Katia De Marco, Marialaura Latrofa, Giovanna Forte, Martina Lepore Signorile, Elisabetta Di Nicola, Paola Sanese, Candida Fasano, Vittoria Disciglio, Erica Candela, Sergio Coletta, Valentina Grossi, Cristiano Simone
{"title":"Targeting the DNA-repair chromatin-modifier protein SMYD3 as a novel epigenetics-based therapy for gastric cancer.","authors":"Katia De Marco, Marialaura Latrofa, Giovanna Forte, Martina Lepore Signorile, Elisabetta Di Nicola, Paola Sanese, Candida Fasano, Vittoria Disciglio, Erica Candela, Sergio Coletta, Valentina Grossi, Cristiano Simone","doi":"10.1186/s13046-026-03823-2","DOIUrl":"10.1186/s13046-026-03823-2","url":null,"abstract":"<p><strong>Background: </strong>SMYD3 is a histone methyltransferase implicated in cancer progression and is overexpressed in several malignancies, including gastric cancer (GC). Building on previous evidence linking SMYD3 to DNA damage repair, we investigated the molecular mechanisms through which SMYD3 regulates double-strand break (DSB) repair in GC and evaluated its therapeutic potential.</p><p><strong>Methods: </strong>In silico and in vitro analyses were performed to investigate the interactions between SMYD3 and key homologous recombination (HR) proteins, and to evaluate the ATM-mediated phosphorylation of SMYD3. Functional assays assessed the impact of pharmacological SMYD3 inhibition on HR and non-homologous end joining (NHEJ) repair pathways.</p><p><strong>Results: </strong>Mechanistically, SMYD3 interacted with key HR factors and facilitated chromatin remodeling at damaged sites. ATM phosphorylated SMYD3 at threonine 22, a modification required for HR complex assembly and validated in GC patient samples following neoadjuvant chemotherapy. Inhibition of SMYD3 abolished HR and partially impaired NHEJ. Combined inhibition of SMYD3 and PARP induced synthetic lethality in GC cells, spheroids, and patient-derived organoids, and overcame resistance to olaparib.</p><p><strong>Conclusions: </strong>These findings reveal the ATM-dependent molecular mechanism by which SMYD3 regulates DNA DSB repair, further supporting SMYD3 as a promising therapeutic target for precision oncology strategies in GC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149031756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction: Supervillin promotes epithelialmesenchymal transition and metastasis of hepatocellular carcinoma in hypoxia via activation of the RhoA/ROCK-ERK/p38pathway.","authors":"Xueran Chen, Shangrong Zhang, Zhen Wang, Fengsong Wang, Xinwang Cao, Quan Wu, Chenggang Zhao, Huihui Ma, Fang Ye, Hongzhi Wang, Zhiyou Fang","doi":"10.1186/s13046-026-03820-5","DOIUrl":"10.1186/s13046-026-03820-5","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fabio Bozzi, Angela Mogavero, Luca Varinelli, Antonino Belfiore, Giacomo Manenti, Claudio Caccia, Chiara C Volpi, Galina V Beznoussenko, Massimo Milione, Valerio Leoni, Annunziata Gloghini, Alexandre A Mironov, Ermanno Leo, Silvana Pilotti, Marco A Pierotti, Italia Bongarzone, Manuela Gariboldi
{"title":"Correction: MIF/CD74 axis is a target for novel therapies in colon carcinomatosis.","authors":"Fabio Bozzi, Angela Mogavero, Luca Varinelli, Antonino Belfiore, Giacomo Manenti, Claudio Caccia, Chiara C Volpi, Galina V Beznoussenko, Massimo Milione, Valerio Leoni, Annunziata Gloghini, Alexandre A Mironov, Ermanno Leo, Silvana Pilotti, Marco A Pierotti, Italia Bongarzone, Manuela Gariboldi","doi":"10.1186/s13046-026-03801-8","DOIUrl":"https://doi.org/10.1186/s13046-026-03801-8","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13488119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148801070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kathryn A F Pennel, Phimmada Hatthakarnkul, Colin S Wood, Guang-Yu Lian, Sara S F Al-Badran, Jean A Quinn, Assya Legrini, Jitwadee Inthagard, Peter G Alexander, Hester van Wyk, Ahmad Kurniawan, Umar Hashmi, Michael A Gillespie, Megan Mills, Aula Ammar, Jennifer Hay, Ditte Andersen, Colin Nixon, Selma Rebus, David K Chang, Caroline Kelly, Andrea Harkin, Janet Graham, David Church, Ian Tomlinson, Mark Saunders, Tim Iveson, Tamsin R M Lannagan, Rene Jackstadt, Noori Maka, Paul G Horgan, Campbell S D Roxburgh, Owen J Sansom, Donald C McMillan, Colin W Steele, Nigel B Jamieson, James H Park, Antonia K Roseweir, Joanne Edwards
{"title":"Correction: JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal‑rich.","authors":"Kathryn A F Pennel, Phimmada Hatthakarnkul, Colin S Wood, Guang-Yu Lian, Sara S F Al-Badran, Jean A Quinn, Assya Legrini, Jitwadee Inthagard, Peter G Alexander, Hester van Wyk, Ahmad Kurniawan, Umar Hashmi, Michael A Gillespie, Megan Mills, Aula Ammar, Jennifer Hay, Ditte Andersen, Colin Nixon, Selma Rebus, David K Chang, Caroline Kelly, Andrea Harkin, Janet Graham, David Church, Ian Tomlinson, Mark Saunders, Tim Iveson, Tamsin R M Lannagan, Rene Jackstadt, Noori Maka, Paul G Horgan, Campbell S D Roxburgh, Owen J Sansom, Donald C McMillan, Colin W Steele, Nigel B Jamieson, James H Park, Antonia K Roseweir, Joanne Edwards","doi":"10.1186/s13046-026-03811-6","DOIUrl":"https://doi.org/10.1186/s13046-026-03811-6","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13476925/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148765972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vrunda Satasiya, Canio Martinelli, Gabriel Pascal, Giacomo Ducci, Elisa Ventura, Stephen J Williams, Sharon Raffaella Burk, Manuela Nana Tchamou, Shendi Shani, Michele Klain, Elena Sacco, Marco Vanoni, Antonino Belfiore, Renato V Iozzo, Antonio Giordano, Andrea Morrione
{"title":"Functional characterization of FAM120A as a novel effector in the progranulin/EphA2 oncogenic axis in bladder cancer.","authors":"Vrunda Satasiya, Canio Martinelli, Gabriel Pascal, Giacomo Ducci, Elisa Ventura, Stephen J Williams, Sharon Raffaella Burk, Manuela Nana Tchamou, Shendi Shani, Michele Klain, Elena Sacco, Marco Vanoni, Antonino Belfiore, Renato V Iozzo, Antonio Giordano, Andrea Morrione","doi":"10.1186/s13046-026-03808-1","DOIUrl":"10.1186/s13046-026-03808-1","url":null,"abstract":"<p><strong>Background: </strong>Bladder cancer (BC) is one of the most deadly diseases in the USA, with 84,530 new cases and 17,870 estimated deaths in 2026. The growth factor progranulin is involved in several human pathologies, including frontotemporal dementia (FTD), immune response, and cancer. We showed that in BC, progranulin and its signaling receptor, EphA2, drive tumor cell motility, invasion, and in vivo tumor formation, making it a critical pathway in tumor establishment. However, the molecular mechanisms of progranulin/EphA2 action are still poorly defined.</p><p><strong>Methods: </strong>Progranulin-dependent EphA2 interactome was explored by proteomic approaches. FAM120A or EphA2 protein levels in BC tissue microarrays (TMAs) and FAM120A protein expression in BC cell lines were analyzed by immunohistochemistry (IHC) and immunoblots, respectively. Progranulin-dependent activation of AKT and ERK1/2 were examined by western immunoblots. EphA2-FAM120A interaction was detected using Co-immunoprecipitation and proximity ligation assays (PLA). In addition, EphA2 and FAM120A colocalization and F-actin cytoskeleton rearrangements were assessed by immunofluorescence. The biological function of FAM120A was determined using lentiviral shRNA approaches, wound healing, motility and invasion, spheroid, soft agar, clonogenic assays, cell cytotoxicity, and in vivo xenograft models.</p><p><strong>Result: </strong>We conducted proteomic approaches and identified novel progranulin-dependent EphA2 interactors, including FAM120A, which is a scaffold protein with a putative role in oncogenic pathways. We confirmed that the EphA2 and FAM120A interaction was enhanced upon progranulin stimulation, and FAM120A was upregulated in BC tissues. We further demonstrated that FAM120A was critical for progranulin-evoked AKT and ERK1/2 activation, clonogenic capacity, wound healing, motility, invasion, and 3D spheroid formation of BC cell lines. In addition, FAM120A was essential for anchorage-independent growth and in vivo tumorigenesis in xenograft models. In addition, FAM120A depletion sensitized BC cells to cisplatin treatment. Mechanistically, we showed that FAM120A depletion inhibited progranulin-dependent F-actin cytoskeleton rearrangement through ERK1/2 and RhoA-dependent pathways. Furthermore, we demonstrated that progranulin-induced activation of RhoA was inhibited upon FAM120A depletion.</p><p><strong>Conclusion: </strong>The discovery of FAM120A as an oncogenic progranulin-dependent EphA2 interactor provides novel insights into the progranulin/EphA2 signaling axis and uncovers putative novel targets for BC therapy. Furthermore, FAM120A expression may work as a biomarker with diagnostic and possibly prognostic value in BC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149031842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Katie Stoker, Roman Laddach, Lucy Booth, Silvia Crescioli, Oscar Maiques, Rebecca Adams, Jitesh Chauhan, Alexander Stewart, Dinethri Patel, Amanda Fitzpatrick, Yin Wu, Jenny L C Geh, Omar Salem, Alastair D MacKenzie Ross, Hawys Lloyd-Hughes, Sean Whittaker, Joseph Ng, Franca Fraternali, David Kipling, Deborah K Dunn-Walters, Katie E Lacy, Thomas J Tull, Sophia Tsoka, Sophia N Karagiannis
{"title":"Tumor-infiltrating B cells evolve towards interferon-rich trajectories aligned with immunotherapy in melanoma.","authors":"Katie Stoker, Roman Laddach, Lucy Booth, Silvia Crescioli, Oscar Maiques, Rebecca Adams, Jitesh Chauhan, Alexander Stewart, Dinethri Patel, Amanda Fitzpatrick, Yin Wu, Jenny L C Geh, Omar Salem, Alastair D MacKenzie Ross, Hawys Lloyd-Hughes, Sean Whittaker, Joseph Ng, Franca Fraternali, David Kipling, Deborah K Dunn-Walters, Katie E Lacy, Thomas J Tull, Sophia Tsoka, Sophia N Karagiannis","doi":"10.1186/s13046-026-03797-1","DOIUrl":"10.1186/s13046-026-03797-1","url":null,"abstract":"<p><strong>Background: </strong>B cells are increasingly recognized regulators of antitumor immunity in melanoma, yet their differentiation states, lineage dynamics, spatial organization and integration within the immune microenvironment, and how these are influenced with immunotherapy remain incompletely defined.</p><p><strong>Methods: </strong>We conducted deep profiling of tumor-resident B cell differentiation and evolutionary features in the melanoma tumor microenvironment using bulk, single-cell and spatial transcriptomic analyses, long-read antibody sequencing and mass cytometry (Cytometry by Time-Of-Flight, CyTOF). We characterized B cell differentiation trajectories, class-switching patterns, antibody isotype usage, signaling pathways, spatial niches against clinicopathological features and immune cell communication, before and after checkpoint blockade and in clinically defined responders and non-responders.</p><p><strong>Results: </strong>Melanoma-infiltrating B cells were enriched across primary and metastatic lesions, were preferentially associated with immune-rich tumors and correlated with T and natural killer (NK) cell densities. Long-read immunoglobulin sequencing demonstrated recurrent class switch recombination (CSR) trajectories with predominant IgG and IgA isotype usage, confirmed by bulk transcriptomic analyses. Across independent single-cell and bulk transcriptomic datasets we identified conserved class-switching, B cell receptor (BCR) activation, and pseudotime analyses showed differentiation trajectories progressing from naïve and memory states toward interferon (IFN)-driven terminal differentiation trajectories that persisted before and after immunotherapy. CyTOF analyses independently confirmed proliferative, germinal center (GC)-like, memory and class-switched B cell subsets, suggesting conserved inflammatory differentiation endpoints. Spatial transcriptomic deconvolution identified IFN-rich B cells within tertiary lymphoid structures (TLS). Following immunotherapy, B cells retained class-switched trajectories, displayed enriched GC-associated profiles, enhanced crosstalk with T cells and Dendritic Cells (DCs) and preserved or induced IFN-rich IgM + /IgD + or IgG4 + phenotypes, suggesting persistence or emergence of non-class switched and atypical class-switched isotype profiles. Transcriptomic analyses of B cells pointed to upregulated antigen-driven stimulation and BCR signaling, whereas in non-responders displayed IFN-rich B cells, IFN-associated genes, and IFN-pathway enrichment.</p><p><strong>Conclusions: </strong>Melanoma-infiltrating B cells follow class-switched differentiation trajectories culminating in IFN signaling, atypical antibody expressing states that persist or emerge after immunotherapy, aligning dynamic B cell evolution and atypical lineage traits with immunotherapy.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13505104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148820173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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