Academic Journal
Tumour endothelial cell reprogramming orchestrates angiocrine signalling to drive chemoresistance in breast cancer.
| Τίτλος: | Tumour endothelial cell reprogramming orchestrates angiocrine signalling to drive chemoresistance in breast cancer. |
|---|---|
| Συγγραφείς: | Gomez-Escudero J; Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK. jesuschgoes@usal.es.; Biochemistry and Molecular Biology Department, Salamanca University, Salamanca, Spain. jesuschgoes@usal.es., Maniati E; Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK., Holdsworth J; Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK., Beattie G; UCL Cancer Institute, CRUK City of London Centre Single Cell Genomics Facility, University College London, London, UK.; Bioinformatics Hub, UCL Cancer Institute, University College London, London, UK., Hijazi M; Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK.; Biochemistry and Molecular Biology Department, Salamanca University, Salamanca, Spain., Guelbert M; Division of Cancer Biology, The Institute of Cancer Research, London, UK., Elorbany S; Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK., Cutillas P; Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK., Wang J; Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK., Hodivala-Dilke K; Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK. k.hodivala-dilke@qmul.ac.uk., D'Amico G; Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK. g.damico@qmul.ac.uk. |
| Πηγή: | Angiogenesis [Angiogenesis] 2026 Jun 22; Vol. 29 (3). Date of Electronic Publication: 2026 Jun 22. |
| Τύπος έκδοσης: | Journal Article; Research Support, Non-U.S. Gov't |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Springer Country of Publication: Germany NLM ID: 9814575 Publication Model: Electronic Cited Medium: Internet ISSN: 1573-7209 (Electronic) Linking ISSN: 09696970 NLM ISO Abbreviation: Angiogenesis Subsets: MEDLINE |
| Imprint Name(s): | Publication: Dec. 2004- : Berlin : Springer Original Publication: London ; Philadelphia : Rapid Science Publishers |
| Ιατρικοί όροι (MeSH): | Drug Resistance, Neoplasm*/drug effects , Signal Transduction*/drug effects , Neovascularization, Pathologic*/pathology , Neovascularization, Pathologic*/metabolism , Endothelial Cells*/pathology , Endothelial Cells*/metabolism , Breast Neoplasms*/pathology , Breast Neoplasms*/drug therapy , Breast Neoplasms*/metabolism , Breast Neoplasms*/blood supply , Cellular Reprogramming*/drug effects, Doxorubicin/pharmacology ; NF-kappa B/metabolism ; Animals ; Female ; Mice ; Humans ; Metabolic Reprogramming |
| Περίληψη: | Despite its established role in breast cancer treatment, Doxorubicin treatment remains subject to adaptive resistance mechanisms that extend beyond cancer cell intrinsic alterations ultimately reducing therapy efficacy. Our study in a MMTV-PyMT-driven mouse breast cancer model reveals that prolonged Doxorubicin (Dox) exposure triggers significant reprogramming of the tumour vasculature, substantially altering the angiocrine landscape and shaping treatment outcomes. Notably, tumours that initially respond, but later revert, display an endothelial cell subclustering with activation of proliferative and NF-κB-dependent cytokine pathways. We further identify a novel endothelial subpopulation characterised by higher expression of drug clearance and oxidative metabolism markers, suggesting an active role in mitigating Dox efficacy and angiogenesis promotion. These findings substantiate endothelial plasticity as a critical mediator of therapeutic failure. By uncovering these vascular adaptations, our work provides a new perspective on the underlying mechanisms of Dox resistance and the prolonged efficacy of chemotherapy in breast cancer. (© 2026. The Author(s).) |
| Competing Interests: | Declarations. Conflict of interest: The authors declare no competing interests. |
| References: | Bisht A, Avinash D, Sahu KK, Patel P, Das Gupta G, Das Kurmi B (2025) A comprehensive review on doxorubicin: mechanisms, toxicity, clinical trials, combination therapies and nanoformulations in breast cancer. Drug Deliv Transl Res 15(1):102–133. https://doi.org/10.1007/s13346-024-01648-0. (PMID: 10.1007/s13346-024-01648-038884850) Christowitz C, Davis T, Isaacs A, van Niekerk G, Hattingh S, Engelbrecht A-M (2019) Mechanisms of doxorubicin-induced drug resistance and drug resistant tumour growth in a murine breast tumour model. BMC Cancer 19(1):757. https://doi.org/10.1186/s12885-019-5939-z. (PMID: 10.1186/s12885-019-5939-z313708186670209) Wang X, Yan J, Shen B, Wei G (2021) Integrated chromatin accessibility and transcriptome landscapes of doxorubicin-resistant breast cancer cells. Front Cell Dev Biol 9. https://doi.org/10.3389/fcell.2021.708066. (PMID: 10.3389/fcell.2021.708066358605988753366) Nicoletto RE, Ofner CM (2022) Cytotoxic mechanisms of doxorubicin at clinically relevant concentrations in breast cancer cells. Cancer Chemother Pharmacol 89(3):285–311. https://doi.org/10.1007/s00280-022-04400-y. (PMID: 10.1007/s00280-022-04400-y35150291) AbuHammad S, Zihlif M (2013) Gene expression alterations in doxorubicin resistant MCF7 breast cancer cell line. Genomics 101(4):213–220. https://doi.org/10.1016/j.ygeno.2012.11.009. (PMID: 10.1016/j.ygeno.2012.11.00923201559) Lovitt CJ, Shelper TB, Avery VM, Dec (2018) Doxorubicin resistance in breast cancer cells is mediated by extracellular matrix proteins. BMC Cancer. https://doi.org/10.1186/s12885-017-3953-6. (PMID: 10.1186/s12885-017-3953-6293047705756400) Tavora B et al (2014) Endothelial-cell FAK targeting sensitizes tumours to DNA-damaging therapy. Nature 514(7520):112–116. https://doi.org/10.1038/nature13541. (PMID: 10.1038/nature13541250793334533916) Sahoo S, Kumari S, Pulipaka S, Chandra Y, Kotamraju S (2024) SIRT1 promotes doxorubicin-induced breast cancer drug resistance and tumor angiogenesis via regulating GSH‐mediated redox homeostasis. Mol Carcinog 63(12):2291–2304. https://doi.org/10.1002/mc.23809. (PMID: 10.1002/mc.2380939136605) Shang M et al (2021) Microfluidic studies of hydrostatic pressure-enhanced doxorubicin resistance in human breast cancer cells. Lab Chip 21(4):746–754. https://doi.org/10.1039/D0LC01103G. (PMID: 10.1039/D0LC01103G33502419) Joyce MH, Sep (2018) Phenotypic basis for matrix stiffness-dependent chemoresistance of breast cancer cells to doxorubicin. Front Oncol. https://doi.org/10.3389/fonc.2018.00337. (PMID: 10.3389/fonc.2018.00337302340126134055) Skandha Gopalan K, Bergers G (2024) The Pan-Tumor Vasculature under the Transcriptomic Magnifying Glass. Cancer Res 84(21):3502–3504. https://doi.org/10.1158/0008-5472.CAN-24-3219. (PMID: 10.1158/0008-5472.CAN-24-321939240688) Maishi N, Hida K (2017) Tumor endothelial cells accelerate tumor metastasis. Cancer Sci 108(10):1921–1926. https://doi.org/10.1111/cas.13336. (PMID: 10.1111/cas.13336287631395623747) Cao Z et al (2014) Angiocrine factors deployed by tumor vascular niche induce b cell lymphoma invasiveness and chemoresistance. Cancer Cell 25(3):350–365. https://doi.org/10.1016/j.ccr.2014.02.005. (PMID: 10.1016/j.ccr.2014.02.005246510144017921) Pasquier J, Ghiabi P, Chouchane L, Razzouk K, Rafii S, Rafii A (2020) Angiocrine endothelium: from physiology to cancer. J Transl Med 18(1):52. https://doi.org/10.1186/s12967-020-02244-9. (PMID: 10.1186/s12967-020-02244-9320140476998193) Wieland E et al (2017) Endothelial Notch1 activity facilitates metastasis. Cancer Cell 31(3):355–367. https://doi.org/10.1016/j.ccell.2017.01.007. (PMID: 10.1016/j.ccell.2017.01.00728238683) Alsina-Sanchis E, Mülfarth R, Fischer A (2021) Control of Tumor progression by angiocrine factors. Cancers (Basel) 13(11):2610. https://doi.org/10.3390/cancers13112610. (PMID: 10.3390/cancers13112610340733948198241) Geldhof V et al (2022) Single cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast. Nat Commun 13(1):5511. https://doi.org/10.1038/s41467-022-33052-y. (PMID: 10.1038/s41467-022-33052-y361274279489707) Li J, Wang D, Tang F, Ling X, Zhang W, Zhang Z (2024) Pan-cancer integrative analyses dissect the remodeling of endothelial cells in human cancers. Natl Sci Rev. https://doi.org/10.1093/nsr/nwae231. (PMID: 10.1093/nsr/nwae2314019124612661574) Zeng Q et al (2023) Understanding tumour endothelial cell heterogeneity and function from single-cell omics. Nat Rev Cancer 23(8):544–564. https://doi.org/10.1038/s41568-023-00591-5. (PMID: 10.1038/s41568-023-00591-537349410) Tang MKS (2018) Soluble E-cadherin promotes tumor angiogenesis and localizes to exosome surface. Nat Commun 9(1):2270. https://doi.org/10.1038/s41467-018-04695-7. (PMID: 10.1038/s41467-018-04695-7298919385995921) Tzima E (2002) Activation of Rac1 by shear stress in endothelial cells mediates both cytoskeletal reorganization and effects on gene expression. EMBO J 21(24):6791–6800. https://doi.org/10.1093/emboj/cdf688. (PMID: 10.1093/emboj/cdf68812486000139108) Christenson JL et al (2017) MMTV-PyMT and derived Met-1 mouse mammary tumor cells as models for studying the role of the androgen receptor in triple-negative breast cancer progression. Horm Cancer 8(2):69–77. https://doi.org/10.1007/s12672-017-0285-6. (PMID: 10.1007/s12672-017-0285-628194662) Attalla S, Taifour T, Bui T, Muller W (2021) Insights from transgenic mouse models of PyMT-induced breast cancer: recapitulating human breast cancer progression in vivo. Oncogene 40(3):475–491. https://doi.org/10.1038/s41388-020-01560-0. (PMID: 10.1038/s41388-020-01560-033235291) Ross SR (2010) Mouse Mammary tumor virus molecular biology and oncogenesis. Viruses 2(9):2000–2012. https://doi.org/10.3390/v2092000. (PMID: 10.3390/v209200021274409) Demircioglu F et al (2020) Cancer associated fibroblast FAK regulates malignant cell metabolism. Nat Commun 11(1):1290. https://doi.org/10.1038/s41467-020-15104-3. (PMID: 10.1038/s41467-020-15104-3321570877064590) Xie Z, Mar (2021) Gene set knowledge discovery with enrichr. Curr Protoc. https://doi.org/10.1002/cpz1.90. (PMID: 10.1002/cpz1.90337801708152575) Kuleshov MV, Jul (2016) Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res 44:W90–W97. (PMID: 10.1093/nar/gkw377271419614987924) Chen EY, (2013) Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 14(1):128. https://doi.org/10.1186/1471-2105-14-128. (PMID: 10.1186/1471-2105-14-128235864633637064) Pan X et al (2024) Tumour vasculature at single-cell resolution. Nature 632(8024):429–436. https://doi.org/10.1038/s41586-024-07698-1. (PMID: 10.1038/s41586-024-07698-138987599) Schupp JC et al (2021) Integrated single-cell atlas of endothelial cells of the human lung. Circulation 144(4):286–302. https://doi.org/10.1161/CIRCULATIONAHA.120.052318. (PMID: 10.1161/CIRCULATIONAHA.120.052318340304608300155) Kalucka J et al (2020) Single-cell transcriptome atlas of murine endothelial cells. Cell 180(4):764–779 https://doi.org/10.1016/j.cell.2020.01.015. (PMID: 10.1016/j.cell.2020.01.01532059779) Goveia J et al (2020) An integrated gene expression landscape profiling approach to identify lung tumor endothelial cell heterogeneity and angiogenic candidates. Cancer Cell 37(1):21–36. https://doi.org/10.1016/j.ccell.2019.12.001. (PMID: 10.1016/j.ccell.2019.12.00131935371) Gómez-Escudero J et al (2019) PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP production. Sci Rep 9(1):15022. https://doi.org/10.1038/s41598-019-50866-x. (PMID: 10.1038/s41598-019-50866-x316363066803685) Schoors S et al (2015) Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520(7546):192–197. https://doi.org/10.1038/nature14362. (PMID: 10.1038/nature14362258308934413024) Kalucka J et al (2018) Quiescent endothelial cells upregulate fatty acid β-Oxidation for vasculoprotection via redox homeostasis. Cell Metab 28(6):881–894. https://doi.org/10.1016/j.cmet.2018.07.016. (PMID: 10.1016/j.cmet.2018.07.01630146488) Pasut A, Becker LM, Cuypers A, Carmeliet P (2021) Endothelial cell plasticity at the single-cell level. Angiogenesis 24(2):311–326. https://doi.org/10.1007/s10456-021-09797-3. (PMID: 10.1007/s10456-021-09797-3340612848169404) Robey IF, Lien AD, Welsh SJ, Baggett BK, Gillies RJ (2005) Hypoxia-inducible factor-1alpha and the glycolytic phenotype in tumors. Neoplasia 7(4):324–330. https://doi.org/10.1593/neo.04430. (PMID: 10.1593/neo.04430159671091501147) De Palma M, Hanahan D (2024) Milestones in tumor vascularization and its therapeutic targeting. Nat Cancer 5(6):827–843. https://doi.org/10.1038/s43018-024-00780-7. (PMID: 10.1038/s43018-024-00780-738918437) Ebos JML, Kerbel RS (2011) Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat Rev Clin Oncol 8(4):210–221. https://doi.org/10.1038/nrclinonc.2011.21. (PMID: 10.1038/nrclinonc.2011.21213645244540336) Deo A, Sleeman JP, Shaked Y (2024) The role of host response to chemotherapy: resistance, metastasis and clinical implications. Clin Exp Metastasis 41(4):495–507. https://doi.org/10.1007/s10585-023-10243-5. (PMID: 10.1007/s10585-023-10243-537999904) Shaked Y (2016) Balancing efficacy of and host immune responses to cancer therapy: the yin and yang effects. Nat Rev Clin Oncol 13(10):611–626. https://doi.org/10.1038/nrclinonc.2016.57. (PMID: 10.1038/nrclinonc.2016.5727118493) Shaked Y et al (2006) Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 313(5794):1785–1787. https://doi.org/10.1126/science.1127592. (PMID: 10.1126/science.112759216990548) Yun W et al (2023) Chemosensitivity to doxorubicin in primary cells derived from tumor of FVB/N-Trp53tm1Hw1 with TALEN-mediated Trp53 mutant gene. Lab Anim Res 39(1):23. https://doi.org/10.1186/s42826-023-00175-2. (PMID: 10.1186/s42826-023-00175-23786425410588074) Wan X et al (2021) Estrogen receptor α mediates doxorubicin sensitivity in breast cancer cells by regulating E-Cadherin. Front Cell Dev Biol. https://doi.org/10.3389/fcell.2021.583572. (PMID: 10.3389/fcell.2021.583572351117588717932) Van Zundert I, Fortuni B, Rocha S (2020) From 2D to 3D cancer cell models—the enigmas of drug delivery research. Nanomaterials 10(11):2236. https://doi.org/10.3390/nano10112236. (PMID: 10.3390/nano10112236331872317696259) Kapałczyńska M et al (2016) 2D and 3D cell cultures – a comparison of different types of cancer cell cultures. Archives Med Sci. https://doi.org/10.5114/aoms.2016.63743. (PMID: 10.5114/aoms.2016.63743) Guerrero-López P et al (2025) 2D versus 3D tumor-on-chip models to study the impact of tumor organization on metabolic patterns in vitro. Sci Rep 15(1):19506. https://doi.org/10.1038/s41598-025-03504-8. (PMID: 10.1038/s41598-025-03504-84046156712134292) Vasaikar SV, Straub P, Wang J, Zhang B (2018) LinkedOmics: analyzing multi-omics data within and across 32 cancer types. Nucleic Acids Res 46:D956–D963. https://doi.org/10.1093/nar/gkx1090. (PMID: 10.1093/nar/gkx1090291362075753188) Rahmani ES et al (2025) OncoProExp: An interactive shiny web application for comprehensive cancer proteomics and phosphoproteomics analysis. Comput Struct Biotechnol J 27:3993–4006. https://doi.org/10.1016/j.csbj.2025.08.038. (PMID: 10.1016/j.csbj.2025.08.0384101782212465049) Singh A et al (2019) Angiocrine signals regulate quiescence and therapy resistance in bone metastasis. JCI Insight. https://doi.org/10.1172/jci.insight.125679. (PMID: 10.1172/jci.insight.125679316137986948871) Oria VO, Erler JT (2023) Tumor angiocrine signaling: novel targeting opportunity in cancer. Cells 12:2510. https://doi.org/10.3390/cells12202510. (PMID: 10.3390/cells122025103788735410605017) Rottenberg S et al (2007) Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc Natl Acad Sci 104(29):12117–12122. https://doi.org/10.1073/pnas.0702955104. (PMID: 10.1073/pnas.0702955104176261831914039) Martinez-Usatorre A et al (2021) Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models. Sci Transl Med. https://doi.org/10.1126/scitranslmed.abd1616. (PMID: 10.1126/scitranslmed.abd1616343807687612153) Zou M et al (2017) Transdifferentiation as a mechanism of treatment resistance in a mouse model of castration-resistant prostate cancer. Cancer Discov 7(7):736–749. https://doi.org/10.1158/2159-8290.CD-16-1174. (PMID: 10.1158/2159-8290.CD-16-1174284112075501744) Cheng C et al (2023) Single-cell transcriptome analysis reveals cellular and molecular alterations in small cell lung cancer tumors following chemotherapy. Int J Cancer 153(6):1273–1286. https://doi.org/10.1002/ijc.34629. (PMID: 10.1002/ijc.3462937334524) Zheng X, Wu W, Zhao Z, Zhang X, Yu S (2024) Single-cell transcriptomic insights into chemotherapy-induced remodeling of the osteosarcoma tumor microenvironment. J Cancer Res Clin Oncol 150(7):356. https://doi.org/10.1007/s00432-024-05787-2. (PMID: 10.1007/s00432-024-05787-23903308911271355) Ahire C et al (2023) Accelerated cerebromicrovascular senescence contributes to cognitive decline in a mouse model of paclitaxel (Taxol)-induced chemobrain. Aging Cell. https://doi.org/10.1111/acel.13832. (PMID: 10.1111/acel.138323724338110352561) Patai R et al (2025) Transcriptomic profiling of senescence effects on blood–brain barrier-related gene expression in brain capillary endothelial cells in a mouse model of paclitaxel-induced chemobrain. Geroscience 47(3):3677–3691. https://doi.org/10.1007/s11357-025-01561-5. (PMID: 10.1007/s11357-025-01561-53997684412181502) Kikuchi H et al (2020) Chemotherapy-induced IL8 upregulates MDR1/ABCB1 in tumor blood vessels and results in unfavorable outcome. Cancer Res 80:2996–3008. https://doi.org/10.1158/0008-5472.CAN-19-3791. (PMID: 10.1158/0008-5472.CAN-19-379132536602) Hongu T et al (2025) Permeable lung vasculature creates chemoresistant endothelial niche by producing SERPINE1 at breast cancer metastatic sites. Cancer Sci 116(6):1604–1615. https://doi.org/10.1111/cas.70050. (PMID: 10.1111/cas.700504021758112127090) Skowron MA et al (2022) Profiling the < scp>3D interaction between germ cell tumors and microenvironmental cells at the transcriptome and secretome level. Mol Oncol 16(17):3107–3127. https://doi.org/10.1002/1878-0261.13282. (PMID: 10.1002/1878-0261.13282358115719441004) Hida K, Maishi N, Annan D, Hida Y (2018) Contribution of tumor endothelial cells in cancer progression. Int J Mol Sci 19(5):1272. https://doi.org/10.3390/ijms19051272. (PMID: 10.3390/ijms19051272296950875983794) Huang M et al (2016) c-Met–mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma. J Clin Invest 126(5):1801–1814. https://doi.org/10.1172/JCI84876. (PMID: 10.1172/JCI84876270432804855929) Li G-Y et al (2023) Overcoming chemoresistance in non-angiogenic colorectal cancer by metformin via inhibiting endothelial apoptosis and vascular immaturity. J Pharm Anal 13(3):262–275. https://doi.org/10.1016/j.jpha.2023.02.001. (PMID: 10.1016/j.jpha.2023.02.0013710210510123948) Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G (1993) Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev 7(5):812–821. https://doi.org/10.1101/gad.7.5.812. (PMID: 10.1101/gad.7.5.8128491378) Belisario DC et al (2020) Hypoxia dictates metabolic rewiring of tumors: implications for chemoresistance. Cells 9(12):2598. https://doi.org/10.3390/cells9122598. (PMID: 10.3390/cells9122598332916437761956) RUMIO C (2024) The Role of Oxidative Metabolism in Tumorigenesis and Drug Resistance. Discov Med 36(185):1109. https://doi.org/10.24976/Discov.Med.202436185.102. (PMID: 10.24976/Discov.Med.202436185.10238926098) Niu N, Ye J, Hu Z, Zhang J, Wang Y (2023) Regulative roles of metabolic plasticity caused by mitochondrial oxidative phosphorylation and glycolysis on the initiation and progression of tumorigenesis. Int J Mol Sci. https://doi.org/10.3390/ijms24087076. (PMID: 10.3390/ijms240870763820332910779322) Hua Y et al (2022) Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1 + T lymphocyte niches through a feed-forward loop. Cancer Cell 40(12):1600–1618. https://doi.org/10.1016/j.ccell.2022.11.002. (PMID: 10.1016/j.ccell.2022.11.002364236359899876) Birdsey GM et al (2008) Transcription factor Erg regulates angiogenesis and endothelial apoptosis through VE-cadherin. Blood 111(7):3498–3506. https://doi.org/10.1182/blood-2007-08-105346. (PMID: 10.1182/blood-2007-08-105346181950902275018) Harel S et al (2021) ETS1, ELK1, and ETV4 transcription factors regulate angiopoietin-1 signaling and the angiogenic response in endothelial cells. Front Physiol https://doi.org/10.3389/fphys.2021.683651. (PMID: 10.3389/fphys.2021.683651343813758350579) Trindade A, Duarte A (2020) Notch signaling function in the angiocrine regulation of tumor development. Cells 9(11):2467. https://doi.org/10.3390/cells9112467. (PMID: 10.3390/cells9112467331983787697556) Wang Q et al (2018) Vascular niche IL-6 induces alternative macrophage activation in glioblastoma through HIF-2α. Nat Commun 9(1):559. https://doi.org/10.1038/s41467-018-03050-0. (PMID: 10.1038/s41467-018-03050-0294226475805734) Grit JL et al (2020) Kinome Profiling of NF1-related MPNSTs in Response to kinase inhibition and doxorubicin reveals therapeutic vulnerabilities. Genes (Basel) 11(3):331. https://doi.org/10.3390/genes11030331. (PMID: 10.3390/genes11030331322450427141129) Abou-Shanab AM et al (2025) PHD-2/HIF-1α axis mediates doxorubicin-induced angiogenesis in SH-SY5Y neuroblastoma microenvironment: a potential survival mechanism. Sci Rep 15(1):7487. https://doi.org/10.1038/s41598-025-89884-3. (PMID: 10.1038/s41598-025-89884-34003289211876694) Bauer J et al (2022) The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma. Nat Commun 13(1):6401. https://doi.org/10.1038/s41467-022-33746-3. (PMID: 10.1038/s41467-022-33746-3363027549613889) Kumari R, Chouhan S, Singh S, Chhipa RR, Ajay AK, Bhat MK (2017) Constitutively activated ERK sensitizes cancer cells to doxorubicin: Involvement of p53-EGFR-ERK pathway. J Biosci 42(1):31–41. https://doi.org/10.1007/s12038-017-9667-8. (PMID: 10.1007/s12038-017-9667-828229963) Keeratichamroen S, Lirdprapamongkol K, Svasti J (2018) Mechanism of ECM-induced dormancy and chemoresistance in A549 human lung carcinoma cells. Oncol Rep 39(4):1765–1774. https://doi.org/10.3892/or.2018.6258. (PMID: 10.3892/or.2018.625829436672) Guo X et al (2018) Dacomitinib potentiates the efficacy of conventional chemotherapeutic agents via inhibiting the drug efflux function of ABCG2 in vitro and in vivo. J Exp Clin Cancer Res 37(1):31. https://doi.org/10.1186/s13046-018-0690-x. (PMID: 10.1186/s13046-018-0690-x294584055819299) Wei F et al (2013) Inhibition of ERK activation enhances the repair of double-stranded breaks via non-homologous end joining by increasing DNA-PKcs activation. Biochim Biophys Acta 1833(1):90–100. https://doi.org/10.1016/j.bbamcr.2012.10.016. (PMID: 10.1016/j.bbamcr.2012.10.01623098854) Sears JC, Broadie K (2025) PKA restricts ERK signaling in learning and memory Kenyon cell neurons. Cell Signal 132:111818. https://doi.org/10.1016/j.cellsig.2025.111818. (PMID: 10.1016/j.cellsig.2025.1118184025069812548963) Gu H et al (2015) Mitochondrial E3 ligase March5 maintains stemness of mouse ES cells via suppression of ERK signalling. Nat Commun 6:7112. https://doi.org/10.1038/ncomms8112. (PMID: 10.1038/ncomms8112260335414458872) Marazita MC et al (2012) CDK2 and PKA mediated-sequential phosphorylation is critical for p19INK4d function in the DNA damage response. PLoS ONE 7(4):e35638. https://doi.org/10.1371/journal.pone.0035638. (PMID: 10.1371/journal.pone.0035638225581863338453) Jessulat M et al (2021) The conserved Tpk1 regulates non-homologous end joining double-strand break repair by phosphorylation of Nej1, a homolog of the human XLF. Nucleic Acids Res 49(14):8145–8160. https://doi.org/10.1093/nar/gkab585. (PMID: 10.1093/nar/gkab585342447918373142) Searle JS, Wood MD, Kaur M, Tobin DV, Sanchez Y (2011) Proteins in the nutrient-sensing and DNA damage checkpoint pathways cooperate to restrain mitotic progression following DNA damage. PLoS Genet 7(7):e1002176. https://doi.org/10.1371/journal.pgen.1002176. (PMID: 10.1371/journal.pgen.1002176217791803136438) Gilbert LA, Hemann MT (2010) DNA damage-mediated induction of a chemoresistant niche. Cell 143(3):355–366. https://doi.org/10.1016/j.cell.2010.09.043. (PMID: 10.1016/j.cell.2010.09.043210298592972353) Hedl M, Abraham C (2012) Nod2-induced autocrine interleukin-1 alters signaling by ERK and p38 to differentially regulate secretion of inflammatory cytokines. Gastroenterology 143(6):1530–1543. https://doi.org/10.1053/j.gastro.2012.08.048. (PMID: 10.1053/j.gastro.2012.08.048229677253618474) Saud K, Herrera-Molina R, Von Bernhardi R (2005) Pro- and anti-inflammatory cytokines regulate the ERK pathway: implication of the timing for the activation of microglial cells. Neurotox Res 8(3–4):277–287. https://doi.org/10.1007/BF03033981. (PMID: 10.1007/BF0303398116371322) Misior AM, Yan H, Pascual RM, Deshpande DA, Panettieri RA, Penn RB (2008) Mitogenic effects of cytokines on smooth muscle are critically dependent on protein kinase A and are unmasked by steroids and cyclooxygenase inhibitors. Mol Pharmacol 73(2):566–574. https://doi.org/10.1124/mol.107.040519. (PMID: 10.1124/mol.107.04051917993511) Finak G et al (2015) MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. Genome Biol 16:278. https://doi.org/10.1186/s13059-015-0844-5. (PMID: 10.1186/s13059-015-0844-5266538914676162) Ouyang JF, Kamaraj US, Cao EY, Rackham OJL (2021) ShinyCell: simple and sharable visualization of single-cell gene expression data. Bioinformatics 37(19):3374–3376. https://doi.org/10.1093/bioinformatics/btab209. (PMID: 10.1093/bioinformatics/btab20933774659) Minello A et al (2025) A recurrent pathogenic BRCA2 truncating variant reveals a role for BRCA2-PCAF complex in modulating NF-κB-driven transcription. Nat Commun 16(1):10953. https://doi.org/10.1038/s41467-025-67209-2. (PMID: 10.1038/s41467-025-67209-24137214112696006) Foty R (May 2011) A simple hanging drop cell culture protocol for generation of 3D spheroids. J Visualized Exper https://doi.org/10.3791/2720. (PMID: 10.3791/2720) |
| Grant Information: | CTRQQR-2021\100004 CRUK CITY OF LONDON CENTRE AWARD; Worldwide Cancer Research (19-0108) United Kingdom AICR_ Worldwide Cancer Research; Medical Research Council (MR/V009621/1) United Kingdom MRC_ Medical Research Council; Barts Charity (MGU0601) Barts Charity; CRUK DRCNPG- May21/100004 United Kingdom CRUK_ Cancer Research UK |
| Contributed Indexing: | Keywords: Angiocrine; Breast cancer; Chemoresistance; Doxorubicin; NF-κB |
| Substance Nomenclature: | 80168379AG (Doxorubicin) 0 (NF-kappa B) |
| Entry Date(s): | Date Created: 20260622 Date Completed: 20260622 Latest Revision: 20260726 |
| Update Code: | 20260726 |
| PubMed Central ID: | PMC13287203 |
| DOI: | 10.1007/s10456-026-10063-7 |
| PMID: | 42329467 |
| Βάση Δεδομένων: | MEDLINE |
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