tbuckley/cabot-search huggingface dataset:
Abstract 5687: Immune-associated genes as potential therapeutic targets in small cell lung cancer
Authors: Akihiko Miyanaga, Yang Yunchu, Kuniko Matsuda, Takehiro Tozuka, Aya Fukuizumi, Kakeru Hisakane, Naomi Onda, Susumu Takeuchi, Koichiro Kamio, Kazuo Kasahara, Masahiro Seike
Journal: Cancer Research (2025)

Abstract Background: Recently, immune checkpoint inhibitors (ICIs) have been increasingly applied in the treatment of small cell lung cancer (SCLC). While their development has enhanced treatment options for SCLC, the effectiveness of immunotherapy remains limited due to the low expression of Programmed Cell Death Ligand 1 (PD-L1) and the emergence of immunotherapy resistance. As a result, there is a pressing need for new biomarkers to guide SCLC treatment. Methods: We obtained four microarray datasets from GEO (Gene Expression Omnibus) database and screened differentially expressed genes (DEGs). After the establishment of protein-protein interaction network through Cytoscape, key hub genes were selected via a volcano plot. To validate these results, we used an independent dataset as a test cohort. We also analyzed differences in immune cell infiltration between normal and SCLC samples. Lastly, we identified a marker gene associated with immune cell infiltration and validated its role in SCLC through in vitro experiments. Results: We screened GEO gene expression database for DEGs, which are immune-related genes, in SCLC. A PPI network analysis revealed seven overexpressed hub genes (AURKB, BIRC5, TOP2A, TYMS, PCNA, UBE2C, AURKA) in the SCLC cohort, which were significantly more expressed than in normal cells. Correlation analysis between immune cells and the seven hub genes showed that BIRC5 expression was inversely correlated with monocytes. In SCLC cell lines such as SBC5 and SBC3, downregulation of BIRC5 using siRNA induced apoptosis and inhibited cell activity, tumor invasiveness and proliferative potential. Furthermore, treatment with a BIRC5 inhibitor (YM155) reduced SCLC cell viability and increased apoptosis. Co-culture experiments with SBC3 and monocytes (e.g., THP1) led to decreased BIRC5 expression in SBC3 cells. Conclusion: We identified AURKB, BIRC5, TOP2A, TYMS, PCNA, UBE2C, and AURKA genes as potential immune-related therapeutic targets for SCLC. In particular, high BIRC5 expression promotes SCLC progression and may influence the immune microenvironment of the tumor by affecting monocytes. Citation Format: Akihiko Miyanaga, Yang Yunchu, Kuniko Matsuda, Takehiro Tozuka, Aya Fukuizumi, Kakeru Hisakane, Naomi Onda, Susumu Takeuchi, Koichiro Kamio, Kazuo Kasahara, Masahiro Seike. Immune-associated genes as potential therapeutic targets in small cell lung 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 5687.
Abstract 5124: Dynamic subcellular localization of the EMT-associated lncRNA lncX in pancreatic cancer
Authors: Shu Hirako, Keiko Shinjo, Miho Suzuki, Tatsunori Nishimura, XingXing Wang, Yoshiteru Murofushi, Shinji Mii, Reo Maruyama, Kohei Kumegawa, Atsushi Enomoto, Yutaka Kondo
Journal: Cancer Research (2025)

Abstract Long non-coding RNAs (lncRNAs) are non-coding RNAs that are longer than 200 nucleotides. These RNAs play essential regulatory roles in processes such as chromatin modification, transcriptional regulation, and protein localization, depending on their subcellular distribution in the nucleus or cytoplasm. These functions have attracted considerable attention in cancer research. LncX, highly expressed in various cancers, has been implicated in promoting tumor malignancy by influencing processes such as proliferation, epithelial-mesenchymal transition (EMT). It has been reported that lncX regulates mRNA by acting as a competing endogenous RNA through binding to miRNAs. However, the subcellular localization of lncX and its interactions with specific proteins in pancreatic ductal adenocarcinoma (PDAC) remain poorly understood. We investigated the localization of lncX in the PDAC cell lines using RNA fluorescence in situ hybridization (RNA-FISH) and super-resolution microscopy. Under conditions where cells were tightly adhered to one another, lncX was localized at the cell membrane. Interestingly, when cell adhesion was disrupted and the cells entered a suspended state, lncX predominantly localized in the nucleus and cytoplasm. A similar localization pattern was observed in PDAC samples from a PDAC mouse model (KPC) and human PDAC tissues. Notably, lncX co-localized with CDH1 at the cell membrane and translocated to the nucleus following specific stimuli. These findings suggest that lncX may play distinct roles depending on its localization, potentially contributing to cancer malignancy. Citation Format: Shu Hirako, Keiko Shinjo, Miho Suzuki, Tatsunori Nishimura, XingXing Wang, Yoshiteru Murofushi, Shinji Mii, Reo Maruyama, Kohei Kumegawa, Atsushi Enomoto, Yutaka Kondo. Dynamic subcellular localization of the EMT-associated lncRNA lncX in pancreatic 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 5124.
Abstract 2618: Methylation-based epigenetic “switches” in group 3/4 medulloblastoma
Authors: Muhammad Awais Khan, Arsalan Riaz, Faisal F. Khan
Journal: Cancer Research (2025)

Abstract Medulloblastoma (MB) is the most common primary brain tumor in children, with group 3 and group 4 (G3/4) being the most aggressive. Methylation studies have identified eight distinct subgroups within G3/4 MB, with observed differences in survival patterns. However, the contribution of specific methylation-based epigenetic changes to the ontogeny of the disease remains poorly understood. We analyzed publicly available methylation profiles of 1, 370 G3/4 MB samples spanning all subgroups. To identify methylation probes important for classifying G3/4 MB into subgroups, we employed a wrapper-based feature selection machine learning (ML) algorithm on 400 samples. Subsequently, we trained a k-nearest neighbor (kNN)-based ML model to classify the remaining 970 samples, evaluating the sensitivity and specificity of the selected methylation probes. The kNN model achieved an accuracy of 90.41% using a panel of 541 methylation probes. We further refined this panel to 179 probes based on sensitivity and specificity metrics and observed a sequential alteration in beta values, suggesting a common developmental lineage for these subgroups. To identify specific genes driving the differentiation of the cells of origin or their transition to a cancerous state via methylation mechanisms, we selected a cohort of 460 samples that best represented the subgroups. Matched expression profiles for 103 samples were integrated with methylation data to infer candidate genes. To determine the spatiotemporal origins of these subgroups, we performed gene set enrichment analysis (GSEA) using published spatiotemporal gene sets of the developing human cerebellum. Our findings suggest that distinct subgroups originate from the Rhombic Lip Ventricular Zone, Intermediate Zone, Sub-ventricular Zone, and Choroid Plexus Epithelium. Further GSEA traced the cells of origin to Rhombic Lip - Progenitor, Unipolar Brush Cell - Progenitor, Differentiating and Defined, and Excitatory Cerebellar Neuron - Defined. In summary, we identified a prioritized methylation signature capable of accurately classifying G3/4 MB into subgroups and developed an R package, PriorityMeth, for further analysis. We also propose a developmental model outlining the origins of the subgroups of G3/4 MB and provide insights about the probable methylation-based epigenetic “switches” that drive the ontogeny of this group. Citation Format: Muhammad Awais Khan, Arsalan Riaz, Faisal F. Khan. Methylation-based epigenetic "switches" in group 3/4 medulloblastoma [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 2618.
Abstract 1864: Folate-mediated delivery of tumor-suppressive miRNA-34a to treat osteosarcoma
Authors: Iman T. Mevaa, Ahmed M. Abdelaal, Ikjot S. Sohal, Shreyas G. Iyer, Kasireddy Sudarshan, Harish Kothandaraman, Nadia A. Landman, Philip S. Low, Andrea Kasinski
Journal: Cancer Research (2025)

Abstract Osteosarcoma is a common type of bone cancer primarily observed in children, teenagers, and young adults. Current treatments (including surgery, chemotherapy, and radiotherapy) are invasive and induce aggressive side effects. Alternative approaches such as using microRNAs (miRNA) are emerging as promising anticancer agents. miRNA modulates tumorigenesis via tumor-suppressive and oncogenic miRNAs. Tumor-suppressive and oncogenic miRNAs respectively downregulate oncogenic and tumor-suppressive mRNA transcripts. Hence, leveraging the anticancer activity of tumor-suppressive miRNAs appears as a viable anticancer treatment approach. The overarching challenges with miRNA therapy are 1) achieving specific non-toxic delivery of tumor-suppressive miRNA to cancer cells, and 2) enhancing the stability of the miRNA, which can be degraded by nucleases. To circumvent these obstacles, we developed a folate-conjugated fully modified miRNA-34a that specifically targets osteosarcoma cells, which often overexpress folate receptor-α on their surface. The fully modified miRNA-34a bears phosphorothioate linkages at the 3’ and 5’ ends of the sense and antisense strands which significantly reduces nucleases attack. The substitution of the 2’ hydroxyl with 2’ methoxy and 2’ fluoro groups in an alternative fashion further enhances stability. Overall, the fully modified miRNA-34a shows continuous downregulation of target genes 120 hours post-delivery in breast cancer in-vivo models. Here, we present preliminary results for folate-mediated delivery of fully modified miRNA-34a in osteosarcoma samples. This study highlights the potential of miRNA-34a as a safe and effective anticancer agent for osteosarcoma treatment. Citation Format: Iman T. Mevaa, Ahmed M. Abdelaal, Ikjot S. Sohal, Shreyas G. Iyer, Kasireddy Sudarshan, Harish Kothandaraman, Nadia A. Landman, Philip S. Low, Andrea Kasinski. Folate-mediated delivery of tumor-suppressive miRNA-34a to treat osteosarcoma [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 1864.
Abstract 2003: Targeting the human adrenomenulin 2 hormone inhibits cancer cell intravasation
Authors: Seyedeh Sara Karimian, John Lewis, Konstantin Stoletov
Journal: Cancer Research (2025)

Abstract Cancer cell intravasation is the crucial step of cancer metastasis, and no therapeutic agents thattarget this process exist. Our laboratory uses high-resolution multidimensional intravital confocalimaging to visualize intratumoral cancer cell invasion and metastasis. Using this techniquecombined with fluorescent reporters, we discovered that in the live tumours, cancer cells withelevated ATF2 transcription factor (ATF+) are lining up the intratumoral vasculature, activelyinvading the perivascular space and responsible for 100% of cancer cell intravasation events. Incontrast, cancer cells low in ATF2 activity (ATF2-) fail to interact with the intratumoralvasculature and do not intravasate. Most cancer cell intravasation events occur in the large(∼50µm) veins deep within the tumour mass (intravasation ports). Isolation of ATF2+ and ATF2-cells followed by their comparative RNAseq analysis revealed that ADM2 (Adrenomennulin 2)peptide hormone is significantly (∼3x) overexpressed in ATF2+ compared to ATF2- tumour cells.shRNA-mediated knockdown of ADM2 expression in cancer cells decreased ATF2 activity, revealing a possible positive feedback loop. We found that shRNA knockdown of ADM2expression drastically inhibited the intratumoral cancer cell invasion and formation of the sizeableintratumoral vasculature. Notably, cancer cells deficient in ADM2 expression fail to invadeintratumoral perivascular space and intravasate. Our findings reveal Adrennomenulin 2 as a noveland potent anti-cancer metastasis target that can specifically inhibit cancer cell intravasation. Citation Format: Seyedeh Sara Karimian, John Lewis, Konstantin Stoletov. Targeting the human adrenomenulin 2 hormone inhibits cancer cell intravasation [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 2003.
Abstract 2590: Characterization of tumor-neuron communication in lung adenocarcinoma brain metastasis
Authors: Sampada Chande, Don Nguyen, Atsushi Yamasaki, Veronica Chiang, Declan McGuone
Journal: Cancer Research (2025)

Abstract 30-40% of cancer patients with lung cancer develop brain metastasis with poor prognosis. The incidence of brain metastasis has increased in patients that have received standard of care treatment, including targeted therapies. The mechanisms which promote lung cancer cell dissemination and colonization of the central nervous system (CNS) remain understudied and identifying novel drug targets to treat brain metastasis is an unmet clinical need. By using a variety of animal models of lung cancer metastasis, we previously identified shifts in epithelial and neuronal like lineage gene expression programs in malignant cells as they adapt to the brain tumor microenvironment (TME) in vivo. Gene set enrichment analysis (GSEA) revealed that most of genes are involved in neuronal guidance and cell adhesion pathways (L2FC &amp;gt; 0.5, padj &amp;lt; 0.05, Log2RPKM &amp;gt; 1 compared to 2D culture). We also examined tumor-neuron interactions in patient derived surgical biopsies and found active areas of interaction between tumors and neurons in human lung adenocarcinoma (LUAD) brain metastasis. Spatial transcriptomics of human brain metastasis also revealed differential profiles for areas of active interaction. In vitro, we established co-culture conditions which demonstrate that primary neurons can directly interact with brain metastatic LUAD cells and improve their fitness. Based on these observations, we performed a custom Clustered regularly interspaced palindromic repeats (CRISPR)-Cas9 loss of function screen targeting 470 neuronal and cell adhesion genes that are up-regulated in LUAD cells that seed the brain in vivo. Moreover, we performed our screens under different conditions which recapitulate tumor cell-tumor cell clustering in 3-dimensional culture conditions (3D) or tumor-neuron co-clustering in 3D. Results from this differential screening approach suggests that LUAD cells are increasingly, but not exclusively, dependent on several neuronal genes as they are co-cultured with neurons. In conclusion, we have modelled direct tumor-neuronal cell interaction in vitro, shown that it is an important component of brain metastasis, and identified putative targets that can be inhibited to disrupt tumor-neuron interactions and potentially limit brain metastatic progression. Citation Format: Sampada Chande, Don Nguyen, Atsushi Yamasaki, Veronica Chiang, Declan McGuone. Characterization of tumor-neuron communication in lung adenocarcinoma brain 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 2590.
Abstract 2987: Role of EIF4G1 network in non-small cell lung cancers (NSCLC) pathogenesis and development of targeted therapy
Authors: Zhiqiang Qin, Steven R. Post, Hong-yu Li, Lu Dai
Journal: Cancer Research (2025)

Abstract Although the Eukaryotic Translation Initiation Factor 4 Gamma 1 (EIF4G1) has been found overexpressed in a variety of cancers, its role in non-small cell lung cancers (NSCLC) pathogenesis, clinical relevance and therapeutic potential remain largely unknown. By using cancer patients tissue assays, our results indicate that EIF4G1 expressional levels are much higher in NSCLC tissues than in adjacent or normal lung tissues, which are also associated with NSCLC patient survival. By using an RNA-Sequencing based pipeline, the data show that EIF4G1 has a significant association with immune checkpoint molecules such as PD-1/PD-L1 in NSCLC. Protein array results identify the signature of proteins controlled by EIF4G1 in NSCLC cells, in which new candidates such as MUC1 and NRG1 are required for NSCLC survival and tumorigenesis with clinical relevance. EIF4G1 small-molecule inhibitors effectively repress NSCLC growth in cell culture and xenograft animal models. To further improve the specificity of EIF4G1 targeted therapies, we recently have designed and synthesized O’PROTAC-based EIF4G1 specific degraders which showing effective anti-NSCLC activities. Taken together, these results demonstrate the immunoregulatory functions, clinical relevance and therapeutic potential of the EIF4G1 network in NSCLC, which may represent a promising and novel target to improve lung cancer treatment. Citation Format: Zhiqiang Qin, Steven R. Post, Hong-yu Li, Lu Dai. Role of EIF4G1 network in non-small cell lung cancers (NSCLC) pathogenesis and development of targeted 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 2987.
Abstract 2956: Anti-tumor activity of camptothecin analog conjugate of a RSPO4-based peptibody targeting LGR4/5/6 in preclinical models of colorectal cancer
Authors: Yukimatsu Toh, Ling Wu, Jianghua Tu, Zhengdong Liang, Adela M. Aldana, Li Li, Jake J. Wen, Sheng Pan, Julie H. Rowe, Martha E. Hensel, Carolyn L. Hodo, Rick A. Finch, Kendra S. Carmon, Qingyun J. Liu
Journal: Cancer Research (2025)

Abstract Antibody-drug conjugates (ADCs) have emerged as a major modality of targeted cancer therapy, yet no ADC has been approved for colorectal cancer (CRC). LGR4/5/6 (leucine-rich repeat containing, G protein-coupled receptor 4, 5, 6) are three related receptors that are expressed at high levels together or alternately in nearly all cases of CRC. ADCs targeting LGR5 have been shown to have robust anti-tumor potency, but not all CRC cells express LGR5 and LGR5-positive tumor cells may lose LGR5 expression due to cancer cell plasticity. R-spondin 4 (RSPO4) is a natural protein ligand of LGR4/5/6 with high affinity for all three receptors. We fused a mutant form of RSPO4 that retains high affinity binding to LGR4/5/6 to IgG1 Fc to create a peptibody designated R462. Conjugation of R462 with a camptothecin analog (CPT2) at eight drugs per peptibody led to the synthesis of R462-CPT2 that showed highly potent cytotoxic activity in vitro in CRC cell lines expressing any of LG4/5/6. In cell line xenograft and PDX models of CRC, R462-CPT2 demonstrated robust anti-tumor effect. Importantly, R462-CPT2 showed no major adverse effect at therapeutically effective dose levels. These results strongly support the use of RSPO ligand drug-conjugates that target LGR4/5/6 simultaneously for the treatment of CRC. Citation Format: Yukimatsu Toh, Ling Wu, Jianghua Tu, Zhengdong Liang, Adela M. Aldana, Li Li, Jake J. Wen, Sheng Pan, Julie H. Rowe, Martha E. Hensel, Carolyn L. Hodo, Rick A. Finch, Kendra S. Carmon, Qingyun J. Liu. Anti-tumor activity of camptothecin analog conjugate of a RSPO4-based peptibody targeting LGR4/5/6 in preclinical models of 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 2956.
Abstract 5132: DNMT1-associated EMT promotes KRAS escape in pancreatic cancer
Authors: Loan Duong, Xin Lu
Journal: Cancer Research (2025)

Abstract Pancreatic adenocarcinoma (PDAC) is presently the 3rd leading cause of cancer death in the United States and is further projected to overcome colorectal cancer to become the 2nd leading cause by 2030. The genetic landscape of PDAC is characterized by pervasive oncogenic mutations in KRAS, observed in over 90% of PDAC tumors. KRAS is considered essential for maintaining tumor progression and so targeting it has long been considered crucial to improving outcomes for PDAC patients. For preclinical studies of KRAS in our lab, we are using an inducible KRAS (iKRAS) model to model KRAS activation and inhibition. This model is based on iKRAS cell lines derived from transgenic tetO_LSL-KrasG12D; p53L/+; p48-Cre mice and upon doxycycline treatment, express oncogenic KrasG12D. Orthotopic implantation of iKRAS cells results in the formation of doxycycline-dependent pancreatic tumor growth in both immune-deficient and immunocompetent models. Withdrawal of doxycycline results in tumor regression. However, we have observed instances of tumor relapse despite the absence of doxycycline and established cell lines from these relapsed tumors. In vitro analyses confirm that these cells are independent of both doxycycline and KRAS, unlike the parental cell line. In vivo, upon reimplantation in the pancreas, they maintain the ability to grow independently of doxycycline. Transcriptome and reverse phase protein array analysis reveal an enrichment of markers associated with epithelial to mesenchymal (EMT) with western blot analyses further confirming increased expression of EMT markers, including Snail, Slug, and αSMA. The KRAS-independent cell line further demonstrated elevated DNMT1 expression, a previously described driver of EMT. Targeting DMNT demonstrated more pronounced effects on cell viability in the KRAS-independent cell line than the parental KRAS-dependent cell line. Deeper insight into the ability of these cells to escape KRAS addiction will enhance our understanding of resistance to KRAS inhibition and suggest further avenues for co-targeting. Citation Format: Loan Duong, Xin Lu. DNMT1-associated EMT promotes KRAS escape in pancreatic 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 5132.