tbuckley/cabot-search huggingface dataset:
Abstract 4117: ADAR1-mediated RNA editing of KCTD13s promotes pancreatic cancer metastasis by impeding RhoA ubiquitination
Authors: Lingxing Zeng, Xiaoyu Wu, Ziming Chen, Jian Zheng
Journal: Cancer Research (2025)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with limited therapeutic options and a poor prognosis. Adenosine-to-inosine (A-to-I) RNA editing, a crucial post-transcriptional modification, introduces nucleotide changes in RNA sequences. However, few protein-recoding editing targets with functional significance have been identified. In this study, we propose that the ADAR1-KCTD13s-RhoA/ROCK1 signaling axis plays a critical role in PDAC progression. Methods: We performed an in-depth analysis of A-to-I RNA editing using RNA-sequencing, validated by Sanger sequencing. In vitro phenotypic assays, including proliferation, colony formation, migration, and invasion tests, were conducted. In vivo studies included an orthotopic pancreatic tumor growth model and a lung metastasis model. Protein interactions were evaluated using immunoprecipitation, protein stability was assessed with cycloheximide (CHX) treatment, and ubiquitination was examined with MG132 treatment. Results: Our analysis of A-to-I modifications in PDAC tissues and cell lines identified KCTD13s as a novel protein-recoding RNA editing target. Increased KCTD13s editing levels, driven by the overexpression of adenosine deaminase acting on RNA 1 (ADAR1), were associated with poor survival in PDAC patients. Functional experiments demonstrated that KCTD13s editing promotes pancreatic cancer metastasis. Mechanistically, this amino acid alteration stabilizes the KCTD13s protein by preventing its ubiquitination. The stabilized KCTD13s competes with KCTD13 for binding to CUL3, inhibiting RhoA ubiquitination. This results in elevated RhoA protein levels and activation of the RhoA/ROCK1 signaling pathway. Conclusion: Our findings illuminate the malignancy-promoting role of the ADAR1-KCTD13s-RhoA/ROCK1 signaling axis in PDAC. This study reveals an epigenetic regulatory mechanism mediated by A-to-I RNA editing and highlights the potential of targeting epitranscriptomic pathways for therapeutic intervention in PDAC. Citation Format: Lingxing Zeng, Xiaoyu Wu, Ziming Chen, Jian Zheng. ADAR1-mediated RNA editing of KCTD13s promotes pancreatic cancer metastasis by impeding RhoA ubiquitination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4117.
Abstract 4118: Decoding the noncoding: An insight into the noncoding genome of breast cancers
Authors: Arnau Cuy Saques, Anita White, Kaneez Rabab, Philip Scarry, Francesca Matra, Craig Monger, Adrian Bracken, John Crown, Alexander Eustace
Journal: Cancer Research (2025)

Introduction: The PI3K/AKT pathway, a key oncogenic signalling pathway, is mutated in 70% of breast cancers (BC). PI3K/AKT coding mutations promote BC progression and are associated with poor survival. However, coding mutations represent &amp;lt;1% of the whole genome. Non-coding mutations (NCMs) can promote oncogenic gene expression in several cancers, including BC. Further study on NCMs can enhance our understanding of BC and help identify novel treatments targets. Experimental procedure: NCMs surrounding kinome genes were identified from whole genome sequencing of 915 BC tumours. NCMs were prioritised based on recurrence and analysed with the Activity by Contact (ABC) bioinformatic model, which estimates their likelihood to interact with transcription start sites (TSS) and indicates their enhancer potential. Epigenetic data (Hi-C and H3K27ac, ChIP Seq) from BC cell lines (n=12) was screened to identify BC subtype-specific epigenetic changes surrounding the prioritised NCMs. The NCMs’ regulatory effect over gene expression was confirmed by luciferase reporter assays. Results: We identified 3,546 recurrent NCMs surrounding kinome genes in BCs and observed an enrichment of NCMs in gene loci of PI3K/AKT pathway members (p=0.005). We discovered subtype-specific enrichment of NCMs around oncogenes, like AKT2 in HR+ BCs (29/398, 7.2%) or AKT3 for TNBC (21/444, 4.7%). Of the 152 NCMs analysed, 17 (11.2%) reported positive by ABC analysis. 6/17 NCMs were identified in the gene loci of AKT2 or AKT3 (ABC scores 0.023-0.1) and were predicted to interact with genes up to 75kb from the NCM. Epigenetic analysis of ER+ and TNBC cell lines reported peaks of enhancer activity near the AKT2 and AKT3 NCMs, thus supporting the ABC analysis. Luciferase assays confirmed a 1.6-fold increase in luciferase expression for an AKT2 gene loci NCM (AC_A, chr19:41858248) and a 3-fold increase in luciferase expression for an AKT3 gene loci NCM (-_AT, chr1:244065861), whilst we observed a 3-fold decrease for a NCM in AKT2 gene loci (CAG_C, chr19:39686510). Conclusions: We have identified that BCs have an enrichment of NCMs surrounding PI3K/AKT pathway genes. NCMs in the gene loci of AKT2 and 3 were predicted to interact with distal genes and luciferase reporter assays confirmed their regulatory effects in vitro. These results highlight the potential of NCMs to drive BC oncogenesis and potentially act as targets for drug development. Citation Format: Arnau Cuy Saques, Anita White, Kaneez Rabab, Philip Scarry, Francesca Matra, Craig Monger, Adrian Bracken, John Crown, Alexander Eustace. Decoding the noncoding: An insight into the noncoding genome of breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4118.
Abstract 3904: Clonal analysis of classical subtypes of pancreatic cancer stem cells in ascites
Authors: Wa Xian, Frank McKeon, Paul Daniel, Saeed Khan, Caycel Desales, Ashley Hoffman, Jaffer Ajani
Journal: Cancer Research (2025)

It is now established that pancreatic cancer often displays an intratumor heterogeneity at the levels of epithelial cell types, stromal activation, and immune signaling that is likely germane to therapeutic resolution. While the extent of epithelial subtypes is under investigation, there is general agreement that pancreatic ductal adenocarcinoma (PDAC) is comprised of p63+ "basal" and GATA6+ "classical" subtypes, as well as various "intermediate", hybrid, and immune subtypes. In this initial report, we have applied technology that clones stem cells of the human gastrointestinal tract (Wang et al., 2015) and of esophageal adenocarcinoma and its precursors (in review) to ascites samples from patients with PDCA. Libraries of clonogenic cells were sorted to CEACAM6+ and CEACAM6- populations that were cloned by single cell sorting. The majority of CEACAM6+ clones form colonies with morphologies distinct from the CEACAM6- clones, and yet both form aggressive tumors in immunodeficient mice. Both CEACAM6+ and CEACAM6- clones express high levels of GATA6 and LGALS4, suggesting their general inclusion into the classical subtype seen in PDCA. However, gene expression profiling and tumor histology indicate that the CEACAM6+ clones display an intestinal fate (high CDH17, CDX2, MUC17) whereas the CEACAM6- clones show a gastric profile (TFF1, TFF2, AQP5, EGR1, EGR2, SOX21, MUC5AC). In addition, the CEACAM6- clones showed high levels of interferon signaling and high levels of chemokine expression including CXCL1, 2, 3, and 8, CCL20. The stromal properties of tumors generated from CEACAM6+ and CEACAM6- clones were also distinct, with the CEACAM6- clones marked by tumors with a highly cellularized extracellular matrix including αSMA+ and FAP+ CAFs, and the intestinal CEACAM6+ clones largely devoid of these CAF subpopulations. Consistently, CEACAM6- clones expressing high levels of pro-fibrotic genes, including PLAU, FN1, and CCN1. Importantly, exome sequencing of the CEACAM6+ and CEACAM6- clones from the same patient reveal shared mutant alleles of the p53 and KRAS genes, suggesting that these phenotypically distinct classical subtypes arose from a post-transformation stage likely by epigenetic mechanisms. Ongoing studies aimed at cloning basal subtypes from ascites and resolving the epigenetic control of CEACAM6+ and CEACAM6- classical subtypes should help to define the stem cell heterogeneity in PDAC. Citation Format: Wa Xian, Frank McKeon, Paul Daniel, Saeed Khan, Caycel Desales, Ashley Hoffman, Jaffer Ajani. Clonal analysis of classical subtypes of pancreatic cancer stem cells in ascites [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3904.
Abstract 4185: A novel USP1 inhibitor enhances PARP inhibitor efficacy in elevated replication stress tumors: Evidence from BRCA-mutant and CCNE1-amplified models
Authors: Ho-Jeong Lee, Hyerim Yoo, Jihye Kim, Sunkyu Kim, Sejeong Park, Sanghoon Lee, Kiwoong Yoo, Jin Kwan Kim, Kwang-Ok Lee, Jaewoo Kang
Journal: Cancer Research (2025)

Abstract Synthetic lethality offers a promising strategy for cancers with elevated replication stress, including BRCA-mutant and CCNE1-amplified tumors. USP1, a deubiquitinating enzyme, stabilizes replication forks by regulating ubiquitinated PCNA (Ub-PCNA). Using the AIGEN ChemTailor AI platform, we developed a novel USP1 inhibitor, which exhibited selective anti-proliferative effects in BRCA-mutant cancer cells and enhanced efficacy when combined with PARP inhibitors in vitro. We evaluated the USP1 inhibitor’s in vivo efficacy in BRCA-mutant breast cancer models and CCNE1-amplified ovarian cancer models. In MDA-MB-436 breast cancer xenografts, the combination of the USP1 inhibitor with PARP inhibitor demonstrated significant tumor suppression in both subcutaneous and orthotopic models, with the orthotopic model better reflecting the cross-talk between tumor cells and the tumor microenvironment. In OVCAR3 ovarian cancer orthotopic metastasis models, the USP1 inhibitor enhanced PARP inhibitor’s anti-tumor activity. Elevated Ub-PCNA expression in tumor tissues from MDA-MB-436 models further supports its potential as a pharmacodynamic marker. These findings highlight the USP1 inhibitor’s potential to enhance PARP inhibitor efficacy in BRCA-mutant and CCNE1-amplified cancers, with Ub-PCNA serving as a promising PD marker. IND-enabling studies, including GLP toxicology, are ongoing, with completion expected by late 2025. Citation Format: Ho-Jeong Lee, Hyerim Yoo, Jihye Kim, Sunkyu Kim, Sejeong Park, Sanghoon Lee, Kiwoong Yoo, Jin Kwan Kim, Kwang-Ok Lee, Jaewoo Kang. A novel USP1 inhibitor enhances PARP inhibitor efficacy in elevated replication stress tumors: Evidence from BRCA-mutant and CCNE1-amplified models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4185.
Abstract 4119: Epigenetic age as an early tumor biomarker for breast cancer
Authors: Su Yon Jung
Journal: Cancer Research (2025)

Abstract DNA methylation (DNAm)-based marker of aging, referred to as ‘epigenetic age’ or ‘DNAm age’ is a highly accurate multi-tissue biomarker for aging, associated with age-related disease risk, including cancer. Breast cancer (BC), an age-associated disease, is associated with older DNAm age and epigenetic age acceleration (age accel) at tissue levels. But this raises a question on the predictability of DNAm age/age accel in BC development, emphasizing the importance of studying DNAm age in pre-diagnostic peripheral blood (PB) in BC etiology and prevention. We included postmenopausal women from the largest study cohort and prospectively investigated BC development with their pre-diagnostic DNAm in PB leukocytes (PBLs). We estimated Horvath’s pan-tissue DNAm age and investigated whether DNAm age/age accel highly correlates with risk for developing subtype-specific BC and to what degree the risk is modified by hormones and lifestyle factors. DNAm age in PBLs was tightly correlated with age in this age range, and older DNAm age and epigenetic age accel were significantly associated with risk for developing overall BC and luminal subtypes. Of note, in women with bilateral oophorectomy before natural menopause experiencing shorter lifetime estrogen exposure than those with natural menopause, epigenetic age accel substantially influenced BC development, independent of obesity status and exogeneous estrogen use. Our findings contribute to better understanding of biologic aging processes that mediates BC carcinogenesis, detecting a non-invasive epigenetic aging marker that better reflects BC development, and ultimately identifying the elderly with high risk who can benefit from epigenetically targeted preventive interventions. Citation Format: Su Yon Jung. Epigenetic age as an early tumor biomarker for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4119.
Abstract 4813: Multi-armored allogeneic CD5 γδ CAR T cells enhance anti-tumor efficacy in T cell malignancies
Authors: Yu Ri Seo, Hyeong Ji Lee, Seung Rok Yu, Hyo Bhin Lee, Je Ho Lee, Hyung Cheol Kim, Youngho Lee
Journal: Cancer Research (2025)

T cell malignancies, such as T cell lymphoma and leukemia (T-NHL/T-ALL), present substantial challenges to conventional first-line therapies, highlighting an urgent need for novel therapeutic approaches. CAR-T therapies targeting T-cell-specific antigens have emerged as promising strategies against these cancers. However, the risk of tumor contamination by patient-derived T cells underscores the necessity for developing allogeneic, blast-free CAR-T therapies. Healthy donor-derived γδ T cells are attractive candidates for allogeneic CAR-T cell therapy due to their blast-free nature and the minimal risk of inducing Graft-versus-Host Disease (GvHD). Nevertheless, the difficulties in large-scale expansion and limited in vivo efficacy remain substantial obstacles to clinical application. To overcome these limitations, we aimed to enhance both the expansion and in vivo efficacy of anti-CD5 γδ CAR-T (γδCAR5) cells by incorporating “signal-3” supplement. A membrane-bound cytokine approach was employed to ensure targeted “signal 3” supplement specifically to CAR-T cells, promoting controlled expansion and activation. Among various cytokines engineered in membrane-bound forms (IL-2, IL-12, IL-15, IL-18, IL-21, and IL-36γ), only membrane-bound IL-18 (mbIL-18) induced a more than 10-fold increase in γδCAR5 cell expansion in vitro and demonstrated robust anti-tumor efficacy in a T-ALL xenograft model. Furthermore, knockdown of CD5 and PD-1, which are associated with fratricide and immunosuppression, respectively, further maximized the anti-tumor activity of γδCAR5-mbIL-18. Consequently, this multi-armoring strategy, which integrates enhanced proliferative capacity, fratricide resistance, and immune checkpoint evasion, represents an innovative approach to maximizing the therapeutic efficacy of allogeneic cell therapies for T cell malignancies. This study provides a promising framework for the advancement of more effective CAR-T therapies against challenging T cell cancers. Citation Format: Yu Ri Seo, Hyeong Ji Lee, Seung Rok Yu, Hyo Bhin Lee, Je Ho Lee, Hyung Cheol Kim, Youngho Lee. Multi-armored allogeneic CD5 γδ CAR T cells enhance anti-tumor efficacy in T cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4813.
Abstract 7295: Reversing resistance to checkpoint inhibitors by treatment with claudin-1 specific antibodies in an orthotopic in vivo model for cholangiocarcinoma
Authors: Romain Desert, Zeina Nehme, Bocar Kane, Emilie Crouchet, Frank Jühling, Vikas Ranvir, Alberto Toso, Mathias Heikenwälder, Catherine Schuster, Thomas Baumert
Journal: Cancer Research (2025)

Abstract Background: Resistance to immunotherapy is a major challenge in the treatment of solid tumors. Cholangiocarcinoma (CCA) exemplifies this challenge by poor outcome and very limited response to approved checkpoint inhibitors (CPI). Claudin-1 (CLDN1) is a transmembrane protein overexpressed in epithelial cancer cells and shown to be a mediator of carcinogenesis, invasion and metastasis. However, the functional role of CLDN1 for the tumor microenvironment (TME) is largely unknown. Using CCA as a model disease, we aimed to study the impact of CLDN1 for the TME and its potential role as a therapeutic target to address CPI resistance. Methods: CLDN1 expression and its association with TME was analyzed by spatial transcriptomics in CCA patient tissues. Immunocompetent orthotopic animal models of intrahepatic CCA were generated by hydrodynamic tail vein injection (HDTV) of proto-YAP/AKT or the KRAS/p19 oncogenes together with a CLDN1 expressing plasmid. Following tumor development within the liver, mice were treated with monoclonal antibodies (mAbs) targeting CLDN1 and/or PD-1. Results: Spatial analyses of patient tissues revealed that CLDN1 was overexpressed in cancer cells and CLDN1 expression was associated with oncogenic signaling and reduced T cell infiltration. In orthotopic mouse models for CCA, CLDN1 gain-of-function studies showed enhanced tumor growth and decreased survival. Treatment with CLDN1 mAbs markedly and significantly reduced tumor burden and intratumoral fibrosis and resulted in increased intratumoral CD3+ and CD8+ T cell infiltration as well as modulation of peritumoral macrophage distribution. Gene expression analyses revealed down-regulation of pathways for fibrogenesis, carcinogenesis and up-regulation of pathways for T cell activation and proliferation. Whereas PD1 mAb single agent therapy did not show significant efficacy, the combination of PD-1 with CLDN1 mAbs markedly and significantly improved overall survival. Conclusions: CLDN1 plays a functional role in the TME by modulating tumor fibrosis and immune cell infiltration. Treatment with CLDN1 mAbs provides an opportunity to overcome resistance and improve the efficacy of CPIs by enhancing tumoral immune responses. Citation Format: Romain Desert, Zeina Nehme, Bocar Kane, Emilie Crouchet, Frank Jühling, Vikas Ranvir, Alberto Toso, Mathias Heikenwälder, Catherine Schuster, Thomas Baumert. Reversing resistance to checkpoint inhibitors by treatment with claudin-1 specific antibodies in an orthotopic in vivo model for cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7295.
Abstract 4175: Momordicine-I modulates head and neck cancer growth by altering key metabolic pathways
Authors: Ellen T. Tran, Debojyoti Bandyopadhyay, Ruchi A. Patel, Ratna B. Ray
Journal: Cancer Research (2025)

Abstract One of the hallmarks of cancer is metabolic reprogramming which controls cellular homeostasis and therapy resistance. Here, we investigated the effect of momordicine-I (M-I), a key bioactive compound from Momordica charantia, on metabolic pathways in human head and neck cancer (HNC) cells and a mouse HNC tumorigenicity model. We found that M-I treatment on HNC cells significantly reduced the expression of key glycolytic molecules at the mRNA and protein levels. We further observed reduced lactate accumulation, suggesting glycolysis was perturbed in M-I treated HNC cells. Metabolomic analyses confirmed a marked reduction in glycolytic and TCA cycle metabolites in M-I-treated cells. M-I treatment significantly downregulated mRNA and protein expression of essential enzymes involved in de novo lipogenesis, including ACLY, ACC1, FASN, SREBP1, and SCD1. Using shotgun lipidomics, we found a significant increase in lysophosphatidylcholine and phosphatidylcholine loss in M-I treated cells. Subsequently, we observed dysregulation of mitochondrial membrane potential and significant reduction of mitochondrial oxygen consumption after M-I treatment. We further observed M-I treatment induced autophagy, activated AMPK and inhibited mTOR and Akt signaling pathways. However, blocking autophagy did not rescue the M-I-mediated alterations in lipogenesis, suggesting an independent mechanism of action. M-I treated mouse HNC MOC2 cell tumors displayed reduced Hk1, Pdk3, Fasn, and Acly expression. In conclusion, our study revealed that M-I inhibits glycolysis, lipid metabolism, induces autophagy in HNC cells and reduces tumor volume in mice. Therefore, M-I-mediated metabolic reprogramming of HNC has the potential for important therapeutic implications. Citation Format: Ellen T. Tran, Debojyoti Bandyopadhyay, Ruchi A. Patel, Ratna B. Ray. Momordicine-I modulates head and neck cancer growth by altering key metabolic pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4175.
Abstract 4518: The use of surgical staging of inguinal lymph nodes in penile squamous cell carcinoma in the HIV era
Authors: Victor Mapulanga, Owen Ngalamika, Edford Sinkala, Mumba Chibamba
Journal: Cancer Research (2025)

Abstract Penile cancer is quite common in developing countries such as sub-Saharan Africa (SSA) and this high incidence in SSA has been attributed to high prevalence of Human Papilloma Virus (HPV). Additionally, Human Immunodeficiency Virus (HIV) prevalence is high in SSA and considering that HIV affects lymph nodes, this may potentially affect the clinical manifestation of draining lymph nodes in penile cancer. These lymph nodes are staged surgically by inguinal lymph node disection which is associated with high complications rates. Data on surgical staging of lymph nodes in penile cancer in SSA are scanty. We set to explore the use of surgical staging of inguinal lymph nodes in penile squamous cell carcinoma (PSCC) in a high HIV endemic setting.A prospective study was conducted from November, 2022 to January, 2024 at the University Teaching Hospital, Lusaka, Zambia. Patients with PSCC with surgically resectable tumor undergoing surgical treatment of primary tumor and inguinal lymph node dissection were recruited into the study. The questionnaire was administered to capture relevant information.Blood was collected pre operatively for HIV testing and viral load determination. The disected lymph node tissue and resected tumor were sent to the pathologist for histological determination of tumor involvement of lymph node and histopathological staging. Immunohistocehmistry was done on tumor tissue using p16 for HPV determination.Forty (40) were enrolled in the study with a median age was 53 years. Thirty-five (88%) were HIV seropositive with most HIV positive patients being virologically suppressed with antiretroviral therapy at the time of surgery. The prevelence of HPV among the participant was 65% with HPV types 16 and 35 being the most common. The prevalence of pathological lymph node metastasis (LNM) was 37.5% (12/32) in patients with clinically palpable (cN+) inguinal lymph nodes. In conclusion surgical staging of inguinal lymph nodes in patients with PSCC in the era of HIV has low yield of positive lymph node involvement with most being reactive adenopathy due do HIV infection and not the cancer Citation Format: Victor Mapulanga, Owen Ngalamika, Edford Sinkala, Mumba Chibamba. The use of surgical staging of inguinal lymph nodes in penile squamous cell carcinoma in the HIV era [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4518.