Neoplasia最新文献

{"title":"Microbe-associated molecular patterns differentially mediate carcinogenic alterations of the breast tissue in the context of obesity","authors":"Mohamed Gaber ,&nbsp;Lauren M. Moulden ,&nbsp;Adam S. Wilson ,&nbsp;Valerie Payne ,&nbsp;Julia Holmes ,&nbsp;Kayla Neary ,&nbsp;Abigail Peoples ,&nbsp;Mary L. Duet ,&nbsp;Adam J. Katz ,&nbsp;Pierre-Alexandre Vidi ,&nbsp;Katherine L. Cook","doi":"10.1016/j.neo.2026.101284","DOIUrl":"10.1016/j.neo.2026.101284","url":null,"abstract":"<div><div>Obesity is a risk factor for breast cancer. Obesity alters the microbiome and microbiome perturbations are reported in breast cancer patients. Yet, the impact of obesity-mediated microbial shifts on breast cancer risk remains unclear. Here, we investigate the effect of microbial-associated molecular pattern (MAMP) signaling on genome instability and inflammation. We show in human samples that obesity chronically elevates breast tissue levels of two MAMPs: lipopolysaccharide (LPS) and flagellin. In contrast, obesity was not associated with chronic elevations in lipoteichoic acid (LTA). Injections of LPS and flagellin in mouse mammary glands (MG) were sufficient to induce DNA damage and inflammation. Moreover, DNA damage was reduced in MG of animals on a high-fat diet by knockdown of toll-like receptors for LPS and flagellin (TLR4 and TLR5), but not TLR2 (LTA receptor). Experiments with breast acini cultures demonstrated LPS and flagellin (but not LTA) induce DNA double-strand breaks via TLR and reactive oxygen species (ROS) generation. Similarly, LPS and flagellin mediated nuclear factor-kappa B (NF-κB) pathway activation and increased expression of inflammatory cytokines. Analyses of non-cancerous breast tissue microbiome revealed an enrichment of Proteobacteria in obese women. Proteobacteria often contain LPS and many of these bacteria are flagellated. Tissue-resident Proteobacteria abundance correlated with breast tissue DNA damage. Our findings show that LPS and flagellin are systemic and local mediators of obesity-induced microbiome alterations, predisposing the breast to pre-malignant changes. These results underscore the importance of considering the tissue-resident microbiome as a biomarker of risk to improve primary prevention of breast cancer. <strong><u>Significance</u></strong>: Obesity differentially modulates non-cancerous breast tissue microbial-associated molecular pattern signaling, enriching LPS and flagellin, to promote oxidative stress and DNA damage.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"73 ","pages":"Article 101284"},"PeriodicalIF":7.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146221627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Experimental study of tumor-associated macrophage-derived SPP1 inhibit CD8+ T cells to promote Colorectal cancer progression","authors":"Cheng-Fei Hao ,&nbsp;Zhao-Nan Sun ,&nbsp;Guo-Shan Chen ,&nbsp;Bao-Tong Zhang ,&nbsp;Wen-Hao Xiong ,&nbsp;Xi-Bo Zhang ,&nbsp;Feng Qi","doi":"10.1016/j.neo.2026.101276","DOIUrl":"10.1016/j.neo.2026.101276","url":null,"abstract":"<div><div>Colorectal cancer (CRC) progression is strongly influenced by the tumor immune microenvironment, yet the immunoregulatory role of tumor-associated macrophages (TAMs) remains incompletely defined. Using integrated single-cell RNA sequencing and spatial transcriptomic analyses, we identified a distinct TAM subset in CRC characterized by high expression of secreted phosphoprotein 1 (SPP1).</div><div>In a macrophage-depleted murine CRC model established with clodronate (CL2MDP) liposomes and MC38 cells, macrophage depletion significantly inhibited tumor growth, accompanied by reduced SPP1 expression and increased infiltration of CD8⁺ T cells and type 1 cytotoxic T (Tc1) cells. Supplementation with recombinant SPP1 partially reversed these antitumor effects. Mechanistically, <em>in vitro</em> coculture experiments demonstrated that TAM-derived SPP1 suppressed CD8⁺ T cell differentiation into Tc1 cells through CD44-mediated signaling, resulting in decreased TNF-α and IFN-γ production and impaired activation of the LCK–ZAP70–LAT signaling pathway. These effects were attenuated by SPP1 neutralization or CD44 inhibition.</div><div>Collectively, these findings elucidated TAM-derived SPP1 as a key mediator of immune suppression in CRC and suggested that the TAM–SPP1 axis is a potential therapeutic target.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"73 ","pages":"Article 101276"},"PeriodicalIF":7.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146114805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the ANXA2-CD63-exosomal PD-L1 axis in hepatocellular carcinoma: A novel mechanism of immune evasion and its implications for precision immunotherapy","authors":"Jian Zhang ,&nbsp;Ying Gu ,&nbsp;Fangchao Zhao ,&nbsp;Yong Chen ,&nbsp;Yuqing Xia ,&nbsp;Dekang Gao ,&nbsp;Qiang Yuan ,&nbsp;Xuming Bai","doi":"10.1016/j.neo.2026.101280","DOIUrl":"10.1016/j.neo.2026.101280","url":null,"abstract":"<div><h3>Background and Purpose</h3><div>Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related deaths globally due to late diagnosis and resistance to therapies, including immune checkpoint blockade (ICB). Tumor-derived exosomes carrying programmed death-ligand 1 (PD-L1) have emerged as key mediators of immune evasion by binding PD-1 on T cells, thereby inducing T cell exhaustion and systemic immunosuppression. This study investigated whether Annexin A2 (ANXA2) modulates exosomal PD-L1 expression in HCC cells to inhibit T-cell function and promote immune escape.</div></div><div><h3>Results</h3><div>Bioinformatic analyses (TIMER2.0, TCGA) showed ANXA2 upregulation in HCC, correlating with fewer CD8⁺ T cells and poor survival. ANXA2 knockout (KO) in Hepa1-6 cells reduced exosome secretion and exosomal PD-L1, confirmed by EM, nanoparticle tracking, and WB. Exosomes from controls suppressed CD8⁺ T cell activation (reducing CD69, IL-2, IFN-γ, TNF-α), while KO exosomes did not. ANXA2 KO tumors grew slower in immunocompetent C57BL/6 J mice but not in immunodeficient BALB/c Nude mice, highlighting immune dependence. ANXA2 depletion reduced CD63 protein stability without affecting mRNA. CD63 re-expression in KO cells restored exosomal PD-L1, indicating ANXA2 maintains CD63 stability for PD-L1 exosomal incorporation. Transcriptomic and pharmacologic evidence further supported a role for lysosome-associated turnover in CD63 loss upon ANXA2 depletion.</div></div><div><h3>Conclusions</h3><div>ANXA2 drives HCC immune evasion by upregulating exosomal PD-L1 via CD63 stabilization, offering a novel target to enhance ICB efficacy. This work highlights a tumor-specific exosome regulation mechanism, with potential implications for immunotherapy across exosome-dependent cancers.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"73 ","pages":"Article 101280"},"PeriodicalIF":7.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146171518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tamoxifen promotes metastasis of breast cancer via reshaping lipid-driven fibrotic microenvironments in the lung","authors":"Seung-Su Kim ,&nbsp;Seungchan An ,&nbsp;Sewon Hwang ,&nbsp;Hae-Min Kwon ,&nbsp;Ga Young Lim ,&nbsp;Na-Lee Ka ,&nbsp;Minsoo Noh ,&nbsp;Mi-Ock Lee","doi":"10.1016/j.neo.2026.101286","DOIUrl":"10.1016/j.neo.2026.101286","url":null,"abstract":"<div><div>Patients with estrogen receptor (ER)-positive breast cancer (BC) remain at risk of distant recurrence for up to 20 years after diagnosis, with an overall recurrence rate of approximately 30%. Although tamoxifen is a cornerstone of endocrine therapy, its long-term effects on metastatic niche formation remain poorly defined. Here, we investigated the impact of long-term tamoxifen treatment on metastatic niche formation. Using PyMT and 4T1 allograft mouse models, we found that tamoxifen increased lung metastasis, despite reduced or unchanged primary tumor size. Lungs from tamoxifen-treated mice exhibited fibrotic features, such as collagen deposition, increased airway wall thickness, and altered expression levels of fibrosis-associated proteins. These changes were accompanied by elevated neutral lipid levels and upregulation of lipid metabolism–related genes. Single-cell RNA sequencing (scRNA-seq) revealed an expansion of a macrophage subpopulation enriched for lipid metabolic gene signatures and exhibiting strong interaction with fibroblasts via TGFβ signaling. Immunofluorescence and flow cytometry further demonstrated an increased number of PRG4+ macrophages in the lungs of tamoxifen-treated mice. Importantly, inhibition of lipid accumulation with the fatty acid synthase inhibitor C75 reduced PRG4+ macrophage numbers, attenuated fibrosis, and suppressed lung metastasis. Together, these findings implicate long-term tamoxifen treatment as a potential risk factor for lung metastasis in ER-positive BC by disrupting the lung microenvironment, and suggest that targeting lipid metabolism may represent a therapeutic strategy to limit metastatic progression, particularly in the lung.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"73 ","pages":"Article 101286"},"PeriodicalIF":7.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic loss of CHD1 regulates distinct histone post-translational modifications in the development of castration-resistant prostate cancer","authors":"Tanaya A. Purohit ,&nbsp;Joseph Gawdzik ,&nbsp;Eric A. Armstrong ,&nbsp;Bing Yang ,&nbsp;Zachery Schultz ,&nbsp;Kayla Bahr ,&nbsp;Truman J. Do ,&nbsp;Rehaan Machhi ,&nbsp;Sean Sardeson ,&nbsp;Mohammad Rizvi ,&nbsp;Sarah A. Nakada ,&nbsp;Anupama Singh ,&nbsp;Karla Esbona ,&nbsp;Wei Huang ,&nbsp;Marjorie L. Roskes ,&nbsp;Ekta Khurana ,&nbsp;Peter W. Lewis ,&nbsp;John M. Denu ,&nbsp;David F. Jarrard","doi":"10.1016/j.neo.2026.101289","DOIUrl":"10.1016/j.neo.2026.101289","url":null,"abstract":"<div><div>Epigenetic alterations accumulate with the development of castration resistance in prostate cancer (PC), yet an understanding of how these patterns arise remains incompletely defined. Through histone post-translational modification (PTMs) profiling in paired hormone-sensitive (HS) and castration-resistant (CR) patient-derived xenografts, we identified a novel chromatin state characterized by CHD1 deficiency and global reductions in H3.3K27 and H3.3K36 methylation, which occurred with castration resistance development. Compared to wildtype, CHD1-deficient tumors exhibited lower expression and enzymatic activity of the histone-modifying enzymes (HMEs) NSD2 and EZH2—key regulators of the altered histone PTM landscape. Gene expression analysis of human CRPC samples revealed strong positive correlations among CHD1, NSD2, and EZH2. <em>CHD1</em> knockout (KO) in CRPC cell lines confirms reduced H3.3K27K36 methylation and downregulation of NSD2 and EZH2. Results from mechanistic studies support a process in which CHD1 occupancy at the promoter regions of NSD2 and EZH2 facilitates transcription via enhanced chromatin accessibility and increased deposition of the activating histone mark H3K4me3. In contrast, CHD1-KO led to promoter accumulation of repressive H3K27me3 modifications. CHD1-KO downregulates interferon (IFN) signaling, including viral mimicry and IFN-stimulated genes. Bulk RNA-sequencing and ChIP-qPCR analyses confirmed co-regulation of these genes by CHD1 and NSD2, coinciding with reduced H3K36me2 enrichment. Notably, this CHD1-deficient epigenetic state confers resistance to NSD2 inhibition. These findings highlight a previously unrecognized role in tumor resistance for CHD1 in modulating HMEs that may influence lineage plasticity as well as suggest new avenues for personalized therapeutic strategies targeting CHD1-specific epigenetic vulnerabilities.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"73 ","pages":"Article 101289"},"PeriodicalIF":7.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146259678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of molecularly targeted therapy-induced immunopeptidome in diffuse midline glioma (DMG)","authors":"Niloofar Khairkhah ,&nbsp;Habeebah Owolabi ,&nbsp;Ali Namvar ,&nbsp;Mostafa M.H. Ibrahim ,&nbsp;Seeta Nyayapathy ,&nbsp;Richard Jones ,&nbsp;Julie M. Rumble ,&nbsp;Christopher E. Whitehead ,&nbsp;Judith S. Sebolt-Leopold ,&nbsp;Arun Everest-Dass ,&nbsp;Stefanie Galban","doi":"10.1016/j.neo.2026.101278","DOIUrl":"10.1016/j.neo.2026.101278","url":null,"abstract":"<div><h3>Introduction</h3><div>Diffuse midline glioma (DMG) with the H3K27M mutation remains one of the most treatment-resistant pediatric brain tumors, in part due to limited antigen presentation and immune visibility. Exploring how glioma biology and therapeutic interventions influence immune recognition offers new opportunities to identify tumor-specific immune targets.</div></div><div><h3>Materials and Methods</h3><div>We performed immunopeptidomics on human cell line derived tumor tissue for DMG and glioblastoma (GBM) and defined how MTX-241F, a selective EGFR/PI3K inhibitor, changes the tumor immunopeptidome. Immunopeptides were isolated from xenografted tumors by capturing MHC-I bound peptides followed by mass spectrometry. Comparative analyses were performed across tumor type (DMG vs. GBM) and treatment condition (vehicle vs. MTX-241F).</div></div><div><h3>Results</h3><div>Immunopeptidomic profiling revealed tumor-specific differences in peptide repertoires between DMG and GBM. GBM tumors exhibited twice as many immunopeptides as DMG, which may be due to the distinct biology of each tumor type or may be indicative of potential HLA allotype composition. We identified highly abundant H2B1K-derived immunopeptides in DMG, suggesting that the H3K27M-driven epitranscriptome may promote turnover of other histones. MTX-241F increased the number of immunopeptides in DMG but reduced them in GBM, indicating a tumor-specific change in the immunopeptidome following EGFR/PI3K inhibition. In addition, we identified brain-enriched, HLA-A*02:01–binding and MTX-241F–exclusive immunopeptides that represent treatment-induced changes and may serve as biomarkers of therapeutic response or potential targets for CAR-T cell-based approaches.</div></div><div><h3>Discussion</h3><div>MTX-241F changes the glioma immunopeptidome, unveiling H2B1K, brain-enriched, and treatment-induced immunopeptides as immunologically visible targets. These findings provide a rationale for integrating molecularly targeted therapy with immunotherapeutic approaches to enhance tumor recognition and treatment efficacy in DMG and GBM.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"73 ","pages":"Article 101278"},"PeriodicalIF":7.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146127250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"OSMR coordinates a self-perpetuating circuit linking chemoresistance and neutrophil-driven immunosuppression in gastric cancer","authors":"Dan Wei ,&nbsp;Jiang Chen ,&nbsp;Feihu Bai ,&nbsp;Donglin Li ,&nbsp;Jie Liu ,&nbsp;Hongjia Dou ,&nbsp;Yan Lei ,&nbsp;Yongzhen Zhang ,&nbsp;Bo Zhang ,&nbsp;Ying Pang ,&nbsp;Changchun Cao ,&nbsp;Tao Yang ,&nbsp;Junling Han ,&nbsp;Tianyu Cao","doi":"10.1016/j.neo.2026.101279","DOIUrl":"10.1016/j.neo.2026.101279","url":null,"abstract":"<div><div>Chemoresistance and immunosuppression present major challenges in gastric cancer (GC) treatment, with their interplay remaining poorly understood. We identify the Oncostatin M receptor (OSMR) as a central regulator coordinating both chemoresistance and neutrophil-mediated immunosuppression. OSMR was significantly upregulated in GC patients, correlating with poor chemotherapy response and reduced CD8⁺ <em>T</em> cell infiltration. Mechanistically, OSMR directly recruits PI3K, amplifying PI3K/AKT signaling to increase cyclin E2 (CCNE2) expression, thereby sustaining tumor cell survival under chemotherapy-induced stress. Crucially, we uncovered a novel immunoregulatory cascade: OSMR drives BMP5 transcriptional activation, orchestrating N2-polarization of tumor-associated neutrophils (TANs) and upregulating PD-L1 expression on TANs, ultimately impairing CD8⁺ <em>T</em> cell cytotoxicity. Dysfunctional CD8⁺ <em>T</em> cells secreted IL31, activating the OSMR pathway in GC cells and thereby forming a self-perpetuating OSMR-BMP5-IL31 feedback circuit that sustains therapeutic resistance. Therapeutically, OSMR neutralization with vixarelimab synergized with fluorouracil to overcome chemoresistance and reinstate anti-tumor immunity in GC preclinical models. Our findings establish OSMR as a molecular linchpin connecting intrinsic tumor survival pathways (PI3K/CCNE2) with extrinsic immunosuppressive reprogramming (BMP5/TANs/CD8⁺<em>T</em> cells), providing a clinically actionable target to overcome treatment resistance in GC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"73 ","pages":"Article 101279"},"PeriodicalIF":7.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"White-to-brown adipose switching promotes bladder cancer progression","authors":"Mingchao Gao ,&nbsp;Chunni Li ,&nbsp;Wenjie Li ,&nbsp;Junyi Xie ,&nbsp;Juntian Long ,&nbsp;Mingli Luo ,&nbsp;Jintao Hu ,&nbsp;Cong Lai ,&nbsp;Tianhang Lan ,&nbsp;Dongxi Zhu ,&nbsp;Wenlong Zhong ,&nbsp;Wang He","doi":"10.1016/j.neo.2026.101282","DOIUrl":"10.1016/j.neo.2026.101282","url":null,"abstract":"<div><div>The invasion of bladder cancer into perivesical adipose tissue represents a watershed event in tumor progression, accompanied by a dramatic deterioration in clinical outcomes. However, the underlying molecular mechanisms governing this cancer-adipose tissue crosstalk remain poorly elucidated. Here, we systematically characterize a bidirectional regulatory network between bladder cancer cells and perivesical adipocytes. Our findings demonstrate that bladder cancer cells secreted parathyroid-hormone-related protein (PTHrP), which induces browning of perivesical adipose tissue through activation of protein kinase A (PKA) signaling. Conversely, thermogenesis induced by browning perivesical adipose tissues leads to the release of excessive free fatty acids. These free fatty acids are subsequently taken up by bladder cancer cells, where they promote lipid metabolic reprogramming and thereby enhance cancer cell proliferation, invasion, and metastatic potential. In vivo experiments further validate that treatment with H89, a specific PKA inhibitor, effectively reverses perivesical adipose tissue browning and attenuates bladder cancer progression. Collectively, our data clarify that PTHrP secreted by bladder cancer cells drives perivesical adipose tissue browning to accelerate cancer progression, providing a novel potential therapeutic target for bladder cancer intervention.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"73 ","pages":"Article 101282"},"PeriodicalIF":7.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146171516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer","authors":"Mariah E. Geisen ,&nbsp;Josiane W. Tessmann ,&nbsp;Courtney O. Kelson ,&nbsp;Daheng He ,&nbsp;Chi Wang ,&nbsp;Abu Saleh Mosa Faisal ,&nbsp;Ellen J. Beswick ,&nbsp;Yasmine Baca ,&nbsp;Stephanie Rock ,&nbsp;Jill M. Kolesar ,&nbsp;Yekaterina Y. Zaytseva","doi":"10.1016/j.neo.2026.101283","DOIUrl":"10.1016/j.neo.2026.101283","url":null,"abstract":"<div><div>The presence of BRAF^V600E mutations is associated with poor prognosis in colorectal cancer (CRC). Although the FDA-approved combination of encorafenib and cetuximab provides clinical benefit in this population, only 22% of patients respond and most eventually develop resistance. This study investigated the mechanisms of resistance to PLX8394, a second-generation BRAF inhibitor. Using primary and established BRAF^V600E CRC cells, we show that the development of resistance to PLX8394 results in cross-resistance of cells to encorafenib. Moreover, the acquired resistance is associated with increased proliferation, invasion, and upregulation of lipid metabolism, including increased expression of fatty acid synthase (FASN), a key enzyme of lipid synthesis. Yet, the combination of PLX8394 and FASN inhibitor TVB3664 has a synergistic effect on cell viability and colony formation in parental CRC cells, but not in PLX-resistant cells. Importantly, we demonstrate that addition of TVB3664 to the PLX8394 or encorafenib regimen significantly postpones development of resistance to BRAF-targeted therapy by inhibiting the cell cycle progression via a decrease in pRb (Ser780) and downregulation of E2F transcription factor and Cyclin D1 expression. Consistently, clinical data show that patients with BRAF^V600E CRC who have high FASN expression in tumor tissues have higher expression of cell cycle-associated genes, including CDKs, E2F, CCDN1 (Cyclin D1), survivin, and MKI67. Collectively, these findings identify FASN-driven lipid metabolism as a critical mediator of resistance to BRAF-targeted therapy and suggest that incorporation of FASN inhibitors may enhance therapeutic efficacy and delay acquired resistance in BRAF^V600E CRC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"73 ","pages":"Article 101283"},"PeriodicalIF":7.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146133388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual CDK4/6–PI3K/mTOR inhibition reinforces cytostatic programs and tumor control in preclinical models of primary and metastatic osteosarcoma","authors":"Farinaz Barghi ,&nbsp;M. Reza Saadatzadeh ,&nbsp;Erika A. Dobrota ,&nbsp;Harlan E. Shannon ,&nbsp;Barbara J. Bailey ,&nbsp;Courtney Young ,&nbsp;Rada Malko ,&nbsp;Ryli Justice ,&nbsp;Niknam Riyahi ,&nbsp;Christopher Davis ,&nbsp;Khadijeh Bijangi-Vishehsaraei ,&nbsp;Keiko Kreklau ,&nbsp;Lauren K. Stevens ,&nbsp;Jenna Koenig ,&nbsp;Shirzat Sulayman ,&nbsp;Sheng Liu ,&nbsp;Jun Wan ,&nbsp;Melissa A. Trowbridge ,&nbsp;Kathy Coy ,&nbsp;Felicia M. Kennedy ,&nbsp;Karen E. Pollok","doi":"10.1016/j.neo.2025.101266","DOIUrl":"10.1016/j.neo.2025.101266","url":null,"abstract":"<div><div>Osteosarcoma (OS) in pediatric, adolescent, and young adult (AYA) patients is an aggressive bone cancer with limited treatment options. Dysregulation of the CDK4/6–cyclin D axis and the PI3K/mTOR pathway contributes to OS pathogenesis, providing a biological rationale for co-targeting these signaling nodes. However, pharmacologic CDK4/6 inhibition can trigger compensatory activation of the PI3K/mTOR pathway, restoring <span>D</span>-type cyclin expression and partially reactivating CDK4/6 signaling. Thus, dual inhibition of the CDK4/6 and PI3K/mTOR pathways not only addresses two parallel oncogenic drivers but may also prevent potential CDK4/6 inhibitor resistance mediated by feedback activation of PI3K/mTOR. In this study, we tested the hypothesis that coordinated targeting of these pathways would improve tumor control in preclinical OS models. In vitro sensitivity analyses using palbociclib and voxtalisib demonstrated additive to synergistic OS growth suppression, with palbociclib inducing G1 arrest and senescence, and the combination enhancing autophagy. Furthermore, the efficacy, tolerability, and mechanisms of palbociclib and voxtalisib, alone or in combination, were evaluated in molecularly defined primary treatment-naïve, and relapsed/metastatic OS models. In the relapsed/metastatic PDX77-TT2 model, short-term palbociclib exposure activated PI3K/mTOR signaling, whereas the combination of palbociclib and voxtalisib in long-term studies produced marked tumor suppression and extended survival. In the primary treatment-naïve PDX96 model, long-term palbociclib exposure generated a robust CDK4/6 pharmacodynamic response. The addition of voxtalisib reinforced autophagy, sustained CDK pathway inhibition, and improved overall tumor control. In an OS lung-colonization model, CDK4/6 inhibition alone markedly reduced OS lung nodules, with combination therapy providing comparable suppression. Dual CDK4/6–PI3K/mTOR inhibition achieves tumor control across various OS models, supporting the use of genomically guided, pathway-targeted strategies for pediatric and AYA OS.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"72 ","pages":"Article 101266"},"PeriodicalIF":7.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145977344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}