tbuckley/cabot-search huggingface dataset:
Abstract 1520: Obesity delays melanoma resistance to BRAF/MEKi inhibitors and alters melanoma metabolism
Authors: Mahnoush S. Shafiei, Mackenzie Mayhew, Jacob Sellers, Allan Tsung, Russell Witt
Journal: Cancer Research (2025)

Background: Obesity is linked to more aggressive melanoma and impaired anti-tumor immunity. However, obese patients show improved survival on BRAF/MEK inhibitors. Obesity induces endoplasmic reticulum stress (ERS), and BRAF/MEK inhibitors shift metabolism from glucose to fatty acid oxidation (FAO), utilizing CPT1A for cell viability. We hypothesize that obesity-induced metabolic reprogramming causes downregulation of CPT1A, impairing melanoma cell metabolism and potentially contributing to longer tumor progression-free survival (PFS) in obese individuals. Methods: Mice were fed either a standard diet (lean) or a high-fat diet (HFD) to induce obesity. Twelve-week-old mice were subcutaneously injected with 1 × 106 YUMMER 1.7 melanoma cells. Tumors were allowed to grow for 2 weeks, after which the mice were treated with BRAF/MEK inhibitors until tumor resistance was observed. Results: Obese mice treated with BRAF/MEK inhibitors showed delayed tumor recurrence compared to lean mice with a median of 80 days in obese mice versus 28 days in lean mice (log-rank p&amp;lt;0.0001). Tumors from obese mice had elevated DRP1 expression (P&amp;lt;0.05) and increased ER stress markers (XBP1, IRE1A, GRP78, PERK). Metabolic reprogramming, including alterations in melanoma state, fatty acid oxidation (FAO), and glycolysis via the BRAF/MEK pathway, resulted in higher levels of CD36, ACADS, and CPT1 in lean mice compared to obese mice (P&amp;lt;0.05). Conversely, NGFR, MITF, DUSP59, HK2, and GLUT-1 levels were elevated in tumors from obese mice (P&amp;lt;0.05). Conclusions: Our findings suggest that obesity contributes to delayed tumor progression, potentially due to alterations in endoplasmic reticulum and mitochondrial function, which disrupt the expression of key metabolic enzymes. These results underscore the potential of targeting metabolic pathways as a complementary therapeutic approach in melanoma treatment. Citation Format: Mahnoush S. Shafiei, Mackenzie Mayhew, Jacob Sellers, Allan Tsung, Russell Witt. Obesity delays melanoma resistance to BRAF/MEKi inhibitors and alters melanoma metabolism [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 1520.
Abstract 921: SOX11-mediated antigen presentation suppression: A mechanism of immune evasion in triple-negative breast cancer
Authors: Salomat Abdulkhuseynova, Ashok Pullikuth, Lance Miller, Shay Soker
Journal: Cancer Research (2025)

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive subtype with no targeted therapies and limited response to immunotherapy. TNBC evades immune surveillance by repressing antigen presentation machinery (APM) genes, reducing MHC Class I expression. Using bioinformatics, we identified SOX11 as a potential transcriptional regulator associated with APM suppression and immune evasion in TNBC. Methods: Gene expression data from basal breast cancer (BRCA) tumors (n = 189) in TCGA and cancer cell lines (n = 1, 189) in DepMap were analyzed. Spearman correlation coefficients were used to evaluate associations between a T-cell infiltration signature (e.g., CD3, CD8) and an APM signature (e.g., TAP1, TAP2, B2M, HLA-ABC). SOX11 was prioritized as it was strongly negatively correlated with both signatures. Differential expression analysis of SOX11-overexpression (OE) and knockdown (KD) datasets confirmed potential downstream targets, including MEX3A. To validate, SOX11 KD was performed in CAL-148 cells (high level of endogenous SOX11) using siRNA for 96 hours. Western blot assessed SOX11 and MEX3A protein levels, while flow cytometry measured surface MHC Class I (HLA-ABC) expression. Results: SOX11 was strongly inversely correlated (rho &amp;lt; -0.4, adjusted p &amp;lt; 0.01) with APM and T-cell infiltration signatures in basal BRCA and DepMap datasets. In basal BRCA tumors, SOX11 expression was enriched in T-cell cold tumors compared to T-cell hot tumors (p &amp;lt; 0.01). Reanalysis of SOX11-modulated datasets (KD and OE) confirmed APM-suppressive downstream targets, with MEX3A showing a strong co-expression pattern (Spearman p&amp;lt;0.05). SOX11 KD in CAL-148 cells significantly reduced MEX3A protein levels and increased surface HLA-ABC expression. These findings suggest that SOX11 represses antigen presentation pathways, contributing to immune evasion in TNBC. Conclusions: SOX11 suppresses HLA-A/B/C expression and may contribute to immune evasion in TNBC. Its high expression in T-cell cold tumors and its regulation of APM targets, including MEX3A, highlight its potential as a therapeutic target. Targeting SOX11 could restore antigen presentation, promote immune recognition, and enhance immunotherapy responses in TNBC. Citation Format: Salomat Abdulkhuseynova, Ashok Pullikuth, Lance Miller, Shay Soker. SOX11-mediated antigen presentation suppression: A mechanism of immune evasion in triple-negative 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 921.
Abstract 923: The role of NNMT in anti-tumor immunity in LKB1 deficient NSCLCs
Authors: Thi Na Nguyen, Wenjing Na, Pawel Nowialis, Thi Kim Ngan Bui, Kunyang Li, Ryan Clay, Lina Song, Lingtao Jin
Journal: Cancer Research (2025)

Abstract Lung cancer is the leading cause of cancer-related deaths with non-small cell lung cancer (NSCLC)accounting for 85% of all lung cancers. Loss or inactivating mutations of serine/threonine kinase STK11 encoding the LKB1 protein occurs in approximately 20% of lung adenocarcinoma (LUAD). Although treatment of NSCLCs with immune checkpoint inhibitors (ICI) has responded in overall survival in a subset of patients, studies have revealed that co-occurring KRAS/LKB1 mutations promote primary resistance to ICIs in NSCLCs, the mechanism of which is still not completely understood. Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that catalyzes the methylation of nicotinamide (Nam) using the co-factor S-adenosyl-L-methionine to form 1-methyl-nicotinamide (1-MNA). In this study, we discovered that levels of NNMT and its product 1-MNA are elevated inNSCLCs with loss of function of LKB1. Mechanistically, we found that LKB1-SIK1/2/3 axisdirectly suppresses NNMT expression transcriptionally. Therefore, loss of function of LKB1 leadsto upregulation of NNMT and its products 1-MNA. Interestingly, knockout of NNMT or 1-MNA treatment did not impact cell proliferation or survival in NSCLC cells with or without functionalLKB1. Global metabolomic and transcriptomic studies revealed that 1-MNA promotes FOXP3induction and regulatory T cell (Treg) expansion, consequently leading to reduced CD8 T cellfunction both in vitro and in vivo. Knockout of NNMT in KPL cells (KrasG12DTp53/LKB1 KO)enhanced anti-tumor immune response and promoted ICI efficacy by suppressing Tregaccumulation in vivo. Importantly, NNMT inhibitor improves the therapeutic efficacy of anti-PD-1antibody in KPL model in vivo. The present study revealed that NNMT/1-MNA signaling plays animportant role in regulating Treg function in LKB1 deficient NSCLC. Targeting NNMT with smallmolecular inhibitor may hold promise to improve the efficacy of ICIs for LKB1 deficient NSCLCs. Citation Format: Thi Na Nguyen, Wenjing Na, Pawel Nowialis, Thi Kim Ngan Bui, Kunyang Li, Ryan Clay, Lina Song, Lingtao Jin. The role of NNMT in anti-tumor immunity in LKB1 deficient NSCLCs. [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 923.
Abstract 268: Ryanodine receptor-1 upregulation alters organellar calcium signaling, modulates gene expression and contributes to ovarian cancer development
Authors: Chi-Lam Au-Yeung, Kay-Pong Yip, Wan-Yee Tang, Samuel C. Mok, James S.K. Sham
Journal: Cancer Research (2025)

Abstract Ca2+ signaling plays crucial roles in cancer development through Ca2+-dependent regulation of gene transcription. However, specific changes of Ca2+ signaling in HGSOC are unclear. Analysis of RNAseq data from TCGA and GEO database and our patient samples identified ryanodine receptor 1 (RYR1) over-expression was associated with poor survival of HGSOC patients. RYR1 expression was also markedly higher in several HGSOC cell lines compared to normal human control cells. To examine Ca2+ signaling in HGSOC cells, cytosolic, nucleoplasmic, and mitochondrial [Ca2+] were monitored by confocal imaging of Ca2+ fluorescence dyes and organelle specific Ca2+ biosenors. Resting cytosolic [Ca2+] and [Ca2+]nucleus was significantly elevated. Ca2+ signals triggered by the RYR-agonist 4-chloro-m-cresol (4-cmc) in cytosol, nucleus, and mitochondria were significantly higher in OVCA432 cells compared to the control HOSE cells. The elevated resting [Ca2+] and the 4-cmc-induced Ca2+ signals in various intracellular compartments were reduced to the control level by RYR1-shRNA in OVCA432 cells. Gene Set Enrichment Analysis of RNAseq data revealed that RYR1 silencing suppressed gene sets related to mitochondrial proteins, mitochondrial membrane potential, fatty acid metabolism and oxidoreductase activity, as well as activated gene sets related to histone 4 lysine acetyltransferase, H2A ubiquitination and protein localization to chromatin, suggesting RYR1 in HGSOC cells plays important roles in modulating mitochondrial functions and epigenetic regulation of gene expression. Furthermore, shRNA knockdown or inhibition of RYR1 with the RYR1 blocker dantrolene suppressed HGSOC proliferation and migration, and significant reduced OC tumor evaluated by bioluminescence and tumor weight in OVCA432 cells injected athymic nude mice These observations are the first direct evidence that RYR1 alters cytosolic, nucleoplasmic and mitochondrial Ca2+ signaling in HGSOC cells, and these changes may contribute to the malignant phenotype for HGSOC development. Citation Format: Chi-Lam Au-Yeung, Kay-Pong Yip, Wan-Yee Tang, Samuel C. Mok, James S.K. Sham. Ryanodine receptor-1 upregulation alters organellar calcium signaling, modulates gene expression and contributes to ovarian cancer development [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 268.
Abstract 1188: Understanding the malignant properties of early-stage lung adenocarcinoma through oncofetal IGF2BP3-mediated miRNA structural diversity
Authors: Naoto Tsuchiya, Yuko Fujiwara, Ryou-u Takahashi, Motonobu Saito, Akiteru Goto
Journal: Cancer Research (2025)

Abstract Although functional abnormalities in microRNAs, a class of small non-coding RNAs, have been implicated in the pathogenesis of various cancer types, the nature of their dysfunction as an integrated cellular system remains poorly understood. Here, we demonstrate that the oncofetal protein IGF2BP3 selectively regulates the production of 3’-isoforms (3’-isomiRs), including miR-21-5p and members of the Let-7 family. This regulation induces significant changes in their cellular seed occupancy and structural composition, thereby establishing a cancer-specific gene expression profile. Notably, the D-score, which reflects the dominant production of miR-21-5p+C (a representative 3'-isomiR), effectively discriminates between early-stage lung adenocarcinoma (LUAD) cases with low and high recurrence risks. This score is also associated with molecular features indicative of cell cycle progression, epithelial-mesenchymal transition pressure, and immune evasion. Mechanistically, we found that IGF2BP3 directs the nuclear Drosha complex to select specific cleavage sites, thereby controlling the production of miR-21-5p+C. IGF2BP3 also modulates the 3’-isomiRs of miR-425-5p and miR-454-3p, which are implicated in the regulation of p53, TGF-β, and TNF pathways in LUAD. Furthermore, IGF2BP3 selectively represses the production of 3’-isomiRs from the Let-7 family, reducing their seed occupancy and subsequently altering the expression of Let-7 target genes involved in cell cycle regulation. These findings suggest that IGF2BP3-mediated miRNA isoform organization constitutes a critical component of cancer progression (Fujiwara et al. PNAS 2024). This principle provides a foundation for developing diagnostic biomarkers with broad applications, including the efficient prediction of early-stage LUAD recurrence. Citation Format: Naoto Tsuchiya, Yuko Fujiwara, Ryou-u Takahashi, Motonobu Saito, Akiteru Goto. Understanding the malignant properties of early-stage lung adenocarcinoma through oncofetal IGF2BP3-mediated miRNA structural diversity [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 1188.
Abstract 119: A multipotent PROX1+ tumor stem/progenitor cell population emerges during intestinal tumorigenesis and mediates radioresistance in CRC
Authors: Pauliina Kallio, Cinzia Bessone, Fatemeh Seyednasrollah, Jefim Brodkin, Marika Lassila, Jenny Högström, Alejandra González-Loyola, Tatiana V. Petrova, Caj Haglund, Kari Alitalo
Journal: Cancer Research (2025)

Colorectal carcinoma (CRC) progression is associated with an increase in PROX1+ tumor cells, which exhibit features of CRC stem cells and contribute to metastasis. Here, we aimed to provide a better understanding to the function of PROX1+ cells in CRC, investigating their progeny and their role in therapy resistance. PROX1+ cells in intestinal adenomas of ApcMin/+ mice expressed intestinal epithelial and CRC stem cell markers, and cells with high PROX1 expression could both self-renew tumor stem/progenitor cells and contribute to differentiated tumor cells. Most PROX1-lineage traced tumor cells were stem/progenitor cells, which can supply cells to multiple intestinal tumor cell lineages, whereas most lineage-traced LGR5+ tumor cells were enterocytes, indicating that PROX1+ and LGR5+ tumor stem cells have distinct differentiation programs. Although the PROX1+ tumor cells proliferated slower than PROX1- cells, irradiation increased the proportion of PROX1+ cells in human CRC cell lines, patient-derived organoids, and tumor xenografts. Furthermore, transcripts related to DNA damage repair (DDR) were enriched in PROX1+ vs. PROX1- cells in adenomas and in CRC tumor cells from patients. Experiments with PROX1 silencing and overexpression indicated that PROX1 expression enhances CRC cell colony formation following irradiation. PROX1 interacted with DDR proteins, including components of non-homologous end-joining (NHEJ) and base excision repair, and inhibition of NHEJ repair led to a decreased proportion of PROX1+ cells following irradiation. In conclusion, PROX1+ cells are irradiation-resistant tumor stem/progenitor cells capable of self-renewal and differentiation. DDR inhibitors could represent a strategy to target the treatment-resistant PROX1+ tumor stem cells. Citation Format: Pauliina Kallio, Cinzia Bessone, Fatemeh Seyednasrollah, Jefim Brodkin, Marika Lassila, Jenny Högström, Alejandra González-Loyola, Tatiana V. Petrova, Caj Haglund, Kari Alitalo. A multipotent PROX1+ tumor stem/progenitor cell population emerges during intestinal tumorigenesis and mediates radioresistance in CRC [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 119.
Abstract 93: Alternative splicing reveals epigenetic subtypes in gastric cancer peritoneal metastasis
Authors: Joseph J. Zhao, Xiaonan Fan, Jia Jia Chan, Daryl Kai Ann Chia, Robert Walsh, Haoran Ma, Wei Peng Yong, Jimmy So, Patrick Tan, Yvonne Tay, Raghav Sundar
Journal: Cancer Research (2025)

Abstract Background: Gastric cancer (GC) with peritoneal metastases (PM) carries a grim prognosis. Despite progress in elucidating transcriptomic mechanisms of metastasis, epigenetic factors and vulnerabilities are still not fully understood. Methods: Primary tumor (PT, n=157), primary normal (PN, n=33) and peritoneal metastases (PM, n=97) from patients with GC were retrieved and sequenced with whole transcriptome sequencing. PSI-Sigma was conducted to retrieve alternative pre-mRNA splicing (AS) changes. Differential splicing events (DSE) that were concordant between PT vs PN and PM vs PT were utilized to identify AS event hubs through non-negative matrix factorization. Transcriptomic derivatives such as epithelial-mesenchymal transition (EMT)-scores, mesenchymal subtypes were retrieved utilizing log2(FPKM) gene expression. Epigenetic subtypes of GCPM samples were retrieved through hierarchical clustering of AS event hubs and survival analyses were conducted with a Cox-proportional hazard model. Results: Nine hundred and nine overlapping DSE were identified between PT vs PN and PM vs PT comparisons, with majority being mutually exclusive exons (44.6%). Of this 909 DSEs, 45 DSE were found to be concordant across comparisons. Unsupervised clustering with gene hubs retrieved from 45 DSEs reveals 2 GCPM epigenetic clusters, characterized by divergent EMT states (p&amp;lt;0.001). The clusters were subsequently coined GCPM-Mesenchymal (n=47, mean EMT-score=1.06) and GCPM-Epithelial (n=50, mean EMT-score=0.17). GCPM-Mesenchymal samples were predominantly found to be nested within an inflamed immune-infiltrated peritoneal niche (p=0.002) and participants with GCPM-Mesenchymal only samples had significantly poorer survival outcomes upon PM diagnosis (Log-rank, p=0.037). Conclusions: This study sheds light on alternative splicing in transcoelomic metastasis and highlights potential for splicing-based patient stratification in GCPM. Citation Format: Joseph J. Zhao, Xiaonan Fan, Jia Jia Chan, Daryl Kai Ann Chia, Robert Walsh, Haoran Ma, Wei Peng Yong, Jimmy So, Patrick Tan, Yvonne Tay, Raghav Sundar. Alternative splicing reveals epigenetic subtypes in gastric cancer peritoneal metastasis [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 93.
Abstract 36: A patient-centered approach to 3D <i>in vitro</i> modeling of pancreatic ductal adenocarcinoma
Authors: Jade Vipond Cotter, Katie Reind
Journal: Cancer Research (2025)

Abstract Matrigel® is the most commonly used hydrogel product for developing and testing 3-D in vitro pancreatic ductal adenocarcinoma (PDAC) models; however, its composition is not reflective of the ECM content of most PDAC tumors. To remedy this pitfall, we have developed a novel approach for generating patient-derived 3D tumor organoids grown in customized hydrogels that better reflect their original tumor tissue. Using surgically resected original patient tissue, we measured the relative area covered by the major ECM constituents in PDAC: collagens I, III, IV, and laminin via IHC. Cells collected from PDX-propagated patient tissues were then embedded in the custom hydrogel comprised of ECM proteins in concentration that mirrored the original patient tissue. Organoids will then be monitored for size and rate of proliferation via MTT assay. Finally, to ensure transmembrane interactions with the customized hydrogel, expression of integrins α1, α2, α6, which bind the aforementioned hydrogel components, will be measured via IHC. We anticipate organoids grown in these custom hydrogels will demonstrate a greater likelihood of successful model development and higher growth rate than those grown in Matrigel®. Additionally, we expect organoids grown by this method will show increased expression of integrins α1, α2, and α6. These results provide preliminary evidence that the composition of the hydrogel used to generate 3D in vitro models may have an impact on their phenotypic expression. Further development and characterization of these models could result in better reflection of in vivo conditions in preclinical therapy testing. Citation Format: Jade Vipond Cotter, Katie Reind. A patient-centered approach to 3D in vitro modeling of pancreatic ductal adenocarcinoma [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 36.
Abstract 360: Discovery of selective and orally bioavailable PKMYT1 inhibitor: characterization of anti-tumor activities as single and dual agents
Authors: Xiaobin Summer Wang, Sining Zhu, Haili Ding, Yang Tang, Minrui Weng, Kelly Chen, Yanna Ma, Pan Wang, Yifan Tu, Juhao Yang, Jun Wu, Dan Zhao, Xuefei Tan, Ying Ji, Xiangyu Yao, Zhipeng Yan
Journal: Cancer Research (2025)

Abstract Advancing effective cancer therapies requires innovative approaches to better understand complex biological interactions. PKMYT1, a crucial regulator of the cell cycle involved in the G2/M transition through inhibitory phosphorylation of CDK1, has emerged as a promising therapeutic target. Inactivation of PKMYT1 is synthetically lethal in tumor cells with genomic alterations leading to high replication stress, such as CCNE1 amplification, which is frequently found in high-grade serous ovarian, uterine, and gastro-esophageal cancers. In this report, we present a series of potent PKMYT1 inhibitors, emphasizing their pharmacokinetic profiles and anti-tumor activities, characterized as either single agents or in combination. Furthermore, we explored the potential of combination therapy using these profiled PKMYT1 inhibitors. We hypothesized that inhibition of the DNA damage response kinase ATR and its downstream pathway may further enhance the tumor cytotoxicity of PKMYT1 inhibitors. Preclinical validation of this hypothesis demonstrated that combining PKMYT1 inhibitors with ATR inhibitors, such as prexasertib and RP-3500, resulted in enhanced antitumor activity in CCNE1-amplified cancer models. Additionally, we observed synergistic effects when combining PKMYT1 inhibitors with standard-of-care chemotherapies that induce DNA damage, such as gemcitabine and hydroxyurea. We also identified novel synergistic partners from library screening, featuring GSK3B inhibitors. These findings were confirmed in cell lines, organoid models, and in vivo CDX models, highlighting the potential of PKMYT1 inhibitors as part of combination therapy strategies. In conclusion, our study underscores the therapeutic potential of selective PKMYT1 inhibitors in CCNE1-amplified cancers and provides a strong rationale for their combination with ATR inhibitors and DNA-damaging chemotherapies. These findings support the continued development and clinical evaluation of PKMYT1 inhibitors as a novel approach to cancer treatment. Citation Format: Xiaobin Summer Wang, Sining Zhu, Haili Ding, Yang Tang, Minrui Weng, Kelly Chen, Yanna Ma, Pan Wang, Yifan Tu, Juhao Yang, Jun Wu, Dan Zhao, Xuefei Tan, Ying Ji, Xiangyu Yao, Zhipeng Yan. Discovery of selective and orally bioavailable PKMYT1 inhibitor: characterization of anti-tumor activities as single and dual agents [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 360.