogenesis are critical for sustaining early tumour growth, supplying oxygen and nutrients to hypoxic malignant cells within the evolving cancerous microenvironments. This review explores key mechanisms underlying these changes in tumorigenic microenvironments, with an emphasis on their collective role for tumour initiation and early tumour growth. It will further delve into present in vitro modelling strategies developed to closely mimic early cancer pathophysiology. Understanding these processes is crucial for developing targeted therapies aimed at disrupting key cancer-promoting pathways and improving clinical 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.