Immune checkpoint blockade (ICB) has significantly advanced tumor therapy, yet its overall response rates remain limited and are often accompanied by immune-related adverse effects. Immunogenic cell death (ICD), a specia...Immune checkpoint blockade (ICB) has significantly advanced tumor therapy, yet its overall response rates remain limited and are often accompanied by immune-related adverse effects. Immunogenic cell death (ICD), a specialized form of regulated cell death, elicits antitumor immunity through the release of damage-associated molecular patterns and cytokines. This review systematically examines the mechanisms by which ICD enhances the efficacy of ICB therapy and evaluates its potential for clinical translation. ICD facilitates the recruitment of dendritic cells into the tumor microenvironment via “find me” signals and, through the exposure of “eat me” signals, enables dendritic cell-mediated phagocytosis and antigen presentation of tumor cells. This cascade effectively transforms immunologically “cold” tumors into “hot” tumors, augmenting cytotoxic T lymphocyte infiltration and function, thereby improving ICB therapeutic outcomes. Additionally, ICD promotes the formation of tertiary lymphoid structures, which further remodel the tumor microenvironment and support sustained immune surveillance. Although preclinical studies underscore the synergistic potential of combining ICD inducers with ICB, clinical trial outcomes have been variable, with efficacy influenced by tumor heterogeneity, treatment sequencing, and the immunosuppressive tumor microenvironment. Future investigations should focus on optimizing ICD induction protocols, developing specific biomarkers, and designing personalized combination strategies to enable more precise and effective immunotherapeutic interventions in oncology.
BACKGROUND: Single organ metastasis to liver typically occurs in uveal melanoma (UM) and colorectal carcinoma (CRC). Colonization in the host organ is a beachhead step of the metastasis process. The governing pathways of...BACKGROUND: Single organ metastasis to liver typically occurs in uveal melanoma (UM) and colorectal carcinoma (CRC). Colonization in the host organ is a beachhead step of the metastasis process. The governing pathways of the seeding cells are far away clarified. OBJECTIVE: This study aimed at deciphering governing pathways of the seeding cells that required for metastatic colonization and developing novel strategies against metastasis. DESIGN: Mass spectrum analysis of Co-IP pellets was applied to identify the kinase and the substrates of BAP1. Findings were further validated using GST-pull down assay and the proximity ligation assay. The function of CDK6/4-BAP1-VHL signaling axis in promoting liver metastasis was investigated by UM and CRC mouse model. RESULTS: Mass spectrum analysis of Co-IP pellets with anti-BAP1 revealed that VHL bound with BAP1. Their physical interaction was further confirmed by GST-pull down assay and proximity ligation assay. We mapped the interacting domains between BAP1 and VHL. In vivo ubiquination assay showed that BAP1 deubiquitinated VHL at K48-linked poly-ubiquitin chain and stabilized VHL protein. Further, exosomal CDK6/4 serine/threonine kinases were identified to phosphorylate BAP1 at S369 to inactivate BAP deubiquitinationase, forming CDK6/4-BAP1-VHL signaling axis. Functionally, BAP1 inhibited CSCs, EMT and metastatic colonization to liver in uveal melanoma and colorectal carcinoma via upregulating VHL protein, which was, however, reversed by targeting CDK6/4. CONCLUSION: In conclusion, VHL is a novel substrate of BAP; and BAP1 suppresses CSCs and metastatic colonization to liver via substrate VHL. These findings may shed lights on the mystery substrates of BAP1 and the underlying mechanism of colonization in liver and intervention targets.
KRAS is a critical proto-oncogene that encodes a protein functioning as a pivotal molecular switch in intracellular signaling. Both KRAS mutations and MYC dysregulation are key drivers of tumor progression and have histo...KRAS is a critical proto-oncogene that encodes a protein functioning as a pivotal molecular switch in intracellular signaling. Both KRAS mutations and MYC dysregulation are key drivers of tumor progression and have historically been regarded as “undruggable” targets. Emerging evidence underscores that the coordinated activation of KRAS and MYC cooperatively fuels tumorigenesis, suggesting that dual inhibition of these oncogenes may constitute a synergistic therapeutic approach for KRAS-mutant cancers. However, the mechanistic basis underlying the effective combined targeting of KRAS and MYC remains poorly defined, largely due to the complexity of their functional interplay. This review examines their collaborative roles in metabolic reprogramming, epigenetic remodeling, and shaping an immunosuppressive tumor microenvironment through crosstalk with immune cells. It also surveys current and emerging anti-KRAS strategies and discusses the challenge of therapy resistance, particularly in the setting of MYC dysregulation. Since resistant tumors often circumvent KRAS inhibition by reactivating MYC to sustain proliferation and survival, interventions that concurrently target these adaptive pathways may hold promise for overcoming resistance in KRAS-driven malignancies.
Multidrug resistance (MDR) remains the principal impediment to curative oncology, driven by complex interplays between cancer cells and the tumor microenvironment (TME). While nanomedicines have sought to overcome these...Multidrug resistance (MDR) remains the principal impediment to curative oncology, driven by complex interplays between cancer cells and the tumor microenvironment (TME). While nanomedicines have sought to overcome these delivery barriers, their clinical translation is often hampered by the heterogeneity of the enhanced permeability and retention (EPR) effect and by inefficient intratumoral delivery. In this review, we argue that overcoming MDR requires a transition beyond traditional passive drug delivery, advocating active, localized remodeling of the tumor ecosystem. Next-generation injectable hydrogels are increasingly recognized as localized viscoelastic niches that combine controlled intratumoral retention with the capacity to actively modulate biological responses within tumor TME. By converging principles of mechanobiology and immunometabolism, these hydrogels enable a multi-tiered strategy to dismantle multidimensional MDR. This approach begins with the biomechanical softening of the extracellular matrix to decouple mechanotransduction driven by Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), followed by the metabolic disruption of hypoxia-driven bioenergetics. Beyond the extracellular landscape, nanogel-enabled trafficking allows payloads to circumvent intracellular sequestration and efflux transporters, while immunomodulatory niches mobilize antitumor immunity through in situ vaccination and myeloid reprogramming. Finally, we evaluate the integration of artificial intelligence-driven design and patient-derived organoids as a technical bridge to reconcile laboratory ingenuity with clinical utility, aiming to transform the TME into a vulnerable therapeutic target.
We recently carefully read the article titled “Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells” published by Chu-An Wang et al. in Molecul...We recently carefully read the article titled “Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells” published by Chu-An Wang et al. in Molecular Cancer. While this study provides valuable insights into tumor-immune crosstalk, we raise two points for clarification to enhance its precision. First, the manuscript classifies T2N0M0 samples as stage II pancreatic ductal adenocarcinoma (PDAC), which conflicts with the eighth edition of the AJCC Cancer Staging Manual that designates T2N0M0 as stage IB. Second, the authors used pancreatic stellate cells (PSCs) as a surrogate for fibroblasts to model stromal effects, but accumulating evidence indicates that PSCs and fibroblasts are not equivalent. To address this, we integrated single-cell, spatial, and bulk transcriptomic data from multiple cohorts. Our analyses revealed substantial differences between fibroblasts and stellate cells in abundance (fibroblasts enriched in primary pancreatic cancer tumor tissues), prognostic relevance (high fibroblasts associated with poorer survival, high stellate cells with better prognosis), spatial distribution (fibroblasts localized around malignant tumor cells), and intercellular communication (fibroblasts as stronger signal senders to malignant tumor cells). These findings confirm that PSCs cannot accurately represent fibroblasts in PDAC. We emphasize that clarifying these points will not undermine the study’s significance but will strengthen its rigor and comparability. Wang et al.’s work remains a valuable contribution to understanding PDAC progression, and we anticipate these clarifications will further advance stromal-immune crosstalk research in PDAC.
Nassar FJ, Cahais V, McKay JA
… +12 more, Strathdee G, Lee YS, Spitz N, Nickels E, Nordlund J, Saffery R, Dwyer T, Magnus P, Munthe-Kaas MC, Herceg Z, Wiemels JL, Ghantous A
Ferroptosis is a novel form of programmed cell death defined by iron-dependent, reactive oxygen species (ROS)-mediated peroxidation of membrane phospholipids containing polyunsaturated fatty acyl chains. Since 2020, rese...Ferroptosis is a novel form of programmed cell death defined by iron-dependent, reactive oxygen species (ROS)-mediated peroxidation of membrane phospholipids containing polyunsaturated fatty acyl chains. Since 2020, research interest in ferroptosis has surged exponentially, outpacing that of other cell death modalities and establishing it as a pivotal regulatory target in oncology. This review offers three key novel contributions compared to prior summaries: first, it systematically integrates the context-dependent roles of ferroptosis either synergistic sensitization or resistance in cancer multi-disciplinary treatment (MDT), including chemotherapy, targeted therapy, radiotherapy, interventional therapy and immunotherapy, with a focus on clinical trial evidence from the past five years; second, it deciphers the dynamic crosstalk between ferroptosis and core components of the tumor immune microenvironment (TIME), while clarifying the regulatory impacts of microenvironmental factors (pH, hypoxia, gut microbiota); third, it comprehensively summarizes breakthrough advances in nanoplatform based ferroptosis regulation, structured around two complementary perspectives: endogenous TME-responsive systems and exogenous stimulus triggered systems. This review aims to bridge basic mechanisms with clinical applicability, providing a framework for translating ferroptosis targeted strategies into optimized MDT regimens.
PURPOSE: To investigate the mechanisms underlying the interaction and influence between microvascular invasion (MVI), which contributes to metastasis and poor prognosis of pancreatic ductal adenocarcinoma (PDAC), and tum...PURPOSE: To investigate the mechanisms underlying the interaction and influence between microvascular invasion (MVI), which contributes to metastasis and poor prognosis of pancreatic ductal adenocarcinoma (PDAC), and tumor microenvironment. METHODS: This study employed an integrative multi-omics approach, combining spatial proteomics (multiplex immunofluorescence), transcriptome sequencing, and single-cell RNA sequencing (scRNA-seq) to profile MVI⁺ and MVI⁻ PDAC samples. The functional role of key genes was validated through in vitro and in vivo assays (migration, invasion, xenograft models). Molecular mechanisms were dissected using Co-IP, ubiquitination assays, and ChIP-qPCR. RESULTS: The epithelial-mesenchymal transition (EMT) process was significantly activated in MVI⁺ tumors, with EMT-positive cells located spatially closer to microvessels. scRNA-seq identified a distinct epithelial subpopulation characterized by CXCL5 that exhibited a strong EMT phenotype and was enriched in MVI⁺ samples. Mechanistically, the transcription factor ZBTB7B was found to directly promote TRIM29 transcription. TRIM29 directly binds to IκBα via its BB2 domain and catalyzes its K48-linked ubiquitination and proteasomal degradation. This event relieves the inhibition of the NF-κB signaling pathway, leading to its activation and the subsequent induction of EMT, ultimately enhancing the invasive and metastatic capabilities of pancreatic cancer cells. Clinical correlation analysis revealed a significant negative correlation between TRIM29 and IκBα protein levels, and high TRIM29, low IκBα, and high CXCL5⁺EMT levels were all associated with poor prognosis. CONCLUSION: This study reveals the critical role of the ZBTB7B-TRIM29-IκBα-NF-κB signaling axis in promoting EMT in CXCL5-marked pancreatic cancer cells surrounding MVI, establishing TRIM29 as a potential therapeutic target for inhibiting early metastasis of PDAC. CLINICAL RELEVANCE: This study provides deep insights into the biology of MVI, a crucial prognostic indicator in pancreatic cancer. TRIM29 expression could serve as a potential biomarker for predicting tumor aggressiveness and patient outcome. More importantly, targeting TRIM29’s E3 ligase activity or its interaction with IκBα represents a promising novel therapeutic strategy to inhibit early metastasis and improve the resectability of pancreatic cancer.
BACKGROUND: Sensitive and specific blood biomarkers for early detection of colorectal (CRC), lung (LuCa) and ovarian (OvCa) cancers are highly warranted. The current blood tests often need to be complemented with other c...BACKGROUND: Sensitive and specific blood biomarkers for early detection of colorectal (CRC), lung (LuCa) and ovarian (OvCa) cancers are highly warranted. The current blood tests often need to be complemented with other clinical methods to achieve adequate diagnostic performance. Recent progress in the molecular profiling of plasma from cancer patients holds potential for improved non-invasive screening. Here, we aimed to identify composite proteomic and metabolomic plasma biomarkers for early cancer detection with performances that exceed those of existing FDA-approved blood and stool-based diagnostic tests for CRC, LuCa and OvCa. METHODS: In a case-control study using samples from the U-CAN and EpiHealth biobanks, we measured plasma levels of 165 proteins and 244 metabolites in 818 patients with CRC, LuCa and OvCa at diagnosis, 119 patients with non-malignant conditions of the corresponding organs, and 1,129 healthy individuals. We performed an exhaustive search over all cut-off values of the ROC for all combinations of up to 4 proteins and metabolites, implementing measures to minimize the impact of cross-cohort comparisons. Ultimately, we benchmarked candidate biomarkers performance to FDA approved blood tests in clinical use for detection of cancer. External validation was performed using publicly available datasets. RESULTS: We found biomarkers composed of 2–4 proteins separating cases of each tumor type from healthy controls with ROC AUC, respectively for CRC: CEACAM5, FLT1, IL19, Ferritin (AUC 0.89), LuCa: FNDC5, MDK, PLAUR, CEACAM5 (AUC 0.91) and OvCa: MUC16/CA125, PLG (AUC 0.97). The diagnostic performance of these biomarkers was comparable to, and in some instances surpassed, the performance of established tests, such as Epi proColon (AUC 0.82) and Cologuard (AUC 0.93). Metabolites were informative for tumor stage discrimination, especially in LuCa and OvCa. External validation in the CancerSeek dataset showed strong agreement in biomarker performance. CONCLUSIONS: The composite protein biomarkers identified in this study represent a novel opportunity for detection, staging and differential diagnosis of common tumor types. Metabolites are more relevant for tumor staging than early detection. A limited number of well-performing analytes enables cost-effective implementation in clinical diagnostics and merits further evaluation.
Evidence of micro- and nanoplastics (MNPLs) presence in human tissues, cells, and biological fluids raises concerns about their potential role in hazardous diseases, including cancer. Higher concentrations of microplasti...Evidence of micro- and nanoplastics (MNPLs) presence in human tissues, cells, and biological fluids raises concerns about their potential role in hazardous diseases, including cancer. Higher concentrations of microplastics (MPLs) in cancerous tissues compared with adjacent healthy tissues, particularly in barrier organs such as the lungs, intestines, and reproductive system, suggest a potential association with tissue pathology and tumor-related processes. Extracted MNPLs from cancerous tissues exhibit diverse polymer compositions and morphologies, predominantly fibers and fragments larger than 1 μm, while smaller nanoplastics (NPLs) are likely underrepresented due to detection limitations. To investigate how MNPLs promote carcinogenesis depending on their physicochemical characteristics, various in vitro and in vivo studies have been analyzed. Most studies use pristine commercial spherical polystyrene (PS) MNPLs, which do not fully exhibit real-life MNPL characteristics but still provide valuable insights into their hazardous effects across a wide size range. Additional studies employing alternative polymers and environmentally relevant particle shapes further advance understanding of MNPL-associated health risks, as addressed in this review. Existing data indicates that smaller NPLs readily cross biological barriers and accumulate within cells due to their high surface area, whereas larger MPLs primarily interact at tissue surfaces, causing physical stress, tight junction disruption, and microbiota perturbation. Notably, MNPL exposure induces multiple hazardous effects and disrupts cellular homeostasis through coordinated and integrated signaling pathways. NF-κB signaling triggers pro-inflammatory and survival gene expression, while JNK-MAPK, ERK1/2-MAPK, and JAK–STAT pathways amplify inflammation, DNA damage responses, and apoptosis. MNPLs also induce ROS-driven ER stress, mitochondrial dysfunction, and dysregulation of AKT, TP53, caspases, and XIAP, activating apoptosis, necroptosis, and fibrosis. Compensatory antioxidant responses are activated via NRF2/HO-1 to counteract oxidative stress, while β-catenin/Wnt signaling is concurrently modulated, linking ROS-induced stress to tumorigenic reprogramming and cellular proliferation. Dysregulation of metabolic and growth regulators, including PI3K–AKT–mTOR, AMPK, mTORC1, and P70S6K, promotes cellular proliferation, survival, and metabolic adaptation. Simultaneously, modulation of ECM–receptor interactions, focal adhesion, Hippo, TGF-β, and cell-cycle regulators (CDK4/6, Cyclin D1, p-Rb) reshapes the tumor microenvironment, supporting potential malignant progression. All these interconnected events establish a tumor-permissive environment, promoting uncontrolled proliferation, metabolic reprogramming, and malignant transformation, thereby supporting the potential role of MNPLs in carcinogenesis.
Epidermal growth factor receptor (EGFR) mutations are common in non-small-cell lung cancer (NSCLC) but typically confer poor responses to immunotherapy, likely owing to an inhibitory tumor immune microenvironment. Here,...Epidermal growth factor receptor (EGFR) mutations are common in non-small-cell lung cancer (NSCLC) but typically confer poor responses to immunotherapy, likely owing to an inhibitory tumor immune microenvironment. Here, Rho-associated coiled-coil containing protein kinase 1 (ROCK1) was identified as having significantly elevated kinase activity in EGFR-mutant NSCLC through phosphoproteomic analyses. Inhibition of ROCK1, while only mildly suppressing tumor cell proliferation, markedly enhances CD8 + T cell-mediated antitumor immune responses in vitro and in vivo. Mechanistically, ROCK1 inhibition suppresses PD-L1 expression via GSK3α-mediated phosphorylation of PD-L1 at serine 283, promoting its ubiquitination and degradation by the E3 ubiquitin ligase SMURF2. This process enhances the cytotoxic activity of CD8 + T cells. Furthermore, combining ROCK1 inhibitors with PD-L1 blockade produces substantial anti-tumor efficacy in EGFR-mutant NSCLC mouse models. Collectively, our findings reveal a critical role for ROCK1 in regulating the tumor immune microenvironment and highlight that targeting ROCK1 could improve immunotherapy outcomes in patients with EGFR-mutant NSCLC.
YAP1 (Yes-associated protein 1), a central downstream effector of the Hippo signaling pathway, is tightly regulated through coordinated post-transcriptional and post-translational mechanisms. At the post-transcriptional...YAP1 (Yes-associated protein 1), a central downstream effector of the Hippo signaling pathway, is tightly regulated through coordinated post-transcriptional and post-translational mechanisms. At the post-transcriptional level, expression stability and translational output of YAP1 are governed by competitive crosstalk among non-coding RNAs, modulation by RNA-binding proteins, and diverse mRNA modification processes. At the post-translational level, protein stability and subcellular distribution are finely controlled by an integrated modification landscape, including ubiquitination, acetylation, and SUMOylation. Functionally, YAP1 participates in senescence regulation, shapes the immune microenvironment through chemokine and immune checkpoint modulation, and drives metabolic reprogramming involving glucose, glutamine, and lipid pathways. Considerable advances have been achieved in therapeutic development directed at these regulatory axes, including disruption of YAP1-TEAD complex assembly, targeting of non-coding RNA-associated signaling cascades, and pharmacologic modulation of enzymes mediating post-translational modifications. Nonetheless, clinical translation remains constrained by limitations in drug selectivity, delivery efficiency, and the emergence of resistance. Subsequent investigations should prioritize refined molecular design, evaluation of rational combination regimens, and expanded clinical validation to accelerate the implementation of YAP1-oriented therapeutic approaches.
Leva G, Santomaso L, Gianesello M
… +23 more, Patrizi S, Ress F, Cocchini F, Antonacci C, Gianno F, Abballe L, Lago C, Pozza N, Trentini G, Cardano M, Minasi S, Buttarelli FR, Antonelli M, Pernici D, Petrucci L, Antonica F, Busarello E, Iannuzzi M, Soldano A, Tebaldi T, Miele E, Ferretti E, Tiberi L
Pediatric low-grade gliomas (pLGGs) are the most common type of brain tumors in children, characterized by their typically slow growth and oncogene-induced senescence. Preclinical models provide the opportunity to invest...Pediatric low-grade gliomas (pLGGs) are the most common type of brain tumors in children, characterized by their typically slow growth and oncogene-induced senescence. Preclinical models provide the opportunity to investigate the effects of various treatments in a controlled setting before they are tested in human patients; however, reliable models for pLGGs are limited. Here we developed two organoid models for pLGGs, which, after engraftment into mice, exhibited low-grade features. Furthermore, the genome-wide DNA methylation and RNA profiles of the organoids demonstrated closer similarity to low-grade glioma entities compared to high-grade counterparts. Additionally, pLGG organoid-derived cells align with oligodendrocyte-like, astrocyte-like and MAPK signature clusters seen in patient tumors, indicating that the organoids generate a heterogeneous population of cancer cells, where cellular diversity may influence disease progression and treatment response.
Digestive system cancer is one of the most lethal forms of aggressive cancer in the world. Although diagnosis and treatment methods have improved, most patients have poor survival expectations due to late detection and r...Digestive system cancer is one of the most lethal forms of aggressive cancer in the world. Although diagnosis and treatment methods have improved, most patients have poor survival expectations due to late detection and rapid disease progress. Some recent studies have delved into the molecular level of the mechanism of non-coding RNA (ncRNA) intervention in digestive system cancer and have conducted a more in-depth and comprehensive discussion. At the same time, it has also been shown that ncRNA plays an important role in early detection and targeted treatment of digestive system cancer. This review summarizes the roles of ncRNAs in modulating multiple key pathways, including Wnt/β-catenin and PI3K/AKT, thereby influencing diverse processes such as tumor proliferation, invasion, immune microenvironment remodeling, glycolytic metabolism, and macrophage polarization. Additionally, the prognostic significance of ncRNAs in digestive system cancers is summarized and appraised. According to the current review, ncRNA is expected to become a potential biological marker and intervention target for digestive system cancer, helping the treatment of digestive system cancer to move further towards precision medicine.
Oncolytic viruses (OVs) have emerged as a distinctive class of cancer therapeutics capable of coupling direct tumor cell lysis with broad immune activation, thereby reshaping antitumor immunity beyond the capacities of c...Oncolytic viruses (OVs) have emerged as a distinctive class of cancer therapeutics capable of coupling direct tumor cell lysis with broad immune activation, thereby reshaping antitumor immunity beyond the capacities of conventional modalities. Despite substantial progress, the clinical translation of OVs remains constrained by challenges such as inefficient delivery, restricted tumor selectivity, premature immune clearance and safety concerns, all of which collectively limit therapeutic efficacy. Recent advances in genetic engineering, viral retargeting and high-dimensional profiling technologies have begun to clarify the molecular and microenvironmental determinants of OV tropism and activity, providing new opportunities to optimize OV design.In this review, we synthesize current OV classifications, mechanisms of action and clinical developments, and highlight emerging innovations spanning synthetic engineering, targeted delivery platforms and combination therapy strategies—including those integrating OVs with immunotherapies, targeted agents and conventional modalities—to amplify therapeutic potency and overcome resistance. Together, these perspectives provide an integrated framework for understanding OV biology, underscore the need to address persistent barriers to safe and effective clinical deployment, and outline key priorities for advancing OVs toward their potential as a foundational component of next-generation, personalized cancer immunotherapy.
Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal gastrointestinal cancers, characterized by rapid progression and resistance to therapy driven by significant metabolic reprogramming. Although alterat...Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal gastrointestinal cancers, characterized by rapid progression and resistance to therapy driven by significant metabolic reprogramming. Although alterations in glycolysis, glutamine, and lipid metabolism are well established, recent studies emphasize a more crucial factor: the emergence of context-specific metabolic dependencies within the nutrient-deprived tumor microenvironment. This review highlights that focusing on these dependencies, particularly those resulting from the distinctive metabolic interactions between cancer cells and the surrounding stroma, offers a promising strategy for overcoming treatment challenges. Evidence demonstrating that stromal-driven metabolic pathways supply energy and building blocks and confer resistance to standard chemo- and immune-therapies is examined. Furthermore, innovative approaches to target these vulnerabilities in PDAC metabolic subtypes, including synthetic-lethal interactions and key transporters in metabolic pathways are explored. How functional precision medicine, which uses patient-derived models to identify metabolic vulnerabilities, may convert these insights into personalized therapies is examined. Moving from broad metabolic inhibition to precise targeting of the tumour-stroma metabolic ecosystem could substantially improve the prognosis for PDAC.
Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy with limited predictive markers to guide personalized treatment, particularly in human papillomavirus (HPV)-negative cases, which exhibit...Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy with limited predictive markers to guide personalized treatment, particularly in human papillomavirus (HPV)-negative cases, which exhibit poor outcomes. Identifying reliable biomarkers for prognosis and therapeutic response remains a critical challenge. In a retrospective cohort of 51 patients with primary HPV-negative HNSCC, we investigated the prognostic significance of the Hedgehog (HH) signaling pathway and its association with imaging biomarkers. Genomic and transcriptomic analysis revealed that HH pathway activation correlated with distinct [18F]FDG PET/CT radiomic features, notably the PET-derived “histogram:ih.max”, a surrogate for peak [18F]FDG uptake that was associated with inferior survival outcomes. Functionally, pharmacologic inhibition of HH signaling demonstrated anticancer efficacy across multiple models, including HNSCC cell lines, patient-derived tumoroids, and in vivo xenograft models. Importantly, HH pathway inhibition induced reproducible changes in imaging characteristics in xenografts, including a measurable reduction in [1⁸F]FDG uptake, closely mirroring patterns observed in patient tumors. Together these findings demonstrate that integration of multi-level molecular profiling with functional imaging captures HH-driven tumor biology in HPV-negative HNSCC. Our study underscores the value of [18F]FDG PET/CT multiomics in linking tumor biology with imaging features, providing a framework for biologically-informed patient stratification and hypothesis-driven evaluation of treatment response. These results support further translational validation of HH pathway inhibition in HPV-negative HNSCC within appropriately designed preclinical and clinical studies.
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) exhibits profound molecular heterogeneity and poor prognosis, necessitating novel tailored therapies. The basal and classical subtypes - driven by glycolysis versus lip...BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) exhibits profound molecular heterogeneity and poor prognosis, necessitating novel tailored therapies. The basal and classical subtypes - driven by glycolysis versus lipid metabolism - have distinct prognostic implications warranting further characterization of their underlying transcriptional mechanisms. METHODS: Using spatial RNA sequencing we mapped PDAC molecular subtype heterogeneity, capturing spatially-resolved gene expression signatures and generating a comprehensive high-resolution dataset of 42,035 spatial spots. Subtype assignments were validated via multiplex immunofluorescence and quantitative analyses in patient-derived organoids and xenografts. RESULTS: Our analysis resolved cancer cell signatures, deconvoluted intra-tumoral heterogeneity, and delineated an evolutional classical-to-basal trajectory. We identified metabolically ‘hot’, high-grade tumor niches characterized by concurrent enrichment of glycolysis and lipogenesis across both subtypes, nominating them as subtype-agnostic therapeutic targets. Preclinical models demonstrated that despite the basal subtype’s glycolysis dependence, both classical and basal tumors are susceptible to glycolysis inhibition. CONCLUSION: This work demonstrates that metabolic identity, spatial context, and tumor–stroma crosstalk are an inseparable triad that drives PDAC behavior. Our findings show that aggressive metabolic tumor niches can be targeted by glycolysis inhibition in a subtype-agnostic manner, challenging the dogma of subtype-specific therapeutic silos and highlighting highly adaptable energetic niches as reservoirs that drive tumor progression.
Comprehensively understanding cancer biology requires complex model systems, typically animal models, to replicate tumor behavior, microenvironment interactions, and cell migration/metastatic processes. Traditionally, ge...Comprehensively understanding cancer biology requires complex model systems, typically animal models, to replicate tumor behavior, microenvironment interactions, and cell migration/metastatic processes. Traditionally, genetically engineered and xenograft mouse models have been the cornerstone of cancer research. In recent years, the 3R principle—Replacement, Reduction, and Refinement—has reshaped ethical cancer research by promoting alternative animal models. Here we critically examine in vitro and in silico as well as four 3R-compliant animal models — the chicken chorioallantoic membrane (CAM) model, Danio rerio, Drosophila melanogaster, and Caenorhabditis elegans — and assess their advantages, limitations, and translational relevance for cancer research. Special emphasis is placed on practical considerations to inform optimal decision-making, including reproducibility and model-specific advantages and challenges. This review aims to support researchers in selecting ethical and effective preclinical models to advance cancer research.