tbuckley/cabot-search huggingface dataset:
Abstract 390: ERAS-0015 is a pan-RAS molecular glue with best-in-class potential in RAS mutant solid tumors
Authors: Erin D. Lew, Alexei Brooun, Justine Lam, Joanne Oh, Taylor Sullivan, Corine Holub, Jae Hyun Bae, Bingzhen Lin, Brian Qua, Alex Stromitis, Sarah M. Griffith, Andrea Shen, Dawei Xuan, Robert F. Shoemaker
Journal: Cancer Research (2025)

Abstract As a key node of the canonical RTK-RAS-MAPK signaling cascade, the RAS family of GTPases plays an essential role in numerous physiological processes including cellular proliferation, migration, survival, and immune cell activation. However, under pathological conditions, oncogenic RAS mutations, particularly in hotspot codons 12, 13, and 61, affect RAS intrinsic hydrolysis and/or GEF-mediated exchange resulting in a shift from GDP-bound to GTP-bound RAS. This shift to the GTP-bound RAS state leads to recruitment of effector proteins through the RAS-binding domains (RBDs) and ultimately leads to prolonged intracellular activation and modulation of the tumor microenvironment (TME). ERAS-0015 is a pan-RAS molecular glue with best-in-class potential designed to target RAS in the GTP-bound state and shut down cellular signaling mediated by both mutant and wild-type RAS. ERAS-0015 exhibited 3-7-fold more potent inhibition of cellular proliferation relative to RMC-6236, a RAS molecular glue comparator, across multiple RAS mutant cell lines harboring G12X/G13X/Q61X mutations. ERAS-0015’s roughly 8-20-fold higher binding affinity to cyclophilin A (CYPA) is thought to contribute to its higher in vitro cellular potency as well as favorable ADME and PK properties resulting in a longer residence time and greater exposure in tumor tissues as compared to RMC-6236. These favorable properties enabled ERAS-0015 to achieve comparable tumor growth inhibition (TGI) relative to RMC-6236 at 1/8th-1/10th the dose across multiple KRAS mutant CDX models irrespective of histology or specific mutation. ERAS-0015 demonstrated promising preclinical activity across multiple RAS mutant models supporting IND filing in 1H 2025. Citation Format: Erin D. Lew, Alexei Brooun, Justine Lam, Joanne Oh, Taylor Sullivan, Corine Holub, Jae Hyun Bae, Bingzhen Lin, Brian Qua, Alex Stromitis, Sarah M. Griffith, Andrea Shen, Dawei Xuan, Robert F. Shoemaker. ERAS-0015 is a pan-RAS molecular glue with best-in-class potential in RAS mutant solid tumors [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 390.
Abstract 219: Uncovering synergistic and antagonistic interactions in epigenetic therapeutics using perturb-seq
Authors: Changde Cheng, Rui Lu, Sajesan Aryal, Doug A. Welsch
Journal: Cancer Research (2025)

Abstract Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by genetic and epigenetic dysregulation, including aberrant activity of chromatin modifiers. The complex interactions among these modifiers and regulators in AML pathogenesis remain poorly understood, posing significant challenges to developing effective combination therapies. To address this, we used Perturb-seq, a CRISPR-based single-cell transcriptomics approach, to profile 16 key genes from the Menin-MLL, Polycomb, and histone acetyltransferase (HAT) complexes in the MOLM-13 AML cell line. We developed a machine learning framework called Composer, which predicts the combinatorial effects of perturbations by analyzing their impact on the transcriptome. We identified cooperative regulation of oncogenic pathways by Menin-MLL and KAT6A, while PRC1 components, such as PCGF1, were found to antagonize DOT1L activity. These predictions were validated using bulk RNA-seq and experiments combining perturbations through small molecule inhibitors and gene knockouts, demonstrating that dual inhibition of Menin-MLL and KAT6A, or DOT1L and KAT6A, significantly reduced AML cell viability. This study underscores the power of combining AI with single-cell Perturb-seq to provide novel insight into the epigenetic landscape of AML and identify promising therapeutic targets to overcome treatment resistance. Citation Format: Changde Cheng, Rui Lu, Sajesan Aryal, Doug A. Welsch. Uncovering synergistic and antagonistic interactions in epigenetic therapeutics using perturb-seq [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 219.
Abstract 8: Identifying the role of KIF20A in stemness and metastasis in hepatocellular carcinoma
Authors: Liuxian Ban, Xiaona Fang, Shan Liu, Jie Luo, Lanqi Gong, Hongyu Zhou, Beilei Liu, Jiao Huang, Nanzhou Yu, Yingchen Lyu, Licheng Tan, Qin Liu, Cuicui Huang, Xin-Yuan Guan
Journal: Cancer Research (2025)

Hepatocellular carcinoma (HCC) is remarkable for its high recurrence and metastasis rate. According to the cancer stem cell (CSC) model, a small group of stem cells is capable of keeping self-renewal, initiating relapse and metastasis in tumors. However, the mechanism of CSCs in regulating HCC recurrence and metastasis awaits further investigation. We previously established an in vitro human hepatocyte differentiation model and defined four developmental stages: embryonic stem cell (ES), endoderm (EN), liver progenitor cell (LN) and premature hepatocyte (PH). Kinesin family member 20A (KIF20A) was found highly expressed in ES and EN stages while decreasing sharply in LP and PH stages. Besides, in an online GEO dataset, we regrouped single cells into the hepatocyte, stem-like HCC and HCC subclusters according to their expression profiles. KIF20A was spotted mostly in the stem-like HCC cluster with a low proportion, sharing the same expression pattern with CD133, suggesting its potential role in cancer stemness. Moreover, KIF20A expression was positively correlated with stemness markers CD133, Epcam, CK19, and MYCN in our clinical cDNA array. In the TCGA-LIHC dataset, KIF20A expressed higher in tumor tissues than normal counterparts, and related to shorter overall survival in patients. Functionally, KIF20A promoted cell proliferation, induced sorafenib resistance, increased sphere formation, and enhanced cell migration and invasion in vitro. In subcutaneous mouse models, liver orthotopic mouse models and hydrodynamic transfection mouse model of HCC, KIF20A fueled tumorigenicity and lung metastasis significantly. After mRNA sequencing of KIF20A knock-down cells, bioinformatic analysis suggested that KIF20A may modulate metastatic biological processes via the Hippo pathway. Western Bloting further confirmed the result of pathway changes in protein level. The underlying mechanism of how KIF20A interacts with Hippo pathway still needs further investigation. In conclusion, we provided new insights into the role of KIF20A in regulating stemness and metastasis in HCC. KIF20A might be a potential target for HCC treatment in the future. Citation Format: Liuxian Ban, Xiaona Fang, Shan Liu, Jie Luo, Lanqi Gong, Hongyu Zhou, Beilei Liu, Jiao Huang, Nanzhou Yu, Yingchen Lyu, Licheng Tan, Qin Liu, Cuicui Huang, Xin-Yuan Guan. Identifying the role of KIF20A in stemness and metastasis in hepatocellular carcinoma [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 8.
Abstract 228: Loss of <i>TET2</i> and <i>TET3</i> mediated DNA demethylation drives intestinal tumor formation
Authors: Oliver Gilliam, Ihab Ansari, Nikolaos Georgakopoulos, Manuel Mastel, Rene Jackstadt, Sebastian Belle, Yehudit Bergman, Frank Lyko
Journal: Cancer Research (2025)

Abstract Non-mutational epigenetic reprogramming is a widely recognized hallmark of cancer, which emphasizes the relevance of epigenetic modifications for cancer development. The discovery of the CpG island methylator phenotype in colorectal cancer (CRC) and promotor hypermethylation of tumor suppressor genes further raised the interest in DNA methylation changes during tumor development. However, despite decades of cancer epigenetics research, our understanding of the function of aberrant DNA methylation remains limited. Thus, new models are needed to study the link between global DNA methylation changes and tumorigenesis. The Ten-eleven translocator (TET) enzymes are critical mediators of active demethylation by oxidizing the C5-methylcytosine, thereby playing a vital role in regulating DNA methylation. Here, we report an intestinal epithelium-specific TET2/3 double knockout (dko) mouse model, which shows invasive adenocarcinomas in the small intestine at high penetrance. We performed a detailed DNA methylation analysis and identified enhancers as the main target of hypermethylation in the tumors. Additionally, we observed substantial overlap in methylation patterns with the fetal developmental stage of the mouse intestine. Subsequent analysis also revealed a fetal gene expression signature and activation of YAP1 signaling, suggesting oncofetal reprogramming. Since fetal reprogramming is enriched in the serrated route to colorectal cancer, we compared our model with models of the classical (APC) and serrated (BRAF- and KRAS-derived) route of CRC. We found similar methylation patterns between the TET2/3 dko tumors and BRAF- and KRAS-derived tumors. To investigate the clinical relevance of our findings, we collected human small bowel adenomas and integrated their methylation profiles with available datasets of colorectal adenomas and carcinomas. We observed notable similarities between adenomas of the small bowel and serrated adenomas of the colon. This finding further confirms the similarities between our TET-deficient mouse model and the serrated route to colorectal cancer and suggests that non-mutational TET deficiency could be an important driver of intestinal cancer. Citation Format: Oliver Gilliam, Ihab Ansari, Nikolaos Georgakopoulos, Manuel Mastel, Rene Jackstadt, Sebastian Belle, Yehudit Bergman, Frank Lyko. Loss of TET2 and TET3 mediated DNA demethylation drives intestinal tumor formation. [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 228.
Abstract 163: Spatiotemporal multi-omics uncover tumor ecosystem dynamics driving metastatic colonization
Authors: Liang Wu, Yu Zhong, None Shang liu, Zefan Zhang, Chunqing Wang, Yunfan Sun, Jia Fan, Jian Zhou, Xun Xu
Journal: Cancer Research (2025)

Abstract The mechanisms underlying the interaction between disseminated tumor cells (DTCs) and their tissue microenvironment during metastasis colonization are poorly understood. We integrated multimodal single-cell and spatial profiling from liver cancer mouse models and human metastases to track the spatiotemporal dynamics of DTCs and their microenvironments across nine sequential time points from single-cell seeding until overt lung metastasis. We identified a residual population of quiescent Phgdhhigh DTCs that survive initial innate immune clearance and become transiently enriched in micrometastases. These cells shape an immune-scarce microenvironment through PHGDH-dependent, H3K27me3-mediated epigenetic silencing of chemokine transcription, promoting metastatic expansion. Cx3cr1high interstitial macrophages were also found to be transiently enriched before DTCs expansion, creating an immune-privileged niche for metastatic outgrowth by recruiting immunosuppressive cells. Inactivating the Phgdh-H3K27me3 axis in DTCs or depleting interstitial macrophages restored immune surveillance and inhibited metastatic colonization. These findings provide new therapeutic concepts for developing micrometastasis-targeting regimens. Citation Format: Liang Wu, Yu Zhong, Shang liu, Zefan Zhang, Chunqing Wang, Yunfan Sun, Jia Fan, Jian Zhou, Xun Xu. Spatiotemporal multi-omics uncover tumor ecosystem dynamics driving metastatic colonization [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 163.
Abstract 35: Hydrogel-based microwell chip for improved organoid culture and on-chip imaging
Authors: Thi Kim Ngan Ngo, Ting-Yuan Tu
Journal: Cancer Research (2025)

Abstract Organoids have become essential tools for modeling complex biological systems, driving significant advancements in drug screening, cancer research, and regenerative medicine. However, traditional dome-shaped organoid culture methods come with notable limitations. These include variability in organoid size, structural heterogeneity, and difficulties in achieving high-resolution imaging due to overlapping positions and artifacts from the surrounding extracellular matrix (ECM). Such issues often hinder the reproducibility and precision of experimental outcomes, especially in long-term culture settings. To overcome these challenges, we developed a hydrogel-based microwell chip designed to standardize organoid culture and enhance imaging quality. The chip contains a grid of 100 microwells, each optimized to support the formation of up to 100 uniform spheroids or organoids. It is designed with a main microwell channel along with two inlet and outlet channels for hydrogel injection, which can be connected to a pump to enable dynamic culture conditions. Using this system, we successfully generated uniform spheroids from various cancer cell lines and consistent mouse intestinal organoids that retained characteristics comparable to those produced with the dome-shaped method. Importantly, the optimized size of the microwells reduces the volume of culture medium and cell suspension required, offering a more cost-effective and resource-efficient solution. This efficiency is particularly advantageous for drug screening, large-scale studies, or research involving precious samples, such as patient-derived organoids. Another notable advantage of our microwell chip is its compatibility with high-quality, live on-chip imaging throughout the culture period. This capability is essential for real-time studies of dynamic processes in organoid models, such as tissue morphogenesis, drug responses, and disease progression. Furthermore, the chip’s glass-bottom design, combined with a thin hydrogel layer, facilitates confocal imaging either with the hydrogel in place or after it has been dissolved. Overall, our hydrogel-based microwell chip represents a robust and versatile platform that not only standardizes organoid culture but also improves the quality of imaging and data collection. By enhancing reproducibility, efficiency, and throughput, this technology holds promise for applications in precision medicine, drug testing, cancer research, and beyond. Citation Format: Thi Kim Ngan Ngo, Ting-Yuan Tu. Hydrogel-based microwell chip for improved organoid culture and on-chip imaging [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 35.
Abstract 1131: Comprehensive genomic profiling in osteosarcoma: Insights from Japanese cohorts and the AACR Project GENIE
Authors: Suehara Yoshiyuki, Rina Kitada, Masachika Ikegami, Satoshi Kamio, Koichi Ogura, Shintaro Iwata, Eisuke Kobayashi, Akira Kawai, Shinji Khosaka
Journal: Cancer Research (2025)

Abstract Background: Osteosarcoma (OS), the most common primary malignant bone tumor, presents challenges in treatment, especially in metastatic or recurrent cases. Genomic profiling may offer novel therapeutic approaches by identifying actionable mutations. This study utilizes data from the Japanese Center for Cancer Genomics and Advanced Therapeutics (C-CAT) and AACR Project GENIE, comparing findings with the MSK-IMPACT dataset to understand differences in genomic landscapes and identify clinically actionable alterations. Methods: We analyzed 223 high-grade OS samples from the C-CAT database, comparing findings to the GENIE cohort and MSK-IMPACT data. Tumor DNA sequencing was performed using FoundationOne® CDx and OncoGuide™ NCC Oncopanel. Genomic alterations were categorized by levels A-F per Cancer Knowledge Database (CKDB) and compared with public databases (cBioPortal). Results: In the C-CAT cohort, 42.2% of samples had actionable mutations (CKDB Levels A-C), including two NTRK fusions (0.9%), one TMB-high case (0.4%), and recurrent ERBB, CDK4, PTEN, and PDGFRA gene alterations. Co-occurring KIT, KDR, and PDGFRA amplifications were observed at 4q12 in 3.6% of cases, while VEGFA and CCND3 co-amplifications at 6p12-21 occurred in 14.8% of cases, suggesting multi-kinase inhibitors as potential treatments. Differences from the MSK-IMPACT dataset (Suehara Y et al, Clin Cancer Res. 2019 25(21):6346-6356), where mutually exclusive amplifications were more pronounced, highlight the genetic diversity between Japanese and U.S. cohorts. Analysis with GENIE and MSK-IMPACT indicates a lower incidence of mutually exclusive alterations in the Japanese cohort. Conclusions: Targetable alterations were present in 42.2% of Japanese OS cases, with a distinct genomic profile compared to U.S. cohorts. Amplifications in 4q12 and 6p12-21, which may be treatable with multi-kinase inhibitors, were found in both datasets, yet mutual exclusivity patterns varied. This study underscores the potential of precision oncology in OS, encouraging continued exploration of genomic data in diverse populations to expand treatment options. Citation Format: Suehara Yoshiyuki, Rina Kitada, Masachika Ikegami, Satoshi Kamio, Koichi Ogura, Shintaro Iwata, Eisuke Kobayashi, Akira Kawai, Shinji Khosaka. Comprehensive genomic profiling in osteosarcoma: Insights from Japanese cohorts and the AACR Project GENIE [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 1131.
Abstract 134: Integrating spatial transcriptomics and second harmonic generation imaging of collagen identifies genes associated with discoidin domain receptor 1 and collagen alignment in colorectal cancer
Authors: Maxwell Stuart Hamilton, Harsimran Kaur, Alan J. Simmons, Ken S. Lau, Ambra Pozzi, Robery J. Coffey
Journal: Cancer Research (2025)

Abstract Immune checkpoint blockade (ICB) has been shown to be an effective treatment for colorectal cancers (CRCs) highly infiltrated by CD8+ T cells. However, there is a paucity of CD8+ T-cell infiltration in the majority of CRCs. Tumors with highly aligned collagen fibers have been shown to have reduced CD8+ T-cell infiltration. We previously identified a four-gene signature associated with T-cell exclusion in CRC. One of the genes, Transforming Growth Factor Beta Induced (TGFBi), is known to be involved in extracellular matrix regulation. Another, Discoidin Domain Receptor 1 (DDR1), promotes collagen fiber alignment in breast cancer. To determine if TGFBi and DDR1 are associated with collagen alignment in CRC, as well as to identify additional genes involved in collagen alignment, we have developed a method to spatially resolve collagen fiber alignment and integrate it with spatial transcriptomics. To do this, 30 μm thick CRC sections are imaged using a Nikon AX multiphoton microscope by second harmonic generation imaging, which permits label-free imaging of collagen fibers. Spatial heatmaps of the collagen alignment are generated from the resulting images. Spatial transcriptomics is performed on a serial tumor section using the Visium v2 platform and the gene expression matrix is integrated with the collagen alignment heatmap data. As proof-of-principle, two CRC tumors have been analyzed using this method. Highly aligned regions were found to be associated with expression of genes involved in extracellular matrix organization, keloidal collagen and specific fibroblast subtypes. The genes that correlate with collagen alignment will be confirmed at the protein level by multiplexed immunofluorescence on serial sections. This method will provide a rich dataset permitting elucidation of the complex interactions between T-cell exclusion, gene expression and collagen fiber alignment and may support the discovery of new strategies to overcome immune exclusion in CRC. Citation Format: Maxwell Stuart Hamilton, Harsimran Kaur, Alan J. Simmons, Ken S. Lau, Ambra Pozzi, Robery J. Coffey. Integrating spatial transcriptomics and second harmonic generation imaging of collagen identifies genes associated with discoidin domain receptor 1 and collagen alignment in colorectal 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 134.
Abstract 283: Cholesterol(C27H46O)identified by metabolomics enhance lipid raft composition for cell proliferation in epithelial ovarian cancer
Authors: Hitomi Sakaguchi-Mukaida, Kosuke Hiramatsu, Tatsuo Masuda, Mamoru Kakuda, Satoshi Nakagawa, Tadashi Iwamiya, Shinya Matsuzaki, Yutaka Ueda
Journal: Cancer Research (2025)

Abstract Objective: We previously reported that lipoprotein promoted cell proliferation of epithelial ovarian cancer (EOC) cells in vitro. Moreover, we demonstrated High-Fat Diet (HFD) strongly promoted the tumor growth of EOC in vivo and HFD mouse serum promoted cell proliferation in vitro. These results suggest that lipid molecules derived from HFD contribute to cell proliferation of EOC. In this study, we aimed to identify the lipid molecules in HFD mouse serum which contribute to cell proliferation of EOC cells by metabolomics and figure out the function of the lipid molecule. Methods: We obtained serum of HFD and normal diet (ND) fed mouse and performed metabolomics to identify the lipid molecules which contribute to cell proliferation of EOC. In vitro, we validated that lipid molecules in HFD mouse serum promote the cell proliferation and analyzed which signaling pathway was activated. In vivo, we evaluated the effect of lipid molecules-rich diet in tumor growth. We also evaluate the association of lipid molecules and lipid rafts in EOC cells. Results: HFD significantly promoted the tumor growth EOC in vivo (p &amp;lt; 0.05), and HFD mouse serum also promoted cell proliferation of EOC cells in vitro (p &amp;lt; 0.05). Metabolomics showed obvious different metabolic profiles of HFD and ND mouse serum (non-tumor bearing). Partial least squares-discriminant analysis revealed that cholesterol (C27H46O) ranked highest as the lipid molecule in HFD mouse serum. In vitro, cholesterol significantly promoted cell proliferation (p &amp;lt; 0.05) via Akt/mTOR signaling pathway. Moreover, we demonstrated that cholesterol-rich diet promoted the tumor growth of EOC (p &amp;lt; 0.05). Finally, we evaluated that lipid raft inhibitor blocked cholesterol induced cell proliferation (p &amp;lt; 0.05). Conclusions: Cholesterol (C27H46O) uptake lead to the cell proliferation of epithelial ovarian cancer via stimulation Akt/mTOR signaling pathway following lipid raft. Citation Format: Hitomi Sakaguchi-Mukaida, Kosuke Hiramatsu, Tatsuo Masuda, Mamoru Kakuda, Satoshi Nakagawa, Tadashi Iwamiya, Shinya Matsuzaki, Yutaka Ueda. Cholesterol(C27H46O)identified by metabolomics enhance lipid raft composition for cell proliferation in epithelial ovarian 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 283.