tbuckley/cabot-search huggingface dataset:
Abstract 7207: Targeting hippo signaling pathway to overcome chemoresistance in glioblastoma
Authors: Cheuk Lun Ethan Wong, Mei Yee Karrie Kiang, Ka Kit Gilberto Leung
Journal: Cancer Research (2024)

Abstract The study aims to investigate whether the Hippo signaling pathway contributes to temozolomide chemoresistance in glioblastoma, and to validate whether the combinational treatment of temozolomide and YAP inhibitor is effective against glioblastoma. Temozolomide-sensitive and temozolomide-resistant U87 and U251 GBM human cell lines were previously established. Temozolomide-resistant cells were maintained in low-dose temozolomide. Here, we investigate whether Hippo signaling contributes to temozolomide chemoresistance. By modulating the Hippo signaling pathway through YAP gene knockdown, the outcome on cell proliferation was studied by cell viability assay (in vitro) and mouse orthotopic xenograft (in vivo). Finally, the therapeutic effect of YAP inhibitor is studied in vitro and in vivo respectively. Our data showed that YAP is overexpressed in temozolomide-resistant glioblastoma cells. Nuclear translocation of YAP (which becomes its active state) is increased in temozolomide-resistant cells. In fact, YAP inhibition show decreased cell viability and higher susceptibility to temozolomide. In addition, mice with tumor injection of the YAP knockdown cells reduced tumor size with temozolomide treatment. Similarly, YAP inhibitor resensitizes temozolomide-resistant cells to temozolomide. Combinational treatment of YAP inhibitor and temozolomide is effective in shrinking tumor size in mouse xenograft models. In conclusion, our data suggest dysregulated Hippo signaling pathway contributes to temozolomide chemoresistance, thus targeting the Hippo signaling pathway resensitizes GBM cells to temozolomide. This research provides pre-clinical evidence on using YAP inhibitor for combinational therapy with temozolomide for the treatment of glioblastoma. Citation Format: Cheuk Lun Ethan Wong, Mei Yee Karrie Kiang, Ka Kit Gilberto Leung. Targeting hippo signaling pathway to overcome chemoresistance in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7207.
Abstract 7564: DNA methylation profiling identifies two distinct groups of oligosarcoma, IDH-mutant with distinct genetic alterations and clinical outcomes
Authors: Kenan Zhang, Lingyu Liu, Xing Liu, Tao Jiang
Journal: Cancer Research (2024)

Abstract DNA methylation has been extensively adopted for the classification of brain tumors and is endorsed by current neuropathology guidelines. Recently, oligosarcoma, IDH-mutant has been characterized as a distinct group of IDH mutant gliomas by DNA methylation classification. However, emerging studies revealed the variety in this group. Here, we employed DNA methylation-based t-SNE analysis to characterize oligosarcomas identified by the dkfz brain tumor classifier (v12.5). Thereby, we uncovered that oligosarcomas were segregated into two distinct groups, namely, subgroup A and subgroup B, which were further validated by genetic alterations and clinical outcomes. Next-generation Sequencing revealed subtype A tumors enriched with chr 1p/19q co-deletion, chr 6q loss, CDKN2A/B homogeneous deletion, TERT promoter mutation, and NF1 mutation, while subtype B tumors showed chr7 gaining and TP53 mutation. RNA sequencing and gene set enrichment analysis (GSEA) revealed that neuronal-tumor interaction and muscular progression pathways were more enriched in subtype A tumors. In contrast, subtype B tumors showed enrichment for angiogenesis and mTOR pathways. Additionally, inter-chromosomal fusion genes were more frequently found in subtype A tumors. Clinically, patients with subgroup A oligosarcomas manifested poorer survival and distinct imaging features in magnetic resonance imaging (MRI) compared to those with subgroup B. Collectively, we provided more cases of oligosarcoma, IDH-mutant, confirming the existence of this newly identified group, and revealed the subgroups harboring different genetic alterations and suffering different prognoses, providing new evidence for the molecular pathology in diffuse glioma. Citation Format: Kenan Zhang, Lingyu Liu, Xing Liu, Tao Jiang. DNA methylation profiling identifies two distinct groups of oligosarcoma, IDH-mutant with distinct genetic alterations and clinical outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7564.
Abstract 5483: Macrospatial ecotype heterogeneity in early-stage breast cancer identified by spatial nucleus barcoding
Authors: Kaile Wang, Zhenna Xiao, Yiyun Lin, Runmin Wei, Shanshan Bai, Jie Ye, Rui Ye, Min Hu, Aatish Thennavan, Emi Sei, Alastair Thompson, Savitri Krishnamurthy, Nicholas Navin
Journal: Cancer Research (2024)

Abstract Ductal carcinoma in situ (DCIS), the predominant form of early-stage breast cancer and a precursor to invasive breast cancer, remains inadequately understood in terms of spatial microenvironment reprogramming. In this study, we developed a Spatial Nucleus Barcoding (SNuBar) approach for single-nucleus RNA sequencing (SNuBar-RNA) that utilizes a single oligonucleotide adaptor to preserve spatial information. The accuracy and scalability of SNuBar was validated using cell line mixture experiments. We then applied SNuBar-RNA to investigate the macrospatial ecotype heterogeneity in early-stage breast cancer. By analyzing single cells from different macrodissected spatial regions in normal breast tissues, matched normal and DCIS tissues, we identified 13 major cell types and 43 distinct cell states, co-localizing in diverse combinations across four primary topographic areas (adipose-enriched, normal epithelial, activated stroma and tumor). Spatial analysis revealed the reprogramming of vascular and myoepithelial cells in localized zones near premalignant cells, while fibroblasts, T-cells, and myeloid cells exhibited reprogramming across broader fields. Validation using the MERSCOPE assay confirmed stromal heterogeneity between tumor and normal areas. Collectively, our data shows that many diverse cell types are reprogrammed in spatially-defined areas in the early-stage breast cancer microenvironment, relative to the normal breast tissue regions. Citation Format: Kaile Wang, Zhenna Xiao, Yiyun Lin, Runmin Wei, Shanshan Bai, Jie Ye, Rui Ye, Min Hu, Aatish Thennavan, Emi Sei, Alastair Thompson, Savitri Krishnamurthy, Nicholas Navin. Macrospatial ecotype heterogeneity in early-stage breast cancer identified by spatial nucleus barcoding [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5483.
Abstract 5370: Tumor-intrinsic cGAS-STING activation promotes anti-tumor inflammatory response in osteosarcoma
Authors: Elizabeth "Betsy" Peale Young, Christine Johnson, Alex G. Lee, Eric Alejandro Sweet-Cordero
Journal: Cancer Research (2024)

Abstract A “cold” tumor microenvironment (TME) is often seen in patients with osteosarcoma (OS). Genomic instability, characteristic of OS, can stimulate the cGAS-STING pathway and activate the innate immune system. Tumor-intrinsic STING pathway silencing mechanisms can link genomic instability to immune evasion in OS. We hypothesize that dysregulation of the cGAS-STING pathway suppresses an innate immune response to genomic instability and plays a key role in tumor progression through establishing an immunosuppressive TME in OS. Using a novel panel of 11 OS patient-derived cell lines, we have identified two groups in terms of capacity for tumor-intrinsic STING activation, and we aim to unravel the mechanism of STING repression in a subset of OS tumors. To investigate the effects of tumor-intrinsic STING activation on macrophage polarization we employed tumor conditioned media (TCM) assays with murine-derived macrophages and tumor lines treated with cGAS-STING agonism. Tumor-intrinsic STING activation resulted in a significant increase in pro-inflammatory macrophages in a manner dependent on tumor STING. Lastly, we performed bulk RNA seq of OS PDX cell lines treated with STING agonist, defining for the first time the OS-specific STING activation signature. We then evaluated primary patient samples for evidence of this signature by single sample GSEA and performed survival analysis after stratifying samples as high or low for this signature, which demonstrated a significant protective effect of the STING activation signature on progression-free and overall survival. We have defined two subtypes of OS in terms of responsiveness to STING activation and demonstrated that STING activation has a protective effect in the human disease, which is the foundation of current efforts to identify targetable mechanism to reverse STING unresponsiveness and activate immune surveillance in this cancer. Citation Format: Elizabeth "Betsy" Peale Young, Christine Johnson, Alex G. Lee, Eric Alejandro Sweet-Cordero. Tumor-intrinsic cGAS-STING activation promotes anti-tumor inflammatory response in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5370.
Abstract 4856: Sex differences in childhood leukemia genomics
Authors: Lindsay A. Williams, Lauren J. Mills, Sofia Barragan, Peter M. Gordon, Jenny N. Poynter
Journal: Cancer Research (2024)

Abstract Males have higher ALL and AML incidence and worse ALL survival using population-based data. Somatic genetics may play a role in ALL survival disparities and highlight potential sex specific treatment strategies for future study. Therefore, we evaluated sex differences in gene expression (RNA seq), copy number variation (CNV), and somatic mutation in ALL and AML. We stratified by cytogenomic subtypes in publicly available data from clinical cohorts using St. Jude PeCan (subtypes in Table 1). Then, we explored survival differences by sex within cytogenetic subtypes in publicly available data collected from Children’s Oncology Group patients in the NCI TARGET dataset (ALL n=387, 63% male; AML n=151, 51% male). Differentially expressed genes by sex were identified for ALL adjusting for subtype (n=214) and within subtypes (Table 1). There were no sex differentially expressed genes shared across subtypes and pathways identified from sex differentially expressed genes were few. In ETV6-RUNX1, there was as suggestion of worse 10-year survival for males (n=44, 61% male; Log-Rank p=0.068). Differentially expressed genes by sex were identified for AML adjusting for subtype (n=537) and within subtypes (Table 1). There were no differentially expressed genes by sex shared across AML subtypes. KMT2A had the highest number of pathways identified from sex differentially expressed genes (Table 1). There were no sex differences in AML survival. In ALL and AML subtypes there were no sex differences in CNVs (all t-test p&amp;gt;0.05) or somatic mutations (all Fisher’s Exact p&amp;gt;0.05). There were no sex differences in AML survival in TARGET, in agreement with population-based studies, and few differentially expressed genes identified in PeCan by subtypes. Sex differences in ALL survival were subtype specific and not heavily dependent on differentially expressed genes, CNVs, or somatic mutation. Sex differences in ALL survival may depend on treatment received, response to therapy, or other characteristics. Table 1. Select characteristics from leukemia cases PeCan ALL SubtypeTotal n=247, 58% male N (% male) Number of differentially expressed autosomal genes by sex (male-female expression) in PeCan Number of biologic pathways identified from differentially expressed genes (Reactome) BCR-ABL1 76 (68) 48 8 DUX4-IGH 54 (57) 218 0 ETV6-RUNX1 50 (52) 86 1 hyperdiploid 14 (64) 3,199 2 iAMP21 12 (50) 120 0 KMT2A 41 (51) 216 0 AML SubtypeTotal n=149, 51% male CBFB-MYH11 34 (55) 7 0 KMT2A 44 (50) 422 19 RUNX1-RUNX1T1 61 (46) 30 1 Citation Format: Lindsay A. Williams, Lauren J. Mills, Sofia Barragan, Peter M. Gordon, Jenny N. Poynter. Sex differences in childhood leukemia genomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4856.
Abstract 4387: Interplay of Notch1 and Notch3 signaling regulates pancreatic neuroendocrine tumor proliferation
Authors: Rachael Guenter, Weisheng Chen, Yuvasri Golivi, Mario Robledo, Cole Adams, Renata Jaskula-Sztul, Herbert Chen, J. Bart Rose
Journal: Cancer Research (2024)

Abstract Background: The 5-year survival rate for patients with advanced pancreatic neuroendocrine tumors (pNETs) is less than 30%. Notch signaling is a transmembrane receptor pathway with four receptor isoforms and five different ligands. Binding between a receptor and ligand triggers pathway activation and is linked to cellular differentiation, cell fate, proliferation, and viability. Both Notch1 and Notch3 signaling have been shown to be dysregulated in pNETs. Notch3 activation has been shown to repress Notch1 activity in other cancers. We hypothesize that activation of Notch3 can reduce Notch1-mediated proliferation in pNETs. Methods: Genetic deletion of Notch1 (N1-KO) in a pNET cell line (BON) was achieved using CRISPR/Cas9 to create a compound heterozygous knockout at exon 3. An inducible Notch1 overexpression cell line was generated by stably transfecting BON with a plasmid construct containing the Notch1 active form (N1ICD) under a Tet-On regulator. A constitutively active Notch3 cell line was generated by lentiviral transduction of BON with a plasmid overexpressing the Notch3 active form (N3ICD). Real-time quantitative PCR was used to measure mRNA transcript levels, and western blot was used to measure protein expression. Two-dimensional (2D) viability was measured by MTT assay, and three-dimensional (3D) proliferation was measured by spheroid size. Results: Genetic knockout of Notch1 (N1-KO) reduced the expression of Notch3 at both mRNA and protein levels. N1-KO had reduced proliferation compared to (WT) BON. Increased cell density (ligand availability) or treatment with valproic acid (known Notch1 inducer) led to increased N3ICD in WT BON but not in N1-KO. Overexpression of N1ICD was associated with increased expression of a known downstream target Hes1, as well as Notch3. In contrast, forced overexpression of N3ICD led to increased Notch1 expression, but not Hes1 when compared to a BON cell line transfected with an empty vector. Functionally, N1-KO and N3ICD overexpression cells both had reduced proliferation in both 2D and 3D cell culture. Conclusions: The Notch1 and Notch3 receptors produce signaling cascades that regulate growth in pNET cells through distinct mechanisms. Reduction of Notch1 signaling suppresses growth, while the same effect can be achieved with Notch3 overexpression. Thus, specifically upregulating Notch3 may be a strategy to block Notch1-mediated proliferation in pNET cells. Citation Format: Rachael Guenter, Weisheng Chen, Yuvasri Golivi, Mario Robledo, Cole Adams, Renata Jaskula-Sztul, Herbert Chen, J. Bart Rose. Interplay of Notch1 and Notch3 signaling regulates pancreatic neuroendocrine tumor proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4387.
Abstract 5364: Progesterone receptor modulates the antigen processing and presentation machinery decreasing MHC class I expression on tumors
Authors: Julio Tinoco, Lauryn Werner, Eilidh Chowanec, Harmony Saunders, Sun Xiaopeng, Jay Gertz, Justin Balko, Zachary C. Hartman, Christy Hagan
Journal: Cancer Research (2024)

Abstract Hormone receptor (HR) positive breast cancers, which account for approximately 75% of all breast cancers and express both estrogen receptor (ER) and progesterone receptor (PR), have been the subject of much research. As such, successful anti-estrogen/ER-based therapies have been very successful in the treatment of HR+ breast cancer. Despite this success, over 1/3 of patients will eventually progress on current ER/estrogen-targeted therapies, underscoring the need for new targeted therapies in HR+ breast cancer. Unlike ER, the role of PR in breast cancer progression has received far less attention. In a previous study, we found that a mouse mammary tumor cell line E0771, modified to express the mouse progesterone receptor (mPR) and the OVA peptide, demonstrated decreased T cell-mediated cell death when treated with progesterone compared to the control group. Progesterone-mediated protection from T-cell death was only observed in mPR+ cell lines. Flow analysis of the E0771-Ova-mPR cells also revealed a decrease in MHC Class I presentation in progesterone-treated cells compared to a vehicle control. To further explore the role of the machinery required for antigen processing and presentation of MHC Class I molecules, we conducted additional experiments using the E0771 cell line. Our results showed that treatment with progesterone led to a reduction in RNA levels of all the machinery required for antigen processing and presentation (APP). Based on these findings, we hypothesize that activation of the progesterone receptor by progesterone may decrease MHC Class I expression by regulating APP. Our results showed that treatment with progesterone resulted in a reduction in RNA levels of Tap1, Tap2, Tapbp, Nlrc5, B2m, and Psmb8, which are essential for APP. We therefore propose that activation of the progesterone receptor by progesterone may decrease MHC Class I expression by directly modulating the APP pathway. The findings of this study may have significant implications for our understanding of how breast cancer cells evade T-cell mediated cytotoxicity. Citation Format: Julio Tinoco, Lauryn Werner, Eilidh Chowanec, Harmony Saunders, Sun Xiaopeng, Jay Gertz, Justin Balko, Zachary C. Hartman, Christy Hagan. Progesterone receptor modulates the antigen processing and presentation machinery decreasing MHC class I expression on tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5364.
Abstract 3395: Polyisoprenylated cysteinyl amide inhibitors: Effects on RAS signaling pathway intermediates and viability of mutant <i>KRAS</i> African American lung cancer cell line
Authors: Justin K. Mensah-Mamfo, Kweku Ofosu-Asante, Jassy Mary Lazarte, Amarender Goud Burra, Sofia A. Lugo, Yong Huang, Ite A. Offringa, Nazarius S. Lamango
Journal: Cancer Research (2024)

Abstract Mutated KRAS is the most common cancer driver gene in lung adenocarcinomas in all racial and ethnic groups, including Blacks/African Americans (B/AAs). Drugs developed to combat KRAS-driven cancers become less effective due to intrinsic changes in the cells resulting in resistance and relapse. Due to the enormous challenges encountered in developing direct KRAS inhibitors, agents targeting alternative downstream RAS mediator kinase enzymes of the MAPK and PI3K/AKT signaling pathways have been developed. However, other avenues that directly target KRAS and similar cancer drivers must be explored to obtain alternative effective therapies. PCAIs constitute a group of potential anticancer agents that we developed to specifically disrupt and suppress signaling by hyperactive G-proteins such as mutated KRAS. In previous studies, PCAIs stimulated MEK1/2, ERK1/2, p90RSK and AKT phosphorylation resulting in cell death. The present study aims to determine whether specific inhibitors of the kinases can reverse PCAIs-stimulated phosphorylation and cell death. PCAIs were thus tested against the KRAS mutant NCI- cell line H23 (from a B/AA patient) and compared to KRASG12C inhibitor Sotorasib and other kinase inhibitors drugs. The EC50 values for the PCAIs NSL-YHJ-2-27 and NSL-AB-45 were 4.1 ± 0.3 and 5.5 ± 0.1 μM, respectively, compared to Gefitinib (EGFR), Sotorasib (KRASG12C), Dabrafenib (BRAF), Selumetinib (MEK1/2), Ulixertinib (ERK1/2) and Ipatasertib (AKT) whose EC50 values were 83 ± 12.9 μM, 38 ± 5.5 μM, 33 ± 1.2 μM, 71 ± 5.3 μM, 11 ± 0.2 μM, 12 ± 1.0 μM, respectively. The results indicate that the PCAIs are more effective against NCI-H23 than the other kinase inhibitor drugs. Future work will determine the effects of co-treating cells with the PCAIs and the respective kinase inhibitors on cell viability and PCAIs-induced phosphorylation of the kinases. Supported by grants U54CA233396, U54CA233444, and U54CA233465 from the National Institutes of Health (NIH)/National Cancer Institute (NCI) and the Norris Comprehensive Cancer Center core grant, award number P30CA014089 from the NIH/NCI Citation Format: Justin K. Mensah-Mamfo, Kweku Ofosu-Asante, Jassy Mary Lazarte, Amarender Goud Burra, Sofia A. Lugo, Yong Huang, Ite A. Offringa, Nazarius S. Lamango. Polyisoprenylated cysteinyl amide inhibitors: Effects on RAS signaling pathway intermediates and viability of mutant KRAS African American lung cancer cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3395.