tbuckley/cabot-search huggingface dataset:
Abstract 6417: Prostate cancer exploits neurolysin to modulate the tumor microenvironment and therapy resistance via KIF11-mediated WNT secretion
Authors: Ping Mu, Choushi Wang, Xiaoling Li, Su Deng
Journal: Cancer Research (2025)

Abstract The rapid emergence of resistance to targeted therapies poses a substantial challenge in managing various advanced cancers, including prostate cancer (PCa). The extent to which PCa cells can autonomously manipulate the tumor microenvironment (TME) and swiftly adapt to therapeutic challenges remains inadequately understood. We have elucidated that PCa cells can exploit neurolysin, a crucial regulator of neuronal signaling, to counter therapeutic interventions. The frequent absence of neurolysin results in increased WNT3A secretion into the TME and activates aberrant WNT signaling in adjacent cancer cells, thereby conferring AR targeted therapy resistance. This escalated WNT secretion and subsequent resistance are dependent on dysregulated cellular trafficking governed by the motor protein KIF11, which can be abolished by targeting either WNT3A or KIF11. These findings reveal an uncharted mechanism where cancer cells divert neuronal signaling molecules to redirect cellular trafficking machinery, thereby autonomously altering the TME and promoting resistance. Statement of Significance: Our study reveals an as-yet-undescribed molecular mechanism by which cancer cells can divert key neuronal molecules to regulate cellular trafficking and thereby autonomously modify the TME and promote resistance. It not only filled a crucial knowledge gap by elucidating how cancer cells autonomously modify cellular trafficking and the TME to resist therapy, but also suggest a novel therapeutic approach to address this challenge in contemporary targeted therapies. Declaration of interests: P.M. served as a scientific consultant to Accutar Biotechnology, Inc. T.W. is a scientific co-founder of NightStar Biotechnologies, Inc. H.L. is a shareholder and scientific advisor of Precision Scientific Ltd. All other authors declare that they have no competing interests. Citation Format: Ping Mu, Choushi Wang, Xiaoling Li, Su Deng. Prostate cancer exploits neurolysin to modulate the tumor microenvironment and therapy resistance via KIF11-mediated WNT secretion [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 6417.
Abstract 3836: Discovery of a highly potent fully human VEGF nanobody from RenNano transgenic mice that exhibits a superior blocking activity on VEGF function
Authors: Yi Yang, Weiqiu Lan, Baihong Liu, Yang Chen
Journal: Cancer Research (2025)

Abstract Background: VEGFA (or VEGF hereafter) is the prototypic member of a family that also includes placental growth factor (PLGF, also known as PGF),VEGFB,VEGFC,VEGFD . VEGFR2 is the major mediator of the physiological and pathological effects of VEGF. VEGFR2 mediates EC proliferation, migration and arterial fate specification [1]. VEGFA monoclonal antibodies have significant therapeutic effects in the treatment of tumors and macular degeneration [2]. In this study, we evaluated a fully human anti-VEGFA mAb generated from our fully human antibody RenNanoTM mice. Methods: Blocking activity of the anti-VEGFA mAb against VEGF/VEGFR2 interaction was assessed using ELISA. The affinity to human VEGFA165 was measured by surface plasmon resonance (SPR). At the same time, we conducted relevant physicochemical property tests on the obtained nanobodies, including purity, Tm value, Tagg, and hydrophobicity assessment. To evaluate the in vitro inhibitory effect of anti-VEGFA on endothelial cell proliferation, we used human umbilical vein endothelial cells (HUVEC) for the experiment. Results: We identified an anti-VEGFA nano-antibody with high affinity to human VEGFA165,and it was able to block the interaction of VEGFA and VEGFR2 in vitro. Our antibody molecule exhibits desirable physicochemical properties, as we found that the purity is above 95% after one step of affinity chromatography. Furthermore, our anti-VEGFA nano-antibody exhibited a strong inhibitory activity on the proliferation of HUVEC cells compared to Bevacizumab analog. Citation Format: Yi Yang, Weiqiu Lan, Baihong Liu, Yang Chen. Discovery of a highly potent fully human VEGF nanobody from RenNano transgenic mice that exhibits a superior blocking activity on VEGF function [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 3836.
Abstract 4153: Biomarker-driven polyamine pathway targeting as a treatment approach for TNBC
Authors: Chloe White, Caroline Liang, Thomas Velenosi
Journal: Cancer Research (2025)

Abstract Triple negative breast cancer accounts for about 15% of all breast cancer diagnoses and represents the most aggressive breast cancer subtype. This study aims to use a polyamine biomarker-driven approach to treat TNBC. Polyamines are small cationic molecules important for cancer cell growth and spermidine/spermine N1-acetlytransferase (SAT1) is the rate-limiting catabolic enzyme in the pathway. Our previous work demonstrated that doxorubicin induces SAT1 expression in moderate-SAT1 expressing TNBC models. We hypothesize that the effectiveness of using an SAT1 agonist to treat TNBC is dependent on baseline SAT1 expression and function. TNBC cell lines and patient-derived xenografts with low, moderate, and high baseline expression levels of SAT1 were used to evaluate the hypothesis. Cell lines were treated with TNBC standard-of-care doxorubicin, the SAT1 agonist N1, N11-diethylnorspermine (DENSpm), combination DENSpm-doxorubicin, or vehicle control. Adding DENSpm to sub-therapeutic doxorubicin treatments further decreased cell viability in moderate and high baseline SAT1 expressing cells (p&amp;lt;0.05). DENSpm depleted spermidine in moderate-SAT1 expressing TNBC-PDX ex vivo tumours slices, which was further depleted by combining with doxorubicin. In vivo, the addition of DENSpm to doxorubicin treatment further attenuated tumour growth in moderate-SAT1 expression TNBC-PDX, which corresponded to an increase in urine diacetylspermine as an indicator of treatment effectiveness. In conclusion, the results of this study suggest that combination doxorubicin and DENSpm treatment may be an effective treatment option for TNBC tumours with moderate baseline SAT1 expression, and that urine diacetylspermine production may be indicative of treatment effectiveness. Citation Format: Chloe White, Caroline Liang, Thomas Velenosi. Biomarker-driven polyamine pathway targeting as a treatment approach for TNBC [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 4153.
Abstract 4152: Disrupting lipid elongation impairs prostate cancer progression in c-MYC driven mouse models
Authors: Silvia D. Rodrigues, Isadora F. Teixeira, Giuseppe N. Fanelli, Caroline F. Ribeiro, Fabio Socciarelli, Jeanne Jiang, Debora C. Bastos, Hubert Pakula, Filippo Pederzoli, Pier V. Nuzzo, Alessandro Barberis, Lisa M. Butler, Johannes V. Swinnen, Massimo Loda
Journal: Cancer Research (2025)

Abstract Background: Altered lipid metabolism is a hallmark of prostate cancer development and progression. Key pathways affected include de novo fatty acid synthesis and downstream fatty acid elongation, which are both activated by androgens and oncogenic signaling, including c-Myc, a downstream target of Fatty Acid Synthase. One of the enzymes that is upregulated in clinical PCa is ELOVL5 (Elongation of Very Long-Chain Fatty Acids Protein 5), a target of the androgen receptor (AR), which catalyzes the initial step of fatty acid elongation. However, its role in cancer progression remains unknown. Methods: Prostate tumors from HiMyc transgenic mice were evaluated for growth, histopathological progression and lipidomics changes up to 48 weeks and compared to HiMyc mice with ELOVL5 homozygous deletion. 3D organoid model derived from the ventral prostate of these GEMMs were assessed for changes in cell proliferation, size, and response to anti-androgen therapy (Enzalutamide). Rescue experiments were performed by supplementation with cis-vaccenic acid, a key fatty acid product of ELOVL5 activity. Results: ELOVL5 KO significantly inhibited progression from prostatic intraepithelial neoplasia to invasive adenocarcinoma in comparison to HiMyc mice. Lipidomic profiling confirmed reduced levels of ELOVL5 elongation products, characterized by shortened acyl chains in phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species, in both serum and prostate tissues. The growth effect was recapitulated in organoids derived from these mice, was further enhanced by Enzalutamide and partially rescued by supplementation with cis-vaccenic acid. Gene expression profiling confirmed downregulation of fatty acid biosynthesis pathways and androgen receptor in HiMyc: ELOVL5 KO models. Conclusion: ELOVL5 curtails c-Myc-driven prostate cancer, providing a direct link between fatty acid elongation and prostate cancer progression. Citation Format: Silvia D. Rodrigues, Isadora F. Teixeira, Giuseppe N. Fanelli, Caroline F. Ribeiro, Fabio Socciarelli, Jeanne Jiang, Debora C. Bastos, Hubert Pakula, Filippo Pederzoli, Pier V. Nuzzo, Alessandro Barberis, Lisa M. Butler, Johannes V. Swinnen, Massimo Loda. Disrupting lipid elongation impairs prostate cancer progression in c-MYC driven mouse 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 4152.
Abstract 3910: Patient-derived conditionally reprogrammed cells in prostate cancer research
Authors: Abdalla Elbialy, Akshay Sood, Shang-Jui Wang, Peng Wang, Jenny Li, Xuefeng Liu
Journal: Cancer Research (2025)

Abstract Prostate cancer (PCa) remains a leading cause of mortality among American men, with metastatic and recurrent disease posing significant therapeutic challenges due to a limited comprehension of the underlying biological processes governing disease initiation, dormancy, and progression. The conventional use of PCa cell lines has proven inadequate in elucidating the intricate molecular mechanisms driving PCa carcinogenesis, hindering the development of effective treatments. To address this gap, patient-derived primary cell cultures have been developed and play a pivotal role in unraveling the pathophysiological intricacies unique to PCa in each individual, offering valuable insights for translational research. This review explores the applications of the conditional reprogramming (CR) cell culture approach, showcasing its capability to rapidly and effectively cultivate patient-derived normal and tumor cells. The CR strategy facilitates the acquisition of stem cell properties by primary cells, precisely recapitulating the human pathophysiology of PCa. This nuanced understanding enables the identification of novel therapeutics. Specifically, our discussion encompasses the utility of CR cells in elucidating PCa initiation and progression, unraveling the molecular pathogenesis of metastatic PCa, addressing health disparities, and advancing personalized medicine. Coupled with the tumor organoid approach and patient-derived xenografts (PDXs), CR cells present a promising avenue for comprehending cancer biology, exploring new treatment modalities, and advancing precision medicine in the context of PCa. Citation Format: Abdalla Elbialy, Akshay Sood, Shang-Jui Wang, Peng Wang, Jenny Li, Xuefeng Liu. Patient-derived conditionally reprogrammed cells in prostate cancer research [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 3910.
Abstract 2844: A cytosolic DNA/Ca2+-dependent signaling pathway for genome protection during replication stress
Authors: Zhongsheng You
Journal: Cancer Research (2025)

Abstract Protecting the replication fork structure, especially under replication stress, is essential for maintaining genome integrity and stability. Defects in fork protection, often linked to mutations in tumor suppressor genes like BRCA1, BRCA2 and FANCD2, can lead to genomic instability and consequently, cancer progression. Such defects may also influence cancer progression by altering the tumor microenvironment through the generation of cytosolic DNA fragments that activate the innate immune response. Intriguingly, our recent findings indicate that cytosolic DNA, produced after replication stress, unexpectedly also supports replication fork protection. This protective effect is mediated through a complex signaling pathway that involves the activation of the cGAS/cGAMP/STING axis, Ca2+ release from the endoplasmic reticulum via the TRPV2 ion channel, activation of CaMKK2 and AMPK protein kinases, and the inhibition of the EXO1 nuclease. Disruption of this pathway results in excessive fork processing, chromosomal instability and heightend sensitivity to replication stress inducers. The newly uncovered links between innate immune factors, intracellular Ca2+ and genome maintenance in this novel signaling pathway may open new avenues for cancer treatment. (Li et al., Mol Cell 2019, 74:1123-1137; Li, Kong et al., Mol Cell 2023, 85:556-573; Kong, Cheng et al., Nat Commun 2024, 15:4609) Citation Format: Zhongsheng You. A cytosolic DNA/Ca2+-dependent signaling pathway for genome protection during replication stress [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 2844.
Abstract 3883: Evolution of genomic and epigenomic heterogeneity in prostate cancer from tissue and liquid biopsies
Authors: Marjorie Roskes, Alexander Martinez-Fundichely, Weiling Li, Sandra Cohen, Hao Xu, Shahd ElNaggar, Anisha Tehim, Metin Balabin, Chen Khuan Wong, Yu Chen, Ben Raphael, Ekta Khurana
Journal: Cancer Research (2025)

Abstract Castration resistant prostate cancer (CRPC) is an aggressive, highly plastic, late-stage disease. We previously showed that the two histological subtypes, adenocarcinoma (CRPC-Adeno) and neuroendocrine (CRPC-NE), show four epigenetic and transcriptomic subtypes: CRPC-AR depends on the androgen receptor pathway, CRPC-SCL is stem-cell like, CRPC-WNT is dependent on the WNT pathway, and CRPC-NE has high expression of neuroendocrine markers. Here, by analyzing data from 500 patients with tissue and/or liquid biopsies, we uncover the landscape of molecular heterogeneity in patient tumors. Analysis of whole-genome sequencing revealed genomic variants associated with CRPC-SCL and allowed development of a computational classifier which can predict presence of CRPC-SCL in patient tumors solely using genomic alterations with 81% accuracy. In particular, analysis of matched chromatin conformation data (Hi-C) showed a complex rearrangement on chromosome 4 disrupts enhancer - promoter contacts leading to downregulation of MOB1B, which can lead to upregulation of the YAP/TAZ pathway that is characteristic of CRPC-SCL. Joint computational inference of epigenomic state and genomic variants from cell-free DNA collected at multiple points during the evolution of resistance to AR signaling inhibitors allowed investigation of genomic and epigenomic co-evolution at an unprecedented resolution. We discuss the current limits of detection for tumoral epigenomic and genomic states using cell-free DNA for clinical application. Importantly, our study demonstrates the utility of liquid biopsies for discovery of basic biological mechanisms leading to treatment resistance, beyond their use for biomarkers. Citation Format: Marjorie Roskes, Alexander Martinez-Fundichely, Weiling Li, Sandra Cohen, Hao Xu, Shahd ElNaggar, Anisha Tehim, Metin Balabin, Chen Khuan Wong, Yu Chen, Ben Raphael, Ekta Khurana. Evolution of genomic and epigenomic heterogeneity in prostate cancer from tissue and liquid biopsies [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 3883.
Abstract 3397: Survival stratification for <i>TP53</i>-mutated endometrial cancers under platinum-based chemotherapy
Authors: Xiaotian Zhao, Haimeng Tang, Xue Wu, Qiuxiang Ou
Journal: Cancer Research (2025)

Background: Endometrial cancers (EC) with mutated TP53 or abnormal p53 show unfavorable clinical outcomes, with high recurrence rates, and additional chemotherapy has been considered within these patients. Genomic biomarkers may be critical to increasing the precision in developing treatment strategy for TP53-mutated EC. Methods: We applied an in-house developed targeted sequencing homologous recombination deficiency (HRD) assessment bioinformatic algorithm (GeneseeqPrime® HRD) on 529 the Cancer Genome Atlas (TCGA) EC samples, covering all exons and translocation-related introns of 437 cancer-relevant genes. The HRD score threshold to determine HRD status as well as to stratify survival outcomes under platinum-based chemotherapy, and associations of HRD status with signaling pathways and protein expression were investigated. Results: Of 529 EC samples, 18.0% was determined as HRD-positive (HRD score threshold: 38), including 85 patients carrying mutated TP53, which was associated with increased HRD scores (p&amp;lt;0.001). However, pathogenic BRCA1/2 mutations appeared to be less common in TP53-mutated EC (p=0.08). HRD-negative EC had higher tumor mutation burden (p=0.03), with more prevalent homologous recombination-related ATM, and RAD50 mutations, whereas positive HRD status was associated with higher aneuploidy score (p&amp;lt;0.001) and fraction of genome altered (p&amp;lt;0.001). Serous and endometrioid carcinomas were enriched in HRD-positive (p&amp;lt;0.001) and HRD-negative EC (p&amp;lt;0.001), respectively. HRD-positive EC exhibited higher patient age (p&amp;lt;0.001), disease stage (p=0.03), and histologic grade (p=0.04) than HRD-negative EC. Under platinum-based chemotherapy, HRD-positive TP53-mutated EC had improved progression-free survival [adjusted hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.29-1.10; p=0.09] and superior overall survival (adjusted HR, 0.49; 95% confidence interval (CI), 0.24-1.00; p=0.05) compared to HRD-negative patients, when adjusting for clinical characteristics and molecular subtypes. Suppressed p53, Hedgehog, and hippo signaling pathways were observed in HRD-positive EC with TP53 mutations (p.adjust &amp;lt;0.05). Additionally, MAPK14 (p&amp;lt;0.001) and PIK3CA (p&amp;lt;0.001) expression were significantly associated with higher HRD score. Conclusions: HRD status may identify patients with TP53-mutated EC who could get survival benefits from platinum-based chemotherapy. Further research is required to determine the utilization of HRD assessment in EC receiving PARP inhibitors. Citation Format: Xiaotian Zhao, Haimeng Tang, Xue Wu, Qiuxiang Ou. Survival stratification for TP53-mutated endometrial cancers under platinum-based chemotherapy [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 3397.
Abstract 2858: Pleiotropy of experimental signatures across species and model systems
Authors: Maria Zhivagui, Shams Al-azzam, Mark Barnes, Ludmil B. Alexandrov
Journal: Cancer Research (2025)

Mutational signatures in cancer genomes provide crucial insights into the etiology and progression of malignancies. While numerous signatures have been identified, many lack known causes, hindering our understanding of cancer development. This study presents a comprehensive analysis of mutational patterns induced by diverse environmental agents across multiple model systems. We compiled data from over 4,000 genome-wide sequencing experiments, exposing various biological models—including human cell lines, rodent tumors, avian cells, and C. elegans—to more than 120 different agents under controlled conditions. By comparing mutational profiles across 30+ model systems, we identified significant inter-model disparities, underscoring the importance of diverse experimental approaches in confidently characterizing mutational signatures observed in human cancers. Our findings enhance the interpretation of clinical and epidemiological data related to specific carcinogen exposures and provide a robust framework for elucidating the role of environmental factors in cancer etiology. This research contributes to a more nuanced understanding of the complex interplay between environmental exposures, genetic susceptibility, and cancer development, potentially informing novel prevention strategies and therapeutic interventions. Citation Format: Maria Zhivagui, Shams Al-azzam, Mark Barnes, Ludmil B. Alexandrov. Pleiotropy of experimental signatures across species and model systems [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 2858.
Abstract 4678: Identifying and exploiting a novel role of FTO in promoting cysteine metabolism for NSCLC therapy
Authors: Nishanth Kuganesan, Stavros Melemenidis, Edward E. Graves, Erinn B. Rankin
Journal: Cancer Research (2025)

Abstract The RNA demethylase enzyme FTO is emerging as an important oncogenic factor and therapeutic target in a variety of solid tumors. However, its effect on cancer metabolism remains largely unknown. Here we show that FTO promotes cysteine metabolism, a hallmark of metabolic rewiring in non-small cell lung cancer (NSCLC) cells. Mechanistically, FTO inhibition reduces the expression of multiple targets in the cysteine metabolism pathway including the cystine transporter SLC7A11 involved in exogenous cystine uptake as well as two key enzymes cystathionine β-synthetase (CBS) and cystathionine γ-lyase (CTH) involved in de novo cysteine synthesis. Functionally, FTO inhibition reduces cystine uptake and NSCLC growth and survival in a homocysteine-dependent manner. As cysteine plays a crucial role in glutathione biosynthesis and maintenance of cellular redox homeostasis, FTO inhibition decreased glutathione levels and increased reactive oxygen species (ROS) levels in NSCLC cells. To therapeutically exploit the increased oxidative stress in NSCLC cells treated with FTO inhibitors, we combined FTO inhibition with radiation therapy. FTO inhibition enhanced the radiosensitivity of NSCLC cells. Our findings reveal a novel role for FTO in NSCLC cysteine metabolism and oxidative stress, highlighting the therapeutic potential of FTO inhibition as a strategy to enhance the efficacy of radiation therapy for the treatment of NSCLC. Citation Format: Nishanth Kuganesan, Stavros Melemenidis, Edward E. Graves, Erinn B. Rankin. Identifying and exploiting a novel role of FTO in promoting cysteine metabolism for NSCLC therapy [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 4678.