Molecular Oncology最新文献

{"title":"Loss of IGF-1R impairs DNA-PKcs recruitment to chromatin leading to defective end-joining.","authors":"Matthew O Ellis, Jack V Mills, Wojciech Niedzwiedz, Valentine M Macaulay","doi":"10.1002/1878-0261.70266","DOIUrl":"https://doi.org/10.1002/1878-0261.70266","url":null,"abstract":"<p><p>The insulin-like growth factor (IGF) axis regulates cancer cell proliferation, growth, invasion, and therapy resistance. Elevated expression of the type 1 IGF receptor (IGF-1R) is linked to radioresistance and biochemical recurrence in prostate cancer, yet the molecular mechanisms underlying IGF-1R-mediated DNA damage responses remain unclear. We investigated the role of IGF-1R in DNA double-strand break (DSB) repair by assessing chromatin recruitment of DNA repair proteins, repair pathway usage, and therapeutic sensitivity in cancer cell models with altered IGF-1R status. Loss of IGF-1R impaired DNA-dependent protein kinase catalytic subunit (DNA-PKcs) localisation to chromatin, resulting in defective non-homologous end-joining (NHEJ) and a compensatory reliance on alternative repair pathways, including microhomology-mediated end-joining (MMEJ). Modulating IGF-1R expression restored radiosensitivity in poly (ADP-ribose) polymerase (PARP) inhibitor-resistant breast cancer cells. IGF-1R inhibition compromises canonical DSB repair and re-sensitises resistant cancer cells to therapy, supporting its potential as a therapeutic strategy in homologous recombination-deficient tumours. Furthermore, IGF-1R mutant cancers may benefit from targeted inhibition of the MMEJ pathway.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840151","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":"Clinical performance of the urine-based TERT promoter AbsoluteQ Digital PCR for non-invasive detection of bladder cancer.","authors":"Anna Nykel, Izabela Kubiak, Lena Rutkowska, Żaneta Kasprzyk, Łukasz Kępczyński, Michał Bednarek, Dariusz Sobieraj, Jacek Wilkosz, Piotr Kania, Adam Jędrzejczyk, Bogdan Kałużewski, Agnieszka Gach, Tadeusz Kałużewski","doi":"10.1002/1878-0261.70262","DOIUrl":"https://doi.org/10.1002/1878-0261.70262","url":null,"abstract":"<p><p>Bladder cancer (BC) is the ninth most common cancer worldwide, with urothelial carcinoma accounting for approximately 90% of all cases and presenting predominantly as non-muscle-invasive disease. Due to its high recurrence rate and the need for long-term surveillance, BC is associated with the highest lifetime treatment costs per patient among all cancers, making its effective management a significant clinical and economic challenge. The most frequently identified variants in the TERT gene promoter are c.-124C>T (C228T) and c.-146C>T (C250T), located within a region characterized by high guanine-cytosine (GC) content, which makes amplification challenging. We aimed to validate the AbsoluteQ Digital PCR assay for the detection of urine-based TERT promoter variants for the diagnosis of urothelial bladder cancer and to assess its diagnostic performance in comparison with standard methods. Urine samples were collected from patients with histopathologically confirmed bladder cancer (n = 58) and compared with a control group (n = 55). The C228T and C250T variants were tested using the AbsoluteQ Digital PCR assay. Sensitivity, specificity, and predictive values were calculated to evaluate the performance of the assessed method. The AbsoluteQ Digital PCR demonstrated superior diagnostic performance compared to conventional Sanger sequencing for detecting TERT promoter variants, achieving a sensitivity of 89.65% (95% CI: 78.16-95.72) and a specificity of 100% (95% CI: 91.87-100), with no false positives observed. Given its robustness and clinical relevance, AbsoluteQ Digital PCR is emerging as a promising tool for non-invasive molecular diagnostics targeting TERT promoter variants.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840218","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":"In vitro models of cancer-associated fibroblast heterogeneity uncover subtype-specific effects of CRISPR perturbations.","authors":"Elysia Saputra, Shamsudheen Karuthedath Vellarikkal, Lixia Li, Hong Sun, Khoa Nguyen, Amber Montano, Suchitra Natarajan, Federica Piccioni, Alex Michael Tamburino, Xin Yu, Aleksandra Katarzyna Olow","doi":"10.1002/1878-0261.70153","DOIUrl":"10.1002/1878-0261.70153","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAFs) are sought after as potential therapeutic targets due to their pro- and antitumorigenic functions, which are attributed to specializations in CAF subtypes. A precise targeting of specific subtypes would be required to design therapies that effectively modulate CAF phenotypes, necessitating translatable model systems to support target discovery efforts. However, not only is our knowledge of CAF heterogeneity in solid tumors lacking, particularly in pancreatic tumors, but the translatability of CAF models has also not been rigorously evaluated. Here, we develop a coculturing model with primary CAFs and immortalized tumor cell lines that can reliably represent CAF phenotypes observed in tumors, with correlations to immuno-resistant and immunomodulatory phenotypes. Using single-cell transcriptomics, we characterize the CAF subtype heterogeneity in the in vitro CAF cell lines isolated from pancreatic cancer patients and investigate the impact of perturbing potential stromal genes on different CAF subtypes. We also infer the continuum of state changes underlying the interconvertibility of CAF subtypes. Finally, we use immortalized CAF cell lines to perform single-cell CRISPR perturbations of stromal targets, revealing the subtype-specific effects of perturbations and the impact of model-type selection on the translatability of insights.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1253-1269"},"PeriodicalIF":4.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145378022","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":"Checkpoint blockade and the stem-like T cell trade-off.","authors":"Julie M Mazet, Johanna A Joyce","doi":"10.1002/1878-0261.70257","DOIUrl":"10.1002/1878-0261.70257","url":null,"abstract":"<p><p>Stem-like T cells are central to the efficacy of programmed cell death protein 1 (PD1) blockade, sustaining long-term immune responses by serving as a renewable reservoir for anti-tumor effector CD8+ T cells. However, the mechanisms governing their maintenance and regulation in cancer remain incompletely understood. Addressing this gap, Hor et al. combined high-dimensional 3D-imaging with immunological profiling to define the niche of stem-like T cells within tumor-draining lymph nodes in murine cancer models. Their study identifies a critical role for conventional type 1 dendritic cells (cDC1s) and the PD1 pathway in preserving high-affinity tumor-specific stem-like T cells. cDC1s deliver sustained T-cell receptor (TCR) stimulation together with PD-L1/2 co-inhibitory signals that support stemness, proliferation, and survival. Strikingly, disruption of PD1 signaling transiently enhances effector T cell expansion but promotes differentiation and apoptosis of stem-like T cells, ultimately depleting this essential pool. These findings reveal a potential long-term vulnerability of immune checkpoint blockade, particularly when tumors are not eradicated during the initial treatment response.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1093-1097"},"PeriodicalIF":4.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147723400","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":"Therapeutic strategies for MMAE-resistant bladder cancer through DPP4 inhibition.","authors":"Gang Li, Shuichi Tatarano, Hirofumi Yoshino, Saeki Saito, Mitsuhiko Tominaga, Junya Arima, Ikumi Fukuda, Takashi Sakaguchi, Ryosuke Matsushita, Yasutoshi Yamada, Hideki Enokida","doi":"10.1002/1878-0261.70187","DOIUrl":"10.1002/1878-0261.70187","url":null,"abstract":"<p><p>Monomethyl auristatin E (MMAE) is used as the cytotoxic payload for enfortumab vedotin (EV) in the treatment of locally advanced and metastatic bladder cancer (BC). However, the development of resistance to MMAE in BC is a therapeutic problem. To explore the mechanism of resistance to MMAE in BC, we established MMAE-resistant BC cells (MR-BCs). RNA sequencing analysis showed that the expression of dipeptidyl peptidase 4 (DPP4, also called CD26) increased significantly in MR-BCs compared with parental BC cells. Knock down of DPP4 expression using small interfering RNA inhibited the viability of MR-BCs. In addition, the DPP4 inhibitor sitagliptin suppressed the proliferation, migration, and invasion of BC cells, and cotreatment with MMAE effectively induced cell apoptosis, arrested cells in the G₂M phase of the cell cycle, increased reactive oxygen species production by inhibiting the AKT pathway, and significantly inhibited the in vivo growth of MMAE-resistant cells. This study provides insights into the use of DPP4 inhibitors as a treatment strategy for MMAE-resistant BC.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1347-1363"},"PeriodicalIF":4.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145804984","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":"Peroxidasin enables melanoma immune escape by inhibiting natural killer cell cytotoxicity.","authors":"Hsu-Min Sung, David Bickel, Lena C M Krause, Daria Ezeriņa, Christian Ickes, Julian Wojtachnia, Christine S Gibhardt, Magdalena Shumanska, Khadija Wahni, Andrea Paluschkiwitz, Julia Malo Pueyo, Ekaterina Baranova, Wim Vranken, Hedwig Stanisz, Ioana Stejerean-Todoran, Michael P Schön, Joris Messens, Ivan Bogeski","doi":"10.1002/1878-0261.70191","DOIUrl":"10.1002/1878-0261.70191","url":null,"abstract":"<p><p>Peroxidasin (PXDN), an extracellular matrix (ECM)-associated peroxidase, has been implicated in cancer progression. However, its roles in melanoma biology and therapeutic sensitivity remain unclear. Here, we demonstrate that elevated PXDN expression is associated with poor prognosis and reduced survival in melanoma patients. Functional studies revealed that PXDN depletion impairs melanoma cell proliferation, disrupts the cell cycle, and reduces melanoma cell invasive capacities. Furthermore, we found that secreted PXDN modulates anti-melanoma immunity by enhancing melanoma resistance to natural killer (NK)-cell-mediated cytotoxicity. Structural modeling identified a trimeric organization of PXDN, stabilized by disulfide-linked peroxidase domains. Molecular dynamics simulations identified a previously unknown inhibitory interaction between the PXDN N-terminal leucine-rich repeat domain and the NK cell-activating receptor NKG2-D type II integral membrane protein (NKG2D). These findings uncover a redox-independent role for PXDN in promoting immune evasion and tumor progression. Overall, our study highlights PXDN as a critical regulator of melanoma cell biology and a potential therapeutic target for NK-cell-based immunotherapy in melanoma and other solid cancers.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1161-1184"},"PeriodicalIF":4.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146065107","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":"Correction to \"Altered splicing of ATG16-L1 mediates acquired resistance to tyrosine kinase inhibitors of EGFR by blocking autophagy in non-small cell lung cancer\".","authors":"","doi":"10.1002/1878-0261.70247","DOIUrl":"10.1002/1878-0261.70247","url":null,"abstract":"","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1379-1380"},"PeriodicalIF":4.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147530572","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":"Combining antibody conjugates with cytotoxic and immune-stimulating payloads maximizes anti-cancer activity.","authors":"Tiexin Wang, Dong Jun Koo, Peter M Tessier, Greg M Thurber","doi":"10.1002/1878-0261.70198","DOIUrl":"10.1002/1878-0261.70198","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) are rapidly expanding in the clinical treatment of cancers, and combinations with checkpoint inhibitors further enhance antitumor activity in patients sensitive to such immunotherapy. However, a method to improve treatment durability, including cases where immunologically cold tumors limit checkpoint inhibitor activity, is needed. Here, we demonstrate that mixtures of ADCs and immune-stimulating antibody conjugates (ISACs) enhance efficacy compared to either agent alone. Our approach utilizes two non-competitive antibodies to increase the internalization of a tumor-associated antigen (carcinoembryonic antigen, CEA), facilitating the entry of the toxic payload (SN-38, a topoisomerase I inhibitor) into cancer cells. With improved FcγR engagement, the designed ISAC better delivered the immunostimulatory agent (STING agonist) into immune cells. After treatment, the average tumor volume in the combination group was ~40% of the ADC group, and ~30% of the PBS group at day 14. The side effects of combination therapy were tolerable, with an average weight loss of 7% or less after injections. We expect this approach can be readily extended to other ADCs to enhance their efficacy, including for the treatment of immunologically cold tumors.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1220-1236"},"PeriodicalIF":4.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145912461","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":"Exploiting metabolic adaptations to overcome dabrafenib treatment resistance in melanoma cells.","authors":"Silvia Eller, Susanne Ebner, Carmen Haselrieder, Julia K Günther, Astrid Drasche, Sophie Strich, Chiara Volani, Andrea Medici, Aleksandar Nikolajevic, Alex Deltedesco, Johannes E Sigmund, Michael J Blumer, Martin Hermann, Johanna Vanacker, Gerald Brandacher, Eduard Stefan, Omar Torres-Quesada, Jakob Troppmair","doi":"10.1002/1878-0261.70169","DOIUrl":"10.1002/1878-0261.70169","url":null,"abstract":"<p><p>The emergence of resistance to mutant BRAF-specific inhibitors (BRAFi) requires novel strategies for melanoma treatment. The progression of these tumors involves metabolic adaptations, which also affect the cellular redox status. Previous studies have linked RAF kinase signaling, a key component of the MAPK/ERK pathway involved in cell division and survival, to the suppression of mitochondrial reactive oxygen species (ROS) production, resulting in protection against cell death. In BRAF-transformed cells, we have identified impaired JNK1/2-dependent activation of the mitochondrial prooxidant protein p66Shc as a potential cause. In the present study, we dissected signaling and mitochondrial alterations that characterize the transition from BRAFi responsiveness to resistance in A375 melanoma cells. Insensitivity to BRAFi dabrafenib exposure was associated with reactivation of ERK1/2 phosphorylation, increased JNK1/2 kinase activity, p66ShcS36 phosphorylation, and elevated ROS production. Utilizing high-resolution respirometry (HRR) and transmission electron microscopy (TEM), we show that dabrafenib-resistant cells displayed mitochondrial damage, compensated by increased respiration, leading to high ROS levels. Moreover, dabrafenib-resistant cells (A375D) have more efficient antioxidant systems, which may explain why despite ongoing cell death, net cell growth was observed. Treatment of both parental and resistant cells with phenethyl isothiocyanate (PEITC) increased ROS production but caused substantial cell death only in A375D melanoma cells. This PEITC effect could be demonstrated in two further dabrafenib-resistant cell lines, WM164D and 451LuP. These results suggest that the altered redox status is linked to compromised mitochondria and is associated with the development of BRAFi resistance, rendering cells exquisitely sensitive to the actions of selective ROS-inducing therapeutics.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1202-1219"},"PeriodicalIF":4.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661514","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":"RIPK4 function interferes with melanoma cell adhesion and metastasis.","authors":"Norbert Wronski, Sławomir Lasota, Ewelina Madej, Anna A Brożyna, Małgorzata Szczygieł, Agnieszka Harazin-Lechowska, Jan Czerbniak, Janusz Rys, Jaroslaw Czyz, Agnieszka Wolnicka-Glubisz","doi":"10.1002/1878-0261.70220","DOIUrl":"10.1002/1878-0261.70220","url":null,"abstract":"<p><p>Receptor-interacting protein kinase 4 (RIPK4) has been implicated in the progression of numerous tumours. In nonmelanoma skin cancer, RIPK4 plays a suppressor role, whereas in melanoma, it functions as an oncogene that modulates key signalling pathways involved in melanoma cell survival and expansion. Increased RIPK4 levels in metastatic melanoma biopsies prompted us to investigate the consequences of RIPK4 loss for the invasive and metastatic phenotype of melanoma cells. Using an integrated approach involving clinical samples, in vivo xenograft models, transcriptomic analysis and 3D functional assays, we show that RIPK4 deletion significantly reduces pulmonary metastasis formation. This reflects its role in late-stage metastatic events, such as extravasation and colonization, particularly since this phenotype correlates with extensive transcriptional reprogramming of adhesion- and motility-related genes in melanoma cells, as evidenced by next-generation sequencing and functional validation in spheroid and collagen-based models. Despite exhibiting features of a partial shift towards an amoeboid phenotype such as membrane blebbing and increased MLC2 phosphorylation, RIPK4 knockout cells display impaired motility and invasion. Re-expression of RIPK4 restores mesenchymal morphology and migratory capacity. Together, our results establish RIPK4 as a critical regulator of melanoma invasion and metastasis. Nonetheless, they also demonstrate that the loss of RIPK4 function activates compensatory phenotypic shifts in melanoma cells that fail to fully rescue their invasive potential.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"1115-1139"},"PeriodicalIF":4.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142894","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}