Molecular Cancer[JOURNAL]
Sun
200 papers
Molecular subtypes in pancreatic cancer: from academic promise to clinical reality.
D'Empaire Altimari DM, Bevere M, Espinet E … +3 more , Martineau Y, Giovannetti E, Sánchez-Arévalo Lobo VJ
Mol Cancer · 2026 Mar · PMID 41796340 · Full text
Pancreatic ductal adenocarcinoma (PDAC) continues to rank among the most lethal malignancies, with five-year survival rates stubbornly below 12%. Over the past decade and a half, transcriptomic analyses have consistently...
Pancreatic ductal adenocarcinoma (PDAC) continues to rank among the most lethal malignancies, with five-year survival rates stubbornly below 12%. Over the past decade and a half, transcriptomic analyses have consistently identified molecular subtypes - particularly the classical/progenitor (GATA6-high) and basal-like/squamous (GATA6-low) - that show clear associations with prognosis and treatment response. Yet, despite compelling biological rationale, the clinical adoption of these subtypes has been constrained by limited reproducibility, technical challenges, and practical barriers to implementation. Recent progress in multi-omics integration has deepened our understanding of subtype biology, while also exposing new layers of complexity in classification frameworks. A pivotal study demonstrated that a straightforward immunohistochemical assessment of GATA6 provides strong prognostic information in treatment-naive patients. However, it also underscored a critical challenge: therapy-induced molecular plasticity can compromise the reliability of static biomarkers. Advances in single-cell RNA sequencing and spatial transcriptomics have further clarified the cellular and microenvironmental dynamics underlying subtype heterogeneity, offering new insights on immune contexture and therapeutic stratification. In this review, we synthesize key developments in PDAC subtyping, critically examine translational hurdles, and propose a pragmatic roadmap for clinical implementation that prioritizes validated simplicity, contextual relevance, and real-world utility.
Machine learning model on multi-omics data enables risk stratification and identifies molecular heterogeneity and therapeutic targets in glioblastoma.
Zhang Z, Wang Z, Li R … +32 more , Pei D, Liu J, Qiu Y, Liu Z, Wang M, Ma Z, Duan W, Wang W, Yan J, Guo Y, Liu H, Li W, Yu Y, Chen T, Ma C, Yu M, Fu J, Su D, Li S, Geng H, Yu B, Zhen Y, Chen R, Sun Q, Zhao Y, Duan J, Zheng H, Liang D, Liu X, Li ZC, Ji Y, Yan D
Mol Cancer · 2026 Mar · PMID 41795092 · Full text
Multimodal data integration reveals causal features often missed by single-modality analyses, offering a more comprehensive view of glioblastoma (GBM) complexity. We collected radiomic, pathomic, genomic, transcriptomic,...
Multimodal data integration reveals causal features often missed by single-modality analyses, offering a more comprehensive view of glioblastoma (GBM) complexity. We collected radiomic, pathomic, genomic, transcriptomic, and proteomic data from patients with IDH-wild-type GBM to construct a machine learning–based risk stratification model. While sample sizes varied across modalities, 147 patients with complete data across all five omics layers were used for integrative analysis. This approach identified two clinically distinct subgroups. The low-risk group, linked to favorable outcomes, showed enhanced neurodevelopmental signatures, increased neuronal infiltration, and more oligodendrocytes. In contrast, the high-risk group, associated with poor prognosis, exhibited strong proliferative signals and hyperactive cell cycle pathways. Downstream multi-omics analysis identified PDIA4, EIF3I, and RFT1 as potential prognostic biomarkers and therapeutic targets in high-risk GBM. These findings underscore the utility of multimodal machine learning in refining prognostic models, characterizing tumor heterogeneity, and informing personalized treatment strategies.
Calibrating the RT-cGAS-STING axis to drive cold-to-hot tumor transformation: mechanistic foundations and translational strategies for combination with immunotherapy.
Kang YF, Chen JM, Xu BC … +8 more , Xu JN, Qin Q, Wu HL, Wang J, Wang RK, Wu YR, Tang WJ, Zeng YC
Mol Cancer · 2026 Mar · PMID 41794716 · Full text
Radiotherapy (RT) is a cornerstone of cancer therapy that exerts cytotoxic effects while also modulating anti-tumor immunity. RT-induced DNA damage can, under specific biological conditions, activate the cytosolic DNA se...
Radiotherapy (RT) is a cornerstone of cancer therapy that exerts cytotoxic effects while also modulating anti-tumor immunity. RT-induced DNA damage can, under specific biological conditions, activate the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) and its downstream stimulator of interferon genes (STING) pathway, eliciting type I interferon (IFN-I) responses and dendritic cell-mediated T-cell priming. This signaling is tightly regulated by TREX1-mediated DNA degradation, apoptotic caspases, and chromatin-bound nuclear DNA, resulting in heterogeneous immune outcomes. Notably, tumors with mismatch repair deficiency, such as MLH1 loss, exhibit pre-existing cGAS-STING activity, in which RT primarily amplifies innate sensing. However, even in this context, excessive or sustained STING activation may paradoxically induce immune tolerance, and the clinical application of STING agonists remains constrained by dose-limiting toxicities and delivery challenges. Here, we review the context-dependent interplay between RT and the cGAS-STING axis, highlighting mechanistic regulation, tumor genetics, and the tumor microenvironment. We propose strategies for precision calibration of RT and STING agonist delivery to enhance anti-tumor immunity, enable cold-to-hot tumor transformation, and guide rational combination with immunotherapy.
Targeting HSP90 in cancer: advances in the development of inhibitors, mechanisms of action, and therapeutic applications.
Wang X, Ni R, Wang X … +1 more , Li X
Mol Cancer · 2026 Mar · PMID 41792781 · Full text
Heat shock protein 90 (HSP90) serves as a central orchestrator of oncogenic protein homeostasis, empowering tumor progression, metastasis, and therapy resistance. However, the clinical translation of HSP90 inhibition has...
Heat shock protein 90 (HSP90) serves as a central orchestrator of oncogenic protein homeostasis, empowering tumor progression, metastasis, and therapy resistance. However, the clinical translation of HSP90 inhibition has been hampered by challenges such as intrinsic and acquired resistance, a lack of reliable biomarkers, and the toxicity associated with pan-inhibitors. This review comprehensively dissects these challenges and presents the evolving landscape of strategies to overcome them. We systematically catalog the development of over 20 representative HSP90 inhibitors, from classical N-terminal ATP-competitive agents to novel C-terminal and middle-domain binders, highlighting their distinct mechanisms and the rise of subtype-selective compounds designed to enhance therapeutic windows. Beyond monotherapy, we emphasize the paradigm shift towards combination regimens, detailing synergistic effects with chemotherapy, targeted agents, and immunotherapies that resensitize tumors to treatment. Critically, we explore the diagnostic frontier, reviewing how radiolabeled HSP90 inhibitors (e.g., [¹²⁴I]PU-H71 and [¹⁸F]San A derivatives) enable non-invasive tumor detection and patient stratification through positron emission tomography (PET). Finally, we chart the future course of the field, underscoring how precision medicine approaches—guided by biomarker identification and liquid biopsy—coupled with nanotechnology-driven delivery systems, are poised to unlock the full potential of HSP90-targeted cancer theranostics. This synthesis provides not only a mechanistic overview but also a strategic roadmap for the next generation of HSP90-directed oncology research.
Multi-omics profiling reveals divergent biology and liver microenvironment in HCC of metastatic and de novo origin.
Boot GF, Haak F, Coto-Llerena M … +16 more , Boldanova T, Dazert E, Sedlaczek P, Rosenberger G, Esposito C, Ercan C, Wieland S, Renne SL, Benjak A, Matter MS, Di Tommaso L, Hall MN, Terracciano LM, Heim MH, Piscuoglio S, Ng CKY
Mol Cancer · 2026 Mar · PMID 41792761 · Full text
BACKGROUND: Multifocal hepatocellular carcinoma (mfHCC) arises via intrahepatic metastasis (IM) or multicentric occurrence (MO), each with distinct biological behavior and clinical implications, though mfHCC origin is ra...
BACKGROUND: Multifocal hepatocellular carcinoma (mfHCC) arises via intrahepatic metastasis (IM) or multicentric occurrence (MO), each with distinct biological behavior and clinical implications, though mfHCC origin is rarely assessed in clinical practice. We aimed to characterize the clinicopathological and molecular features of IM-HCC, MO-HCC, and their surrounding non-tumor liver (NTL) tissues using multi-omics analyses. METHODS: We analyzed 76 tumor and 44 NTL biopsies from 22 patients, using whole-exome sequencing, RNA-sequencing, and proteomic/phosphoproteomic profiling. Patients were classified as IM, MO or mixed (IM + MO) according to their somatic mutations. A comparator cohort of 48 unifocal HCC and 15 normal livers was used. Clinicopathological parameters, pathway and transcription factor activities, immune infiltration, and targetable alterations were assessed. RESULTS: Clonality analysis identified 10 IM, 9 MO, and 3 mixed patients. IM-HCCs showed more frequent macrovascular invasion and extrahepatic metastases, with upregulation of E2F/MYC-related cell cycle pathways, higher expression of metastasis-associated genes (e.g., TTK, BUB1, NUF2), higher CD8 + T-cell exhaustion, and shared actionable mutations (e.g. PTEN). MO-HCCs within patients displayed molecular dissimilarity comparable to tumors from different patients, though they also showed convergent kinase and pathway dysregulation. NTLs of IM-HCC patients had lower fibrosis, extracellular matrix signaling and pro-regenerative pathways (e.g., SOX2, TGFA) than those of MO-HCC. CONCLUSIONS: The aggressive molecular features and immune exhaustion of IM-HCC support the need for combined therapies, while the convergence of kinase and pathway dysregulation of MO-HCC provides unified therapeutic opportunities. Key differences in fibrogenic and regenerative pathways may influence metastatic potential. Our findings provide insights into the biological behavior and therapeutic opportunities in mfHCC.
KDM5B-driven glucose metabolic reprogramming promotes enzalutamide resistance in prostate cancer via the lactate/hnRNPA1 lactylation/AR-V7 axis.
Sun R, Huang Y, He H … +20 more , Li Q, Wang L, Zhang G, Wei Z, Cao Y, Li J, Wang X, Yang F, Chen W, Li X, Yu J, Liu S, Lei C, Jiang Y, Peng Y, Su H, Gao Y, He W, Yang L, Liu J
Mol Cancer · 2026 Mar · PMID 41787526 · Full text
AIMS: Resistance to enzalutamide (Enza) in castration-resistant prostate cancer (CRPC) is linked to poor prognosis. While KDM5B is highly expressed in Enza-resistant CRPC, the mechanisms of resistance remain poorly under...
AIMS: Resistance to enzalutamide (Enza) in castration-resistant prostate cancer (CRPC) is linked to poor prognosis. While KDM5B is highly expressed in Enza-resistant CRPC, the mechanisms of resistance remain poorly understood. METHODS: We applied an integrated approach to study KDM5B using bioinformatics analyses of single-cell and multi-omics data, along with in vitro and in vivo validation. We explored mechanisms through lactylation proteomics, CRISPR/Cas9 editing, ChIP, and dual-luciferase reporter assays. RESULTS: KDM5B induces Enza resistance by epigenetically suppressing PTEN, which in turn activates the PI3K/Akt signaling pathway to upregulate PGK1 and drive metabolic reprogramming and lactate production. Lactate acts as a substrate for p300-mediated lactylation of hnRNPA1 at lysine 179 (K179), stabilizing hnRNPA1 by blocking NEDD4L-mediated ubiquitination and promoting AR-V7 splicing. A potential positive feedback loop enhances this effect: KDM5B activates AR, and AR, in turn, increases KDM5B expression. Inhibiting KDM5B or p300 can reverse Enza resistance in vivo. CONCLUSIONS: We identify a mechanism linking metabolism, epigenetics, and a KDM5B/AR feedback loop in drug resistance. These findings suggest that multi-target strategies may represent a promising approach to overcome Enza resistance in CRPC.
Micropeptide YG-6 encoded by exosomal LINC01123 derived from highly migratory ovarian cancer cells promotes tumor progression.
Lei H, Zhou Z, Li C … +9 more , Fan L, Wu Q, Wang M, Guo K, Pan Q, Mor G, Shu G, Li J, Yin G
Mol Cancer · 2026 Mar · PMID 41787522 · Full text
BACKGROUND: Intercellular crosstalk plays a pivotal role in tumor progression and metastasis. Exosomes can package long non-coding RNAs (lncRNAs) to mediate extracellular communication. Although exosome research in vario...
BACKGROUND: Intercellular crosstalk plays a pivotal role in tumor progression and metastasis. Exosomes can package long non-coding RNAs (lncRNAs) to mediate extracellular communication. Although exosome research in various cancers has made remarkable progress, it remains unclear in ovarian cancer (OC) whether the cellular communication between OC cells with different metastatic potentials influences progression via exosomal-lncRNA. Besides, lncRNA can encode functional micropeptides, yet the association between OC and micropeptides encoded by exosomal-derived lncRNA has not been reported. METHODS: OC cell-derived exosomes were characterized using transmission electron microscopy, nanoparticle tracking analysis, and WB. Exosomal lncRNA sequencing results of highly migratory OC cells (HMOs) and low migratory OC cells (LMOs) were analyzed, and LINC01123 was selected for further study. The effect of exosome LINC01123 on the function of LMOs was detected by the co-culture experiment. Bioinformatics prediction, mass spectrometry (MS), WB, and a series of functional experiments showed that LINC01123 encodes a small 59 aa peptide, named YG-6 (LINC01123 Yield peptide Gaining metastasis function: ORF no.6). Immunofluorescence, qPCR, WB, immunohistochemistry, and MS analysis were used to detect the endogenous expression of YG-6 in OC cells and tissues. The function of YG-6 in OC was investigated by detecting cell migration ability and observing tumor metastasis in nude mice. Mechanistically, the relationship between the YG-6 and ACTC1 in OC was verified by Co-Immunoprecipitation, WB, MS, immunofluorescence, and functional experiment. RESULTS: LINC01123 was significantly up-regulated in exosomes derived from HMOs and was readily internalized by LMOs, promoting their malignant behavior. Interestingly, LINC01123 encodes a small peptide composed of 59 amino acids, named YG-6, which exhibits endogenous high expression in OC cells and tissues. Functional experiments demonstrated that LINC01123 promotes tumor progression by encoding the peptide YG-6, rather than via an RNA-dependent mechanism. Furthermore, we identified ACTC1 as a binding protein of YG-6, which can synergistically activate the focal adhesion signaling pathway together with YG-6, thereby promoting the migration and adhesion of LMOs. CONCLUSIONS: Our findings not only demonstrate the YG-6 peptide encoded by LINC01123 as a potential prognostic biomarker for OC but also uncover a new mechanism of OC progression driven by YG-6 peptides.
LncRNA NEAT1 promotes immunosuppression in gastric cancer under endoplasmic reticulum stress by maintaining the MA methylation of SEMA3A in CAFs.
Xu Y, Xu R, Chen Z … +10 more , Zhou H, Liao J, Ji K, Yang S, Zhong X, Li Y, Xi D, Zhang Q, Zhao L, Zuo Q
Mol Cancer · 2026 Mar · PMID 41782001 · Full text
BACKGROUND: Despite PD1 inhibitors offering new gastric cancer therapies, disease burden persists. Cancer-associated fibroblasts were found to be important in gastric cancer regarding tumor promotion and immunosuppressio...
BACKGROUND: Despite PD1 inhibitors offering new gastric cancer therapies, disease burden persists. Cancer-associated fibroblasts were found to be important in gastric cancer regarding tumor promotion and immunosuppression, but its role in gastric cancer under endoplasmic reticulum stress remained unknown. METHODS: We conducted mass spectrometry in cancer-associated fibroblasts and transcriptomic-seq in exosomes from gastric cancer, combined with single-cell RNA sequencing analysis and spatial transcriptome sequencing analysis in gastric cancer to uncover the cellular crosstalk. Endoplasmic reticulum stressed models were established, and the isolation of primary cells and exosomes were used to uncover the communication between gastric cancer cells and cancer-associated fibroblasts. RNA pull-down, RIP-qPCR, flow cytometry detection and ELISA were used to demonstrate the interaction and immunity function in gastric cancer under endoplasmic reticulum stress. Moreover, we developed αvβ3-targeted cationic liposomes delivering siRNA of lncRNA NEAT1 towards tumor cells in gastric cancer in vivo. RESULTS: We found m6A protein METTL3, SEMA3A and lncRNA NEAT1, which interacts with METTL3, were highly expressed in cancer-associated fibroblasts under endoplasmic reticulum stress. Endoplasmic reticulum stress stimulation enhanced exosome secretion from gastric cancer cells and significantly elevated the expression of lncRNA NEAT1 in cancer-associated fibroblasts. LncRNA NEAT1 upregulated METTL3 in CAFs, which resulted in the enhanced m6A methylation of SEMA3A mRNA and amplified Treg-mediating immunosuppression. The combination therapy of siNEAT1@Lip-cRGD and anti-PD1 boosted T-cell infiltration and suppressed tumor growth in vivo. CONCLUSIONS: Our study unveiled the lncRNA NEAT1/METTL3/SEMA3A axis stimulated by endoplasmic reticulum stress that sustained gastric cancer immunosuppression, providing a rationale for targeting this pathway to improve immunotherapy efficacy.
Autophagy in cancer-associated fibroblasts: its role in gastrointestinal cancers.
Kuppala V, Chintapudi H, Kovuru G … +2 more , Nagaraju GP, El-Rayes BF
Mol Cancer · 2026 Mar · PMID 41781963 · Full text
Gastrointestinal (GI) cancers are a heterogeneous group of cancers with high morbidity and mortality rates. Despite advancements in early detection markers and therapy, the outcome remains poor due to high tumor heteroge...
Gastrointestinal (GI) cancers are a heterogeneous group of cancers with high morbidity and mortality rates. Despite advancements in early detection markers and therapy, the outcome remains poor due to high tumor heterogeneity and metastasis. The microenvironment (ME) in GI cancers is highly dynamic and enriched with immune and endothelial cells, extracellular matrix (ECM), and stromal components, including cancer associated fibroblasts (CAFs), which play an essential role in tumor progression. CAFs modulate tumor progression through extensive crosstalk with cancer cells, immune cells, and ECM remodeling. CAFs secrete cytokines, growth factors, and exosomes that modulate tumor progression, epithelial to mesenchymal transition, angiogenesis, immune tolerance, and therapy resistance. By remodeling the ECM, CAFs create a protumorgenic microenvironment through the activation of key signaling pathways such as YAP/TAZ and integrin/FAK. CAFs are also heterogeneous, with diverse subsets exhibiting context-dependent pro- or anti-tumor function, as discussed in this review. Autophagy is a process that removes damaged cellular components to maintain homeostasis. In the early stage of cancer, autophagy suppresses tumor progression. Still, in the later stages of tumors, CAFs support survival, metabolic alterations, therapy resistance, and immune evasion, as such are regulated by signals like TGF-β/IL-6/ROS and pathways including AMPK/STAT3/NF-κB/SMAD and mTOR. The review discusses CAFs and modulation of autophagy in GI cancer progression, metastasis, and resistance to therapy. CAFs remodel the ME and induce immune tolerance, while autophagy in both cancer cells and CAFs allows survival under stress. By showing these interconnected mechanisms, the review identifies CAF autophagy as a critical therapeutic target to overcome resistance in GI cancers.
Correction: N6‑methyladenosine‑modified TRAF1 promotes sunitinib resistance by regulating apoptosis and angiogenesis in a METTL14‑dependent manner in renal cell carcinoma.
Chen Y, Lu Z, Qi C … +15 more , Yu C, Li Y, Huan W, Wang R, Luo W, Shen D, Ding L, Ren L, Xie H, Xue D, Wang M, Ni K, Xia L, Qian J, Li G
Mol Cancer · 2026 Mar · PMID 41776635 · Full text
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m6A-dependent translation of circPICALM encodes a novel metastasis-promoting oncoprotein in intrahepatic cholangiocarcinoma.
Li H, Wang S, Dai F … +13 more , Liu H, Zhang C, Liu M, Wang Y, Xiang L, Zhang X, Shen A, Wang Y, Wu N, Zhou H, Wang G, Wu Y, Li D
Mol Cancer · 2026 Mar · PMID 41776633 · Full text
BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive liver cancer with a poor prognosis and rapid metastatic potential. Although circular RNAs (circRNAs) have emerged as important regulators in cancer...
BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive liver cancer with a poor prognosis and rapid metastatic potential. Although circular RNAs (circRNAs) have emerged as important regulators in cancer biology, their translational potential and mechanistic contributions to ICC metastasis remain largely unexplored. METHODS: CircRNA-seq was performed on paired primary and recurrent ICC tissues to identify the differentially expressed circRNAs. Mass spectrometry and functional assays were used to characterize the novel protein encoded by circPICALM. The molecular mechanisms and biological functions of circPICALM and its encoded proteins were evaluated using in vitro and in vivo models, respectively. RESULTS: CircPICALM is significantly upregulated in recurrent ICC tumors and is associated with poor patient prognosis. Its biogenesis and expression are regulated by N6-methyladenosine (m6A) modifications within the introns flanking the circulating exons, facilitated by the m6A reader protein YTHDC1. Additionally, the RNA-binding protein, DEAD-box helicase 3 (DDX3), promotes circPICALM accumulation. Importantly, circPICALM encodes a novel protein, circPICALM-219aa, that drives ICC metastasis. Mechanistically, circPICALM-219aa disrupted the inhibitory interaction between SOCS3 and STAT3 by directly binding to both proteins. This interference alleviates SOCS3-mediated suppression of JAK activity and enhances IL-6/JAK/STAT3 signaling. Silencing circPICALM-219aa expression significantly suppressed the activation of this signaling pathway and metastatic potential. CONCLUSIONS: This study identified circPICALM-219aa as a novel oncoprotein translated from an m6A-modified circRNA, and a key driver of ICC metastasis. Our findings uncover a previously unrecognized mechanism of m6A-mediated circRNA translation in ICC and highlight circPICALM-219aa as a promising therapeutic target for improving patient outcomes.
Spatiotemporal dynamics of radioresistance: decoding macrophage-driven radioprotective niches through temporal-spatial reprogramming.
Zhang M, Zhang X, Song X … +4 more , Bai R, Qiao Q, Wei M, Zhao L
Mol Cancer · 2026 Mar · PMID 41776613 · Full text
Within the intricate tumor microenvironment (TME), tumor-associated macrophages (TAMs) engage in dynamic cross-communication with neighboring cellular and acellular components, orchestrating dual pro- and anti-tumorigeni...
Within the intricate tumor microenvironment (TME), tumor-associated macrophages (TAMs) engage in dynamic cross-communication with neighboring cellular and acellular components, orchestrating dual pro- and anti-tumorigenic programs, including tumor proliferation, immune suppression, angiogenesis, extracellular matrix remodeling, and metabolic reprogramming. Radiotherapy, while inducing direct tumoricidal effects, paradoxically triggers vascular injury and inflammatory cascades that recruit and reprogram TAM populations. These radiation-educated TAMs subsequently establish therapy-resistant niches through multifaceted mechanisms, driving post-radiation tumor recurrence and treatment failure. Emerging evidence highlights that TAM polarization states critically determine therapeutic outcomes in both standalone radiotherapy and combination regimens with immunotherapy. However, translating TAM-targeting strategies into clinical practice faces substantial biological and technical challenges.In this review, we systematically analyze the spatial-temporal mechanisms underlying radiotherapy-induced TAM recruitment and radioresistance development, with particular emphasis on their bidirectional interactions with tumor cells, immune effectors, hypoxic niches, and stromal cells. Specifically, we map the therapeutic landscape by evaluating promising targets for TAM reprogramming in combination with radiotherapy and/or immune checkpoint blockade. Furthermore, we critically appraise emerging technologies for TAM manipulation in the radioimmunotherapy context, including nanotheranostics and novel therapeutic approaches. Finally, we discuss unresolved mechanistic questions, translational barriers, and strategic opportunities for developing personalized combination therapies that leverage TAM biology to overcome radioresistance. This synthesis provides a conceptual framework for rationally designing next-generation radiosensitization strategies grounded in TME immunomodulation.
An exosome-based liquid biopsy to predict molecular residual disease for the identification of high-risk patients with stage II-III colorectal cancer: the CLEAR study.
Miyazaki K, Montcusí B, Morine Y … +9 more , Okuno K, Pascual M, Tokunaga T, Noma T, Kinugasa Y, Shimada M, Cai G, Pera M, Goel A
Mol Cancer · 2026 Mar · PMID 41776599 · Full text
BACKGROUND: Exosomal miRNAs have drawn increasing attention in the field of liquid biopsy owing to their high degree of cancer specificity and stability. This study aimed to establish an exosome-based liquid biopsy signa...
BACKGROUND: Exosomal miRNAs have drawn increasing attention in the field of liquid biopsy owing to their high degree of cancer specificity and stability. This study aimed to establish an exosome-based liquid biopsy signature to predict molecular residual disease (MRD) in stage II and III colorectal cancer (CRC). METHODS: We analyzed 175 postoperative serum samples from stage II and III CRC patients from 2 independent institutions, performed quantitative reverse-transcription polymerase chain reaction, and developed and validated a risk-stratification model using logistic regression. RESULTS: We first evaluated the expression of the 8 miRNAs identified in our previous tissue-based study in exosomes, and found that 5 of 8 were significantly downregulated in the recurrent group. A panel of 5 miRNAs robustly predicted recurrence after surgery in a training cohort (area under the curve [AUC]: 0.83). Subgroup analysis of the adjuvant chemotherapy (ACT) naïve group demonstrated that recurrence rates were 3.1% (1/32) in the low-risk group and 64.7% (11/17) in the high-risk group. We successfully validated the performance of this exosomal miRNA panel in an independent testing cohort (AUC: 0.77). Furthermore, when we developed our risk model, named Clinical Liquid Biopsy via Exosomes for Assessment of Molecular Residual Disease in Colorectal Cancer Score (CLEAR score), by adding tumor factor and stage to the panel, predictive accuracy was dramatically improved (AUC: 0.84). CONCLUSIONS: We have developed an exosome-based liquid biopsy signature that enables robust detection of MRD in patients with stage II-III CRC. These findings could help facilitate more informed clinical decision-making for ACT. TRIAL REGISTRATION: NCT06654622.
Orosomucoid 2 promotes colorectal cancer liver metastasis by suppressing natural killer cell-mediated antitumor immunity by remodeling the serine and one-carbon metabolism pathway.
Zhou J, He X, Xiang Z … +7 more , Wang M, Xu W, Wang Y, Chen Y, Zhang T, Wang L, Mao A
Mol Cancer · 2026 Mar · PMID 41776586 · Full text
BACKGROUND: The liver is the most common site of distant metastasis in colorectal cancer (CRC), and liver metastasis (LM) remains the leading cause of CRC-related mortality. The immune microenvironment plays a crucial ro...
BACKGROUND: The liver is the most common site of distant metastasis in colorectal cancer (CRC), and liver metastasis (LM) remains the leading cause of CRC-related mortality. The immune microenvironment plays a crucial role in regulating LM progression, but the key molecular drivers involved in its remodeling remain poorly understood. METHODS: We performed an in vivo CRISPR-Cas9 screen in a murine model of colorectal cancer liver metastasis (CRLM) to identify key regulators of metastatic colonization. In vitro and in vivo functional studies were conducted to evaluate the role and mechanisms of ORM2 in modulating CRLM. RESULTS: We identified orosomucoid 2 (ORM2) as a top candidate whose knockout markedly suppressed CRLM. Clinically, ORM2 expression was significantly upregulated in CRLM tissues and correlated with poor patient prognosis. Genetic ablation of ORM2 significantly reduced LM in vivo. Mechanistically, the pro-metastatic role of ORM2 was dependent on natural killer (NK) cells. Further analyses revealed that ORM2 interacts with activin A receptor type 1 (ACVR1) to activate the Hippo signaling pathway, leading to the suppression of serine and one-carbon metabolism, a key pathway for NK cell cytotoxic function. CONCLUSIONS: Our findings uncover a novel immunometabolic mechanism by which tumor-derived ORM2 promotes immune evasion and liver metastasis in CRC. Targeting the ORM2–ACVR1 axis may offer a promising therapeutic strategy for CRLM.
Clonal dynamics shaped by diverse drug-tolerant persister states in melanoma resistance.
Li H, Chen Y, Kaster J … +30 more , Dunne M, Xiao M, Li L, Thomas M, Promi N, Fingerman D, Brown GS, Zheng Q, Zhu X, Reale M, Patterson A, Gao L, Zhang X, Jiang S, Hu T, Fang H, Ren J, Qi C, Wang L, Mou H, Thacker G, Salazar ER, Villanueva J, Raj A, Hoon DS, Bin T, Madzo J, Wei Z, Auslander N, Herlyn M
Mol Cancer · 2026 Mar · PMID 41776501 · Full text
BACKGROUND: Most advanced melanomas initially respond to targeted therapy but eventually relapse. Increasing evidence suggests that drug-tolerant persister cells can adopt a reversible drug-refractory state and represent...
BACKGROUND: Most advanced melanomas initially respond to targeted therapy but eventually relapse. Increasing evidence suggests that drug-tolerant persister cells can adopt a reversible drug-refractory state and represent a key driver of therapeutic resistance. METHODS: We developed MeRLin, a lineage tracing platform that integrates cellular barcoding, single-cell transcriptomic profiling, RNA fluorescence in situ hybridization, and computational analyses to track clonal and transcriptional dynamics in a patient-derived melanoma model during prolonged targeted therapy. Longitudinal analyses enabled the characterization of clonal fates, transcriptional states, and spatial organization of persister populations. RESULTS: Clonal dynamics showed that persister subpopulations initially responded to therapy, persisted through minimal residual disease, and expanded during tumor recurrence. Four persister-associated transcriptional states characterized by stress-like, lipid metabolism, PI3K signaling, and extracellular matrix remodeling programs were associated with persister populations arising from minor pre-treatment subpopulations under sustained drug pressure. Spatial transcriptomic analyses revealed structured spatial organization of these programs and suggested coordinated autocrine and paracrine interactions among persister states. Targeted barcode RNA fluorescence in situ hybridization enabled spatial mapping of clonal identity and gene expression, revealing in situ co-localization of a dominant resistant clone marked by SLC2A1 expression. CONCLUSIONS: Together, MeRLin provides a robust framework for dissecting cancer heterogeneity and characterizing persister subpopulations. Our findings demonstrate that melanoma recurrence is associated with diverse, spatially organized persister states linked to adaptive transcriptional programs.
Artificial intelligence models: transforming early diagnosis and precise treatment of gastrointestinal cancers.
Liu K, Luo Z, Zhang W … +8 more , Pan Q, Su X, Yang Z, Zhang Q, Wang B, Tang B, He Z, Guo J
Mol Cancer · 2026 Mar · PMID 41772662 · Full text
Artificial intelligence (AI) has become an integral force in the clinical landscape of gastrointestinal (GI) oncology. Recent advances in model architectures ranging from traditional machine learning and convolutional ne...
Artificial intelligence (AI) has become an integral force in the clinical landscape of gastrointestinal (GI) oncology. Recent advances in model architectures ranging from traditional machine learning and convolutional neural networks (CNNs) to transformer-based foundational models and graph neural networks (GNNs) have enabled the extraction of complex features from diverse data modalities, including endoscopic images, radiology, pathology whole-slide images, and multi-omics profiles. In this review, AI models are systematically classified into supervised learning, unsupervised clustering, multimodal fusion, and interpretable modeling. The advantages of each model are delineated in unravelling tumor heterogeneity, anatomical characteristics, and treatment-relevant biomarkers. Furthermore, three types of clinical application are emphasized: (1) early screening and lesion localization via segmentation or anomaly detection; (2) molecular subtyping and patient stratification for diagnosis with risk assessment; (3) therapy guidance through response prediction and personalized treatment planning. We also discuss major challenges on the application of AI in integration of heterogeneous clinical data, model generalizability across centers, and the interpretability of predictions. Collectively, this review highlights the transformative potential of AI in better understanding tumor biology and its clinical value in advancing personalized medicine for GI cancer patients.
ATP synthasome contributes to efficient energy flux in malignant breast cancer.
Tzeng YT, Kang YT, Hsiao TH … +12 more , Chu PY, Yong SB, Lin SC, Wu MY, Tseng LM, Hou MF, Wen ZH, Hsu TS, Hung CC, Chiang AJ, Tsui KH, Li CJ
Mol Cancer · 2026 Mar · PMID 41772583 · Full text
BACKGROUND: This study investigates the metabolic alterations associated with breast cancer progression and elucidates the underlying mechanisms. Adenine nucleotide translocase 2 (ANT2), a mitochondrial protein essential...
BACKGROUND: This study investigates the metabolic alterations associated with breast cancer progression and elucidates the underlying mechanisms. Adenine nucleotide translocase 2 (ANT2), a mitochondrial protein essential for cellular energy metabolism, facilitates the exchange of ADP and ATP across the inner mitochondrial membrane. The role of ANT2, particularly its interaction with the ATP synthasome, in breast cancer metastasis remains poorly understood. METHODS: We analyzed ANT2 in breast cancer using genetic and clinical methods, validating its expression in human tissues. Gene enrichment studies and functional assays assessed ANT2’s role in mitochondrial function and cancer metabolism. Knockdown experiments and pharmacogenomic screening evaluated ANT2’s impact on metastasis and identified potential inhibitors in 3D cultures and orthotopic mouse models. RESULTS: ANT2 was significantly overexpressed in metastatic breast cancer, correlating with reduced survival. Knockdown of ANT2 impaired cell migration and invasion, reduced ATP production, and diminished oxidative phosphorylation (OXPHOS) activity in MCF7-F4 cells. In vivo, siRNA-mediated ANT2 silencing in JC-M3 cells decreased tumor growth and lung metastases in mice. Pharmacogenomic analysis identified cymarin as an ANT2 inhibitor, reducing spheroid formation in 3D cultures and tumor burden in vivo, alongside downregulation of epithelial-to-mesenchymal transition (EMT) and OXPHOS markers. ANT2 colocalized with ATP5B, forming an ATP synthasome that enhanced energy flux in hyperinvasive cells. CONCLUSIONS: ANT2 drives breast cancer metastasis by enhancing mitochondrial energy production via the ATP synthasome. Its inhibition, particularly with cymarin, disrupts tumor bioenergetics and metastatic potential, positioning ANT2 as a promising therapeutic target.
IGF2BP3 promotes progression of head and neck cancers through the circHECTD2/hsa_miR_4310/7157-5p/Smad2 signaling axis in an mA modification-dependent manner.
Wu K, Chang F, Peng T … +18 more , Wang S, Sun X, Wang Y, Li Z, Duan C, Li J, Zhang Y, Su T, Li W, Wei D, Cao S, Liu J, Fang J, Chen L, Li G, Gross N, Zhao J, Lei D
Mol Cancer · 2026 Mar · PMID 41765878 · Full text
BACKGROUND: Accumulating evidence indicates that N6-methyladenosine (m6A) modification of circular RNAs (circRNAs) plays a pivotal role in regulating cancer progression. However, in head and neck squamous cell carcinoma...
BACKGROUND: Accumulating evidence indicates that N6-methyladenosine (m6A) modification of circular RNAs (circRNAs) plays a pivotal role in regulating cancer progression. However, in head and neck squamous cell carcinoma (HNSCC), the biological functions and underlying mechanisms of m6A modification in circRNAs remain insufficiently elucidated. METHODS: In this study, we analyzed the association between the expression of IGF2BP3—an upstream m⁶A reader—and clinical outcomes of HNSCC patients, followed by investigating the interaction between IGF2BP3 and circHECTD2 as well as the effect of m⁶A modification on this interaction. Additionally, we explored the molecular mechanism by which IGF2BP3 and circHECTD2 regulate HNSCC progression, focusing on their roles in modulating microRNAs (miRNAs) and target mRNAs, and validated the functional impacts of the IGF2BP3/circHECTD2 axis on HNSCC cell proliferation, invasion, and metastasis. RESULTS: We found high expression of the m⁶A reader IGF2BP3 was significantly associated with poor clinical outcomes in HNSCC patients. Further experiments showed that IGF2BP3 directly bound to circHECTD2 and stabilized it, and m⁶A modification of circHECTD2 enhanced this binding and stabilization effect. Mechanistically, circHECTD2 functioned as a competing endogenous RNA (ceRNA) to sponge hsa-miR-4310 and hsa-miR-7157-5p, thereby preventing the miRNA-mediated degradation of SMAD2 mRNA. Ultimately, the IGF2BP3/circHECTD2/SMAD2 axis was shown to promote HNSCC cell proliferation, invasion, and metastasis. CONCLUSION: We delineate an m6A-dependent IGF2BP3/circHECTD2/SMAD2 regulatory axis that contributes to HNSCC malignancy. Elevated IGF2BP3 expression correlates with poor patient outcome and enhances circHECTD2 stability through m6A-facilitated binding; circHECTD2 in turn acts as a ceRNA to sequester hsa-miR-4310 and hsa-miR-7157-5p, thereby maintaining SMAD2 expression. Functionally, this axis promotes HNSCC cell proliferation, invasion and metastasis. Collectively, these findings suggest that IGF2BP3 and circHECTD2 may serve as promising prognostic biomarkers and therapeutic targets for HNSCC.
Integrated single-cell and spatial transcriptomic profiling decodes lineage plasticity and immune microenvironment remodeling in prostate cancer progression.
Yu H, Wang Y, He M … +4 more , Chen Y, Bi J, Lin X, Cui X
Mol Cancer · 2026 Feb · PMID 41764551 · Full text
This study presents a comprehensive single-cell and spatial transcriptomic atlas of prostate cancer progression, integrating 127 single-cell RNA sequencing samples and 9 spatial transcriptomics profiles spanning the dise...
This study presents a comprehensive single-cell and spatial transcriptomic atlas of prostate cancer progression, integrating 127 single-cell RNA sequencing samples and 9 spatial transcriptomics profiles spanning the disease continuum from healthy prostate to neuroendocrine carcinoma. Our analysis defines four evolutionarily connected malignant epithelial subtypes: luminal-identity (sub1), stress-adaptive luminal (sub2), neuroendocrine (sub3), and a double-negative basal-like state (sub4). We identify FOSL1 as a key driver of lineage plasticity through direct transcriptional regulation of HMGA1, promoting treatment resistance via enhanced proliferation, EMT and stemness. The tumor microenvironment undergoes coordinated reprogramming during progression, with neoadjuvant hormone therapy inducing distinct cellular responses: FOLR2 + and CX3CR1 + TAMs upregulate TGF-β signaling to establish immunosuppressive niches, while CXCL12 + iCAFs and ACTA2 + myCAFs maintain spatial co-localization and facilitate immune cell recruitment. Spatial analyses reveal enhanced chemokine signaling post-therapy, particularly in specific TAM subsets, driving increased but functionally impaired lymphoid infiltration characterized by T-cell exhaustion and regulatory T-cell expansion. This integrated analysis establishes a unified paradigm connecting epithelial plasticity with microenvironmental reprogramming, revealing FOSL1-HMGA1 signaling and macrophage-driven immunosuppression as promising therapeutic targets for advanced prostate cancer.
MCM10, a novel YAP1/TEAD4 target, drives gastric cancer progression by bridging DNA replication to stemness acquisition.
Xie F, Leung HW, Lyu Y … +32 more , Yu P, Feng T, Chen B, Wu J, Tham J, Fang C, Cheung AHK, Chow C, Jiang J, Hu J, Zhang F, Zhu C, Zhong K, Sun M, Zhang G, Yu S, Xu D, Wang S, Huang B, Zhuang K, Luo X, Li A, Guo Q, Gao C, Zhang B, Ma Y, Wu WK, An L, Wong CC, Yu J, To KF, Kang W
Mol Cancer · 2026 Feb · PMID 41761192 · Full text
OBJECTIVES: Gastric cancer (GC) remains a major global health challenge, with chemotherapy resistance significantly hindering treatment efficacy. A significant proportion of chemotherapeutics impact DNA replication, yet...
OBJECTIVES: Gastric cancer (GC) remains a major global health challenge, with chemotherapy resistance significantly hindering treatment efficacy. A significant proportion of chemotherapeutics impact DNA replication, yet the mechanisms by which tumors evade this lethality remain incompletely understood. Notably, minichromosome maintenance 10 replication initiation factor (MCM10) is pivotal in initiating DNA replication, holding promise in mediating acquired chemotherapy resistance. This work aims to elucidate the driving roles of MCM10 GC pathogenesis and chemotherapeutic resistance. METHODS: The expression pattern of MCM10 and its clinical relevance in GC patients were investigated by adopting single-cell RNA-seq data and in-house GC tissue microarray. Functional roles were evaluated through bioinformatic analyses and experimental assays, including in vivo xenograft formation assay and patient-derived organoid (PDO) models. The transcriptional regulation of MCM10 by the YAP1-TEAD4 complex was examined via Yap1−/−;Taz−/− transgenic mice models and functional rescue assays. Candidates for targeting MCM10 were predicted by virtual screening and further validated by cellular thermal shift assay (CETSA). RESULTS: MCM10 was the most upregulated MCM family member in GC cell lines, and its elevated levels correlated with poor patient prognosis. Bioinformatic analysis linked MCM10 to DNA replication and DNA damage repair, a finding confirmed by functional assays showing that MCM10 depletion induced DNA damage accumulation and impaired DNA replication. MCM10 was further proven to promote GC cell malignancy and tumorigenesis by activating Wnt/β-catenin signaling in GC cell lines, clinical samples, and xenograft models. Critically, MCM10 conferred resistance to chemotherapeutic agents by enhancing cancer cell stemness acquisition and DNA damage response. Mechanistically, YAP1/TEAD4 was identified as the transcriptional activator of MCM10, as TEAD4 silencing downregulated MCM10. TEAD4 overexpression failed to rescue the tumor-suppressing effects in MCM10-depleted cells. Furthermore, Momordin Ic was identified as a promising MCM10-targeted inhibitor, which effectively attenuated GC cell malignancy and chemoresistance. CONCLUSION: MCM10 drives gastric tumorigenesis by enhancing DNA replication and maintaining cancer stemness, positioning it as a key mediator of YAP1-TEAD4 oncogenic signaling. These findings establish MCM10 as a promising therapeutic target to overcome chemotherapy resistance in GC.
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