Cancer researchPub Date : 2025-08-01DOI: 10.1158/0008-5472.CAN-25-1272
Brent A Hanks
{"title":"Unlocking the Therapeutic Potential of the cGAS-STING Pathway through TREX1 Targeting.","authors":"Brent A Hanks","doi":"10.1158/0008-5472.CAN-25-1272","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-25-1272","url":null,"abstract":"<p><p>Given the limitations observed during the development of stimulator of IFN gene (STING) agonists, investigators have searched for alternative strategies to promote IFN signaling and augment antitumor immunity. Upstream pathways that promote the accumulation of cytosolic cyclic dinucleotides trigger STING activation, revealing a critical role for the three-prime repair exonuclease 1 (TREX1) enzyme, which serves to degrade cytosolic cyclic dinucleotides. In this issue of Cancer Research, Xing and colleagues describe the discovery and immunologic testing of a novel TREX1 inhibitor that augments IFN signaling in situ while promoting CD8+ T-cell immunity and suppressing tumor progression in preclinical tumor models. Utilizing an engineered inducible Trex1 knockout mouse model, the authors show that systemic TREX1 ablation in adult mice induces only modest inflammatory pathology. These studies demonstrate that systemic delivery of a small-molecule inhibitor of TREX1 enhances anti-PD-1 efficacy and suggest that TREX1 targeting may represent an effective strategy for activating the cyclic GMP-AMP synthase-STING pathway in future clinical trials. See related article by Xing et al., p. 2858.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"85 15","pages":"2778-2780"},"PeriodicalIF":16.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer researchPub Date : 2025-08-01DOI: 10.1158/1538-7445.fcs2024-p27
Michał Marek Hoppe, Qing Hao Miow, Nimmi Baby, Carmen Yu Fei Yuen, Yu Hui Cheng, Vikneswari D/O Rajasegaran, Chak Shih Cheah, Xin Xiu Sam, Suman Sarma, Ngak Leng Sim, Anders Martin Jacobsen Skanderup, Radhika Sharma, Yaw Chyn Lim, Jia Hui Liew, Sudhaharan Thankiah, Ruifen Weng, Xing Yi Woo, Jeffrey Lim, Joe Poh Sheng Yeong, Timothy Kwang Yong Tay, Jabed Iqbal, Diana Gkeok Stzuan Lim, Raghav Sundar, Soon Thye Lim, Wee Joo Chng, Alexander Lezhava, Jason Yongsheng Chan, Anand Jeyasekharan
{"title":"Abstract P27: STCC Unified PD1/PD-L1 Evaluation of Response (SUPER) – a Use-Case Study of the Translational Research Integration and Support Platform","authors":"Michał Marek Hoppe, Qing Hao Miow, Nimmi Baby, Carmen Yu Fei Yuen, Yu Hui Cheng, Vikneswari D/O Rajasegaran, Chak Shih Cheah, Xin Xiu Sam, Suman Sarma, Ngak Leng Sim, Anders Martin Jacobsen Skanderup, Radhika Sharma, Yaw Chyn Lim, Jia Hui Liew, Sudhaharan Thankiah, Ruifen Weng, Xing Yi Woo, Jeffrey Lim, Joe Poh Sheng Yeong, Timothy Kwang Yong Tay, Jabed Iqbal, Diana Gkeok Stzuan Lim, Raghav Sundar, Soon Thye Lim, Wee Joo Chng, Alexander Lezhava, Jason Yongsheng Chan, Anand Jeyasekharan","doi":"10.1158/1538-7445.fcs2024-p27","DOIUrl":"https://doi.org/10.1158/1538-7445.fcs2024-p27","url":null,"abstract":"Background & Objectives: Immune Checkpoint Inhibitors hold a significant proportion of the cancer drug market, yet varied responses they elicit present challenges in the clinical setting. Patients who show exceptional and poor responses to this cancer treatment, provide invaluable insights into the factors determining survival outcomes. The SUPER study, a collaboration among multiple institutions, aims to develop and validate a combined assay of predictive biomarkers for PD-1/PD-L1 inhibition leveraging on Singapore Translational Cancer Consortium (STCC)’s Translational and Pre-clinical Research Pipeline. Methods & Results: The study sought to identify one hundred exceptional responders, case-control matched with one hundred hyperprogressors, to PD-1/PD-L1 inhibition across diverse cancer types within two prominent cancer centers in Singapore (NCCS and NCIS). Their archival histopathological specimens were extensively profiled with a suite of genomic and proteomic assays (DNA/RNA sequencing, highly-plexed immunohistochemistry, digital spatial profiling and others) to establish a comprehensive multi-dimensional molecular data repository. This invaluable resource will serve as a foundational tool for developing biomarkers and predictive models that will impact cancer management, optimize public healthcare expenditure, and improve cancer outcomes locally and globally. The process of case identification, coupled with extensive molecular profiling, will be finalized in 2024, with resources and initial analyses slated for public release in 2025. Conclusions: The SUPER study stands as a prime example of conducting cutting-edge, large-scale clinical research studies involving multiple public institutions in Singapore (STCC, NCIS, NCCS, SGH, NUS, GIS, IMCB, DxD Hub, and BII). STCC, a national cancer consortium, operates as an one-stop-shop platform created to meet the demand for a synergized, nationwide translational cancer research. Citation Format: Michał Marek Hoppe, Qing Hao Miow, Nimmi Baby, Carmen Yu Fei Yuen, Yu Hui Cheng, Vikneswari D/O Rajasegaran, Chak Shih Cheah, Xin Xiu Sam, Suman Sarma, Ngak Leng Sim, Anders Martin Jacobsen Skanderup, Radhika Sharma, Yaw Chyn Lim, Jia Hui Liew, Sudhaharan Thankiah, Ruifen Weng, Xing Yi Woo, Jeffrey Lim, Joe Poh Sheng Yeong, Timothy Kwang Yong Tay, Jabed Iqbal, Diana Gkeok Stzuan Lim, Raghav Sundar, Soon Thye Lim, Wee Joo Chng, Alexander Lezhava, Jason Yongsheng Chan and Anand Jeyasekharan. STCC Unified PD1/PD-L1 Evaluation of Response (SUPER) – a Use-Case Study of the Translational Research Integration and Support Platform [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl): nr P27.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"26 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer researchPub Date : 2025-08-01DOI: 10.1158/1538-7445.fcs2024-p38
Reema Baskar, Vairavan Lakshmanan, Audrey Lee, Wilfred Wong, Dane Bagaoisan, Yuhan Peng, Marc Bosse, Ferda Filiz, Christine Fullaway, Sean Bendall, Iain Beehuat Tan, Shyam Prabhakar
{"title":"Abstract P38: Spatial Profiling of Colorectal Cancer Extracellular Milieu Reveals Novel Axes of Immunosuppression and Inflammation","authors":"Reema Baskar, Vairavan Lakshmanan, Audrey Lee, Wilfred Wong, Dane Bagaoisan, Yuhan Peng, Marc Bosse, Ferda Filiz, Christine Fullaway, Sean Bendall, Iain Beehuat Tan, Shyam Prabhakar","doi":"10.1158/1538-7445.fcs2024-p38","DOIUrl":"https://doi.org/10.1158/1538-7445.fcs2024-p38","url":null,"abstract":"Colorectal cancer (CRC) progression is driven by a complex interplay of immunosuppressive and inflammatory mechanisms involving various cell types, functional states, and extracellular milieu. To unravel this intricate relationship, we took a systems biology approach using high resolution spatial distributions of multiple key markers in clinically diverse CRC tumors. We employed Multiplexed Ion Beam Imaging (MIBI-TOF) to capture 65 protein markers across 3,700 fields of view from 250 CRC tumors. This allowed us to deeply characterize the phenotypes and functional states of 5.7 million cells. To incorporate extracellular geography information, we developed a computational approach named CellExt. This quantified and modeled the gradated abundance of key structural and functional proteins found extracellularly, such as fibronectin, granzymeB and vimentin, from each cell boundary to a 40-micron distance in pixelwise steps. CellExt detected a distinct immunosuppressive modality characterized by extracellular PDL1, TNF-related apoptosis-inducing ligand (TRAIL), and matrix metalloproteinase-9 (MMP9). Investigating the cell types involved led us to map the potential receivers and emitters by linking extracellular trends to cellular enrichment and gene expression. We found that Pankeratin-high epithelial cells were acting as TRAIL receivers with downstream activation of non-canonical pro-tumorigenic signaling through S6 phosphorylation. In parallel, we found that T cell suppressive CD40+ antigen-presenting B cells with PD1 expression were acting as MMP9 emitters. Additionally, CellExt was able to identify two spatially segregated inflammatory modalities: IFNgamma cytokine with mucin protein, MUC5AC and prostaglandin synthase, cyclooxygenase-2 with extracellular matrix component, Collagen1A1. This suggests a strong inflammatory role for Collagen1A1 in CRC. We then contextualized our identified modalities by genetic background, tumor stage and CMS subtype of CRC tumors. Taken together, our approach revealed novel axes of immunosuppression and inflammation and puts forward potential extracellular targets for therapeutic intervention in specific CRC patient subsets. Citation Format: Reema Baskar, Vairavan Lakshmanan, Audrey Lee, Wilfred Wong, Dane Bagaoisan, Yuhan Peng, Marc Bosse, Ferda Filiz, Christine Fullaway, Sean Bendall, Iain Beehuat Tan, Shyam Prabhakar. Spatial Profiling of Colorectal Cancer Extracellular Milieu Reveals Novel Axes of Immunosuppression and Inflammation [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl): nr P38.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"136 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer researchPub Date : 2025-08-01DOI: 10.1158/1538-7445.fcs2024-p11
Pauline Lascaux, Gwendoline Hoslett, Sara Tribble, Ivan Antičević, Cecile Otten, Ignacio Torrecilla, Yichen Zhao, Wei Song, Cristiano Peron, Giulio Deangeli, Enric Domingo, James Bancroft, Loïc Carrique, Errin Johnson, Alvin Wei Tian Ng, Joanne Ngeow, Nuno Raimundo, Tim Maughan, Marta Popović, Ira Milošević, Kristijan Ramadan
{"title":"Abstract P11: TEX264 DRIVES SELECTIVE AUTOPHAGY OF DNA LESIONS TO PROMOTE DNA REPAIR AND CELL SURVIVAL","authors":"Pauline Lascaux, Gwendoline Hoslett, Sara Tribble, Ivan Antičević, Cecile Otten, Ignacio Torrecilla, Yichen Zhao, Wei Song, Cristiano Peron, Giulio Deangeli, Enric Domingo, James Bancroft, Loïc Carrique, Errin Johnson, Alvin Wei Tian Ng, Joanne Ngeow, Nuno Raimundo, Tim Maughan, Marta Popović, Ira Milošević, Kristijan Ramadan","doi":"10.1158/1538-7445.fcs2024-p11","DOIUrl":"https://doi.org/10.1158/1538-7445.fcs2024-p11","url":null,"abstract":"DNA repair and autophagy are distinct biological processes vital for cell survival. Although autophagy helps maintain genome stability, there is no evidence of its direct role in the repair of DNA lesions. We discovered that lysosomes process Topoisomerase 1-cleavage complexes (TOP1cc) DNA lesions in human cancer cell. TOP1 resolves DNA topological stress ahead of DNA replication and transcription. If not promptly repaired, TOP1cc hinder the progression of DNA replication and transcription fostering genomic instability. Thus, stabilising TOP1cc with TOP1 poisons, such as Camptothecin or its analogue, is highly effective and widely used in cancer therapy. Proteolysis of TOP1cc by the proteasome is described at excessively high doses of CPT that are not relevant in a clinical setting, calling into question the relevance of the proteasome role in TOP1cc repair for cancer therapy and patient response. Here we described that repair of TOP1cc induced by clinically relevant dose of Camptothecin depends on selective autophagy. Proteomics, sequencing, biochemistry techniques and live imaging all demonstrate the lysosomal uptake of TOP1cc upon induction of replication stress. Selective degradation of TOP1cc by autophagy directs DNA damage repair and cell survival. TOP1cc are exported from the nucleus to lysosomes through transient alteration of the nuclear envelope and independent of the proteasome. Mechanistically, the autophagy receptor TEX264 acts as a TOP1cc sensor at DNA replication forks, triggering TOP1cc processing by the p97 ATPase and mediating the delivery of TOP1cc to lysosomes in an MRE11 nuclease and ATR kinase-dependent manner. We found an evolutionarily conserved role for selective autophagy in DNA damage repair that enables cell survival, protects genome stability, and is clinically relevant for colorectal cancer patients. Citation Format: Pauline Lascaux, Gwendoline Hoslett, Sara Tribble, Ivan Antičević, Cecile Otten, Ignacio Torrecilla, Yichen Zhao, Wei Song, Cristiano Peron, Giulio Deangeli, Enric Domingo, James Bancroft, Loïc Carrique, Errin Johnson, Alvin Wei Tian Ng, Joanne Ngeow, Nuno Raimundo, Tim Maughan, Marta Popović, Ira Milošević, and Kristijan Ramadan. TEX264 DRIVES SELECTIVE AUTOPHAGY OF DNA LESIONS TO PROMOTE DNA REPAIR AND CELL SURVIVAL [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl): nr P11.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"94 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer researchPub Date : 2025-08-01DOI: 10.1158/1538-7445.fcs2024-p61
Phuong Mai Hoang, Wai Khang Yong, Dennis Kappei, Anand D. Jeyasekharan
{"title":"Abstract P61: SURFACEOME PROFILING TO IDENTIFY TARGETABLE CELL SURFACE ANTIGENS IN SOFT TISSUE SARCOMAS","authors":"Phuong Mai Hoang, Wai Khang Yong, Dennis Kappei, Anand D. Jeyasekharan","doi":"10.1158/1538-7445.fcs2024-p61","DOIUrl":"https://doi.org/10.1158/1538-7445.fcs2024-p61","url":null,"abstract":"Soft tissue sarcomas (STS) represent rare cancers originating from mesenchymal tissues, featuring over 70 histological subtypes with diverse genetic defects and clinical outcomes. Current treatment options for STS mainly involve surgical procedures and anthracycline-based chemotherapy, which often prove ineffective across multiple STS subtypes. Consequently, there's a pressing need for novel, STS-specific therapies. Targeting cell surface antigens expressed exclusively in STS has emerged as a promising approach. However, the surfaceome of STS remains largely uncharacterized. In our research, we employed mass spectrometry to analyze biotinylated and immunoprecipitated cell surface proteins expressed in STS cell lines and patient samples. Through this method, we've identified several promising cell surface antigens that could potentially serve as therapeutic targets for STS. Further validation of these antigens across various experimental settings is crucial to confirm their efficacy and pave the way for new strategies in STS treatment. Citation Format: Phuong Mai Hoang, Wai Khang Yong, Dennis Kappei, Anand D. Jeyasekharan. SURFACEOME PROFILING TO IDENTIFY TARGETABLE CELL SURFACE ANTIGENS IN SOFT TISSUE SARCOMAS [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl): nr P61.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"68 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer researchPub Date : 2025-08-01DOI: 10.1158/1538-7445.fcs2024-lt03
Aleksandr Mitriashkin, Josephine Yu Yan Yap, N. Gopalakrishna Iyer, Gianluca Grenci, Eliza Li Shan Fong
{"title":"Abstract LT03: Cell confinement by micropatterning induces phenotypic changes in cancer-associated fibroblasts","authors":"Aleksandr Mitriashkin, Josephine Yu Yan Yap, N. Gopalakrishna Iyer, Gianluca Grenci, Eliza Li Shan Fong","doi":"10.1158/1538-7445.fcs2024-lt03","DOIUrl":"https://doi.org/10.1158/1538-7445.fcs2024-lt03","url":null,"abstract":"Recent advances in single-cell studies have unveiled the extensive transcriptomic heterogeneity of cancer-associated fibroblasts (CAFs), with each subset potentially playing unique roles in the tumor microenvironment. Despite these insights, it remains unclear how to culture different subsets of CAFs in vitro while preserving their in vivo phenotype. The inherent plasticity of CAFs, characterized by their ability to dynamically alter their phenotype in response to various environmental stimuli, presents significant challenges in inducing and maintaining specific CAF states in vitro. In this study, we investigated the effects of cell shape and confinement on two-dimensional culture substrates on the transcriptomic profile and phenotype of cultured CAFs. By inducing cytoskeletal rearrangement and activating mechanotransductory pathways through micropatterning of polyacrylamide hydrogels, we observed significant shape- and confinement-dependent changes in cell morphology. Our results showed that micropatterned CAFs exhibited phenotypic shifts towards more myofibroblastic, desmoplastic and inflammatory subsets. Additionally, micropatterning allowed for control over a range of CAF-specific markers and pathways, significantly altering their transcriptome landscape and behavior. Lastly, we demonstrated that micropatterned and non-micropatterned CAFs responded differently to anti-cancer drugs, underscoring the importance of phenotype-oriented therapy that accounts for CAF plasticity and regulatory networks. Control over CAF morphology through micropatterning presents a unique opportunity to establish highly robust CAF phenotypes in vitro, thereby facilitating a deeper understanding of CAF plasticity and heterogeneity. This approach also holds promise for the development of novel therapeutic targets, as it allows for the precise manipulation of CAF states to better model and study their interactions within the tumor microenvironment. Citation Format: Aleksandr Mitriashkin, Josephine Yu Yan Yap , N. Gopalakrishna Iyer , Gianluca Grenci, Eliza Li Shan Fong. Cell confinement by micropatterning induces phenotypic changes in cancer-associated fibroblasts [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl): nr LT03.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"136 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer researchPub Date : 2025-08-01DOI: 10.1158/1538-7445.fcs2024-p16
Daryl Chin, Ziliang Ma, Wei Wu
{"title":"Abstract P16: Characterisation of the MSS-CRC surface proteome for novel immunotherapeutic target discovery","authors":"Daryl Chin, Ziliang Ma, Wei Wu","doi":"10.1158/1538-7445.fcs2024-p16","DOIUrl":"https://doi.org/10.1158/1538-7445.fcs2024-p16","url":null,"abstract":"The integral role of cell-surface proteins as key communicators and interactors with the external environment can orchestrate cancer initiation and progression. Consequently, the tumour surface proteome (‘surfaceome’) is often remodelled during tumorigenesis and metastasis, representing an abundant resource for potential immunotherapeutic target discovery. Microsatellite-stable colorectal cancer (MSS-CRC) is notorious for its immunosuppressive tumour microenvironment and poor efficacy towards existing single-arm and combinations of immunotherapies. With a paucity of immune-druggable surface targets, we focused on deconvoluting the MSS-CRC ‘surfaceome’ for novel immunotherapeutic target identification. Here, we performed extracellular biotinylation of MSS-CRC patient-derived organoids, and quantitative proteomics on affinity-enriched membrane proteins, comparing healthy, primary and metastatic MSS-CRC. From a total pool of 487 highly confident surface proteins, we first demonstrate the reliability and clinical relevance of our dataset through the detection of high levels of prominent CRC progression markers CDH17, LY75 and CA9. Importantly, we shortlisted 2 potential targets DPEP1 and SCARB1 which displayed differentially upregulated protein expression in primary MSS-CRC and further validated using tissue microarray and gene silencing approaches. In this clinically relevant dataset, we also unveil a novel MSS-CRC progression marker, ITGB8, which showed sequential downregulation from healthy to metastatic MSS-CRC. The discovery of these MSS-CRC-specific targets and progression markers holds promise in elucidating underlying molecular mechanisms driving MSS-CRC. Ultimately, we aim to progress targeted therapeutic approaches in MSS-CRC which culminates in the construction of a therapeutic decision tree for precise clinical intervention selection tailored to each MSS-CRC patient. Citation Format: Daryl Chin, Ziliang Ma, Wei Wu. Characterisation of the MSS-CRC surface proteome for novel immunotherapeutic target discovery [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl): nr P16.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"15 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer researchPub Date : 2025-08-01DOI: 10.1158/1538-7445.fcs2024-p18
Fatima Alaydaroos, Yoko Itahana, Koji Itahana
{"title":"Abstract P18: p53-induced Methyltransferase Increases Cancer Cell Vulnerability to Cell Death","authors":"Fatima Alaydaroos, Yoko Itahana, Koji Itahana","doi":"10.1158/1538-7445.fcs2024-p18","DOIUrl":"https://doi.org/10.1158/1538-7445.fcs2024-p18","url":null,"abstract":"p53 is a transcription factor that regulates the expression of target genes involved in anti-proliferative processes such as cell cycle arrest, apoptosis, and senescence, thereby establishing its canonical role as a tumor suppressor. Due to its substantial network of target genes, p53 is also involved in non-canonical tumor suppression pathways that are yet to be fully explored. During the search of these pathways, we identified one of the methyltransferases as a novel p53 target gene. It’s been reported that this methyltransferase is downregulated in various cancers, suggesting potential tumor suppressive function. However, the specific target of this methyltransferase and its role in the mechanism of p53-mediated tumor suppression remains elusive. In this study, we show that p53 directly binds to intron 1 of this methyltransferase gene and activates its transcription and protein expression. Furthermore, we identify dihydrolipoic acid (DHLA), an important redox cofactor, as a novel target of this methyltransferase. We show that this methyltransferase enhances cellular sensitivity to oxidative stress-induced cell death by potentially methylating DHLA. Our studies reveal a novel role for p53 in regulating the well-known antioxidant DHLA to control cell death and suggest potential therapeutic strategies in promoting cancer cell death through p53 activation drugs. Citation Format: Fatima Alaydaroos, Yoko Itahana, Koji Itahana. p53-induced Methyltransferase Increases Cancer Cell Vulnerability to Cell Death [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl): nr P18.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"326 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer researchPub Date : 2025-08-01DOI: 10.1158/1538-7445.fcs2024-p60
Yunmi Ko, Heejung Na, Jun Ah Lee
{"title":"Abstract P60: CD47 in Osteosarcoma: Correlation with Metastasis and Macrophage-Mediated Phagocytosis","authors":"Yunmi Ko, Heejung Na, Jun Ah Lee","doi":"10.1158/1538-7445.fcs2024-p60","DOIUrl":"https://doi.org/10.1158/1538-7445.fcs2024-p60","url":null,"abstract":"CD47 is expressed on cell surfaces and act as “don’t eat me” signal by interacting with SIRPα of the macrophage surface. In certain types of cancer, cancer cells express CD47 protein and are presumed to evade macrophage phagocytosis. In this study, we evaluated the feasibility of targeting CD47 for osteosarcoma by analyzing its expression patterns, clinicopathological correlations, and immunotherapeutic potential. We performed a retrospective analysis on 24 biopsy samples from osteosarcoma patients to investigate correlations between CD47 protein positivity and clinicopathologic characteristics. CD47 protein expression was identified in 20.8% of the biopsy samples, with a correlation between CD47 positivity and metastasis at diagnosis (P=0.04). Patients with CD47-positive tumors tended to be older than those with CD47-negative tumors (P=0.07). However, no association was found between CD47 protein expression and sex, tumor size, or histologic response to preoperative chemotherapy. In vitro, CD47 antibody (B6H12) did not significantly affect osteosarcoma cell proliferation or apoptosis. In a wound-healing assay, CD47 antibody (B6H12) inhibited the migration of osteosarcoma cells. Furthermore, differentiated macrophages exhibited significantly higher phagocytic activity against osteosarcoma cells when pretreated with CD47 antibodies (B6H12), compared to isotype control (P&lt;0.01). Taken together, our preliminary data suggest a possible interaction between CD47 protein and macrophage phagocytosis in metastasis of osteosarcoma. Further studies are necessary for a better understanding the role of CD47 in osteosarcoma and an innovative immunotherapy approach against this formidable malignancy. Citation Format: Yunmi Ko, Heejung Na, Jun Ah Lee. CD47 in Osteosarcoma: Correlation with Metastasis and Macrophage-Mediated Phagocytosis [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl): nr P60.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"77 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer researchPub Date : 2025-08-01DOI: 10.1158/1538-7445.fcs2024-p50
Isaac Lin, Rutharra Ghayadthri Manisekaran, Joanne Ngeow
{"title":"Abstract P50: Whole Genome Sequencing Reveals a High Incidence of Germline Pathogenic Variants in Genes Associated with Sarcoma Across Subtypes","authors":"Isaac Lin, Rutharra Ghayadthri Manisekaran, Joanne Ngeow","doi":"10.1158/1538-7445.fcs2024-p50","DOIUrl":"https://doi.org/10.1158/1538-7445.fcs2024-p50","url":null,"abstract":"Sarcomas are heterogeneous mesenchymal cancers originating from bone and soft tissue, accounting for 1% of adult and 21% of paediatric solid tumours [1]. Despite their sporadic nature, sarcomas have been linked to genetic predisposition, particularly in children, contributing to their poor prognosis and subtype-specific genomic alterations [2][3]. This study aims to identify pathogenic variants predisposing individuals to sarcoma, thereby enhancing genetic screening, prognosis, and treatment. Additionally, it seeks to investigate genotype-phenotype correlations and explore genetic differences across subtypes. We included 115 probands from the National Cancer Centre Singapore, comprising 50% liposarcomas, 45% leiomyosarcomas, and 5% malignant peripheral nerve sheath tumours (MPNST). The median age of diagnosis was 54 years with a balanced gender ratio. Whole genome sequencing on peripheral blood DNA was performed using Illumina short reads, and germline variants were called with both DeepVariant and GATK HaplotypeCaller. Pathogenic (P) and likely pathogenic (LP) variants were identified following ACMG criteria. Our analysis revealed 5.2% of probands carried at least one P variant, while 10.4% carried at least one LP variant in genes associated with sarcoma risk, such as DMNT3A, NF1, TP53, and TYK2. One notable case involves a proband with both NF1 and TYK2 variants, where our analysis suggests that both variants likely contribute to the development of liposarcoma, as NF1 loss-of-function variants and TYK2 mutations have been implicated in sarcoma and related cancer syndromes [4][5]. To ensure the accuracy of our findings, all identified P and LP variants will be validated through Sanger sequencing, strengthening the evidence for their role in sarcoma predisposition. In conclusion, our study highlights the need for genetic screening in patients with sporadic sarcomas. Citation Format: Isaac Lin, Rutharra Ghayadthri Manisekaran, Joanne Ngeow. Whole Genome Sequencing Reveals a High Incidence of Germline Pathogenic Variants in Genes Associated with Sarcoma Across Subtypes [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl): nr P50.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"20 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144755784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}