tbuckley/cabot-search huggingface dataset:
Abstract 1222: Mechanisms of succinate-mediated drug resistance in ER+ breast cancer
Authors: Jenny Hogstrom, Boryana Petrova, Camila Perea, Madelyn Ward, Gerburg Wulf, Laura Collins, Naama Kanarek, Taru Muranen
Journal: Cancer Research (2024)

Abstract Breast cancer is the most prevalent cancer among women worldwide with estrogen receptor-positive (ER+) cancer constituting 70% of all breast cancers. Although ER+ breast cancers initially respond well to ER-targeted therapies and CDK4/6 inhibitors, approximately 30% patients acquire resistance to targeted therapies. In addition to intrinsic resistance that tumors develop, cancer-associated fibroblasts (CAFs) residing in the tumor microenvironment, also contribute to treatment-resistance and poor survival. The role of secreted metabolites by CAFs has been poorly studied in the context of targeted drug resistance. Therefore, to investigate the mechanism of stroma-mediated resistance to CDK4/6-inhibitors, we propagated patient-derived organoids (PDOs) and CAFs from treatment-naïve and treatment-resistant ER+ breast tumors. Our data show that the CAF conditioned media containing the polar metabolite fraction stimulates resistance to CDK4/6 inhibitors. Therefore, to identify metabolites that drive resistance, we performed an untargeted metabolomics on CAF conditioned media. We observed that the CAF conditioned media was enriched for TCA cycle intermediates, including succinate. Succinate is an oncometabolite that has an essential function in energy metabolism. Aside from causing metabolic reprogramming, succinate can be transported out of the mitochondria to perform other biological processes, such as epigenetic modifications and pseudohypoxia. Furthermore, succinate in the extracellular space binds to the succinate receptor SUCNR1 and induces G-protein coupled receptor-mediated signaling in cells expressing SUCNR1. To assess mechanism of resistance that these metabolites might induce, we treated breast cancer cells with the most enriched metabolites we had identified in our metabolomics assay. These experiments identified succinate as driver of CDK4/6 inhibitor resistance in ER+ breast cancer cells. Furthermore, treating tumor cells with SUCNR1 antagonist increased their sensitivity to CDK4/6-inhibitors, showing that succinate mediated resistance is conveyed via SUCNR1. This suggests that CAF secreted succinate plays a role in supporting a pro-tumor environment by promoting drug resistance towards CDK4/6 inhibitors. Defining this mechanism of resistance will elucidate potential therapeutic targets to augment patient response to therapy. Citation Format: Jenny Hogstrom, Boryana Petrova, Camila Perea, Madelyn Ward, Gerburg Wulf, Laura Collins, Naama Kanarek, Taru Muranen. Mechanisms of succinate-mediated drug resistance in ER+ breast cancer [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 1222.
Abstract 455: Identification of hsa-miR-6794-3p as a key regulatory factor in human pancreatic cancer metastasis
Authors: Ha Gyeong Kim, Eun-Taex Oh, Yunmi Cho, Heon Joo Park
Journal: Cancer Research (2024)

Abstract Metastasis is a major factor in treatment failure in patients with pancreatic cancer, but the underlying mechanisms remain unclear, and new, effective treatment strategies are needed. Here, we sought to identify novel microRNAs (miRNAs) with a key role in pancreatic cancer metastasis. Using a microarray analysis to evaluate miRNA expression in metastatic and non-metastatic pancreatic cancer, we found that expression of the miRNA, hsa-miR-6794-3p, was significantly lower in metastatic pancreatic cancer tissues than in non-metastatic pancreatic cancer tissues. Methylation-specific polymerase chain reaction analyses revealed that hsa-miR-6794-3p expression was downregulated in metastatic pancreatic cancer cells by hypermethylation of CpG islands within the hsa-miR-6794-3p promoter. Gain- and loss-of-function approaches using the human pancreatic cancer cell lines, MIA-PaCa-2 and HPAF-II, expressing low and high levels of hsa-miR-6794-3p, respectively, suggested a role for hsa-miR-6794-3p in decreasing cell invasion, migration, and epithelial-mesenchymal transition (EMT) signaling. Notably, we found that hsa-miR-6794-3p exerts its effects by inhibiting expression of the chromatin remodeling factor, RBBP4, through direct binding to the 3’-untranslated region of its mRNA. The resulting suppression of RBBP4 expression increases levels of the transcription factor GRHL2, which is involved in regulating invasion, migration, and EMT signaling in metastatic pancreatic cancer cells. Thus, lower levels of hsa-miR-6794-3p disrupt GRHL2-mediated regulation of these pathways by disinhibiting expression of the GRHL2 negative regulator, RBBP4. Consistent with these findings, an investigation of the relationship between hsa-miR-6794-3p and clinicopathological features in pancreatic cancer patients using publicly available datasets and immunohistochemistry showed that low levels of hsa-miR-6794-3p are correlated with a poorer prognosis in pancreatic cancer patients. Additional preclinical experiments in nude mice clearly demonstrated that hsa-miR-6794-3p is capable of suppressing pancreatic cancer cell metastasis. Taken together, these results suggest that hsa-miR-6794-3p suppresses tumor metastasis and thus represents a promising prognostic biomarker and therapeutic target in pancreatic cancer. Citation Format: Ha Gyeong Kim, Eun-Taex Oh, Yunmi Cho, Heon Joo Park. Identification of hsa-miR-6794-3p as a key regulatory factor in human pancreatic cancer metastasis [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 455.
Abstract 5352: SOX9-dependent immune microenvironment remodeling drives KRAS-induced lung adenocarcinoma progression
Authors: Dinoop Ravindran Menon, Hua Zhong, Shridar Ganesan, Hatim Sabaawy, Sharon Pine
Journal: Cancer Research (2024)

Abstract Interactions between tumor intrinsic factors and tumor microenvironment play a vital role in disease progression and treatment response. SOX9, a transcription factor crucial for tissue development and homeostasis, has been linked to the advancement of tumor growth. However, its specific role as a driver in lung adenocarcinoma (LUAD) is not well-defined. Additionally, the impact of SOX9 on the tumor microenvironment has not been previously explored. We here identify SOX9 transcription factor to play a critical role in defining tumor immune microenvironment and driving disease progression. We employed CRISPR/Cas9 and Cre-LoxP gene knockout methods within the Kras G12D-induced mouse model of lung adenocarcinoma (LUAD). Our objective was to investigate the mechanisms through which SOX9 contributes to the development and advancement of lung adenocarcinoma. To substantiate our findings, we conducted immune profiling, gene expression analyses, RT-qPCR, and immunohistochemistry assessments in the Kras G12D-driven murine LUAD. These results were subsequently validated by examining bulk and single-cell gene expression profiles, as well as immunohistochemistry, in human lung adenocarcinoma. Our studies indicated that SOX9 played a very important role by enhancing lung tumor development, burden, and progression, leading to lower overall survival. SOX9. SOX9 consistently facilitated the growth of organoids in vitro. However, the promotion of tumor growth by SOX9 was notably reduced in immunocompromised mice compared to syngeneic mice. SOX9 demonstrated a suppressive effect on immune cell infiltration, particularly affecting the functionality of tumor-associated CD8+ T cells, natural killer cells, and dendritic cells. CD8+ T cells in the SOX9 overexpressing tumors showed upregulation of exhaustion markers. SOX9-mediated tumor growth advantage could not be observed in the CD8 knockout mice model, suggesting a CD8+ T cell-dependent role. In addition, SOX9 significantly upregulated collagen-related gene expression, leading to a substantial increase in collagen fibers possibly affecting the migration of immune cells into the tumor microenvironment. Together, our studies indicate that SOX9 plays a very critical role in modulating tumor microenvironment by controlling immune cell infiltration and CD8+ T cell exhaustion driving Kras G12D- driven lung tumor progression. Citation Format: Dinoop Ravindran Menon, Hua Zhong, Shridar Ganesan, Hatim Sabaawy, Sharon Pine. SOX9-dependent immune microenvironment remodeling drives KRAS-induced lung adenocarcinoma progression [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 5352.
Abstract 4146: Brain permeable bioluminescent substrates for NanoLuc based reporters
Authors: Chao Gao, Yichi Su, Yan Wu, Connor Fitzgerald, Tetsuo H. Uyeda, Hui Wang, Thomas A. Kirkland, Michael Z. Lin, Wenhui Zhou
Journal: Cancer Research (2024)

Abstract Non-invasive imaging methods for tracking gene expression, cell growth and migration and other biological events in vivo are indispensable tools for biomedical studies. Bioluminescence imaging (BLI) can achieve sensitive detection with low background in vivo, which is desirable for body imaging of small animals. Yet, BLI in the central nervous system (CNS) is challenging because many luciferase substrates show limited permeability of the blood-brain-barrier (BBB). To address this issue, we developed a family of new brain-permeant NanoLuc (NLuc) substrates, cephalofurimazine (CFz). CFz family paired with Antares, a fusion of CyOFP and NLuc that emits orange light instead of blue, produces an order of magnitude more signal from the brain than the standard combination of D-luciferin with firefly luciferase and matches the peak output of AkaLumine with AkaLuc but without the need of ATP. One of the substrates in the family, CFz-9, not only produces outstanding signal as other CFz substrates when paired with Antares, but also is able to be formulated into lyophilized cake that can be reconstituted in aqueous buffers for i.p. injections. Toxicity studies demonstrate that CFz-9 and its reconstituted solutions are non-toxic to mice and thus multiple injections are allowed. Citation Format: Chao Gao, Yichi Su, Yan Wu, Connor Fitzgerald, Tetsuo H. Uyeda, Hui Wang, Thomas A. Kirkland, Michael Z. Lin, Wenhui Zhou. Brain permeable bioluminescent substrates for NanoLuc based reporters [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 4146.
Abstract 4149: Real-time intravital trafficking of tumor infiltrating lymphocytes in breast cancer models
Authors: Soyeon Ahn, Kubra Akyildiz, Hyunseok Kim, Pilhan Kim
Journal: Cancer Research (2024)

Abstract Cancer immunotherapy utilizing the immunoreactive efficiency of immune cells via adoptive cell therapy (ACT) has been a novel method of cancer treatment. In tumor microenvironment, immune cell reactivity of tumor-infiltrating lymphocytes (TILs) can facilitate cancer cell attack, which finally derives efficient suppression of tumor growth. However, the conventional evaluation for cancer immunotherapy has been generally performed by ex vivo methods, providing restricted information on lymphocyte motility and immune cell dynamics within the tumor microenvironment. In vivo data with the dynamic behavior of TILs in breast cancer can provide new insight to investigate novel targets of immune checkpoint inhibitors. In this research, longitudinal intravital imaging of motility trafficking of TILs in breast cancer animal models has been performed by utilizing intravital microscopy to unveil the immunoreactive dynamics of T cell activity in early stage. In vivo analysis of TIL motility within different breast cell lines, including 4T1 (mouse breast cancer cell), MDA-MB-231 (human triple-negative breast cancer cell), and MCF7 (human breast cancer cell), respectively, has been investigated for immune responses to cancer. We’ve monitored spatiotemporal dynamics of TIL over 11 days in breast cancer xenograft mouse model generated by tumor implantation into the dorsal skinfold imaging chamber and adoptive T cell transfer by blood circulation. In the results, the adoptive immunoreactivity of TIL has been differentiated by the timepoint of adoptive T cell transfer, distance proximity of T cells in tumors, and breast cancer types. Furthermore, anti-cancer effect coordinated with dendritic cells behaviors showed induced immune responses with accumulated dendritic cells with increased TIL count over time in breast cancer model treated with various cancer therapy such as immunotherapy, radiation therapy and anti-cancer drug (anti-PD-L1), which implied a relationship between programmed death-ligand 1 expression levels and TIL/dendritic cell motility. The result demonstrates that intravital TIL motility trafficking analysis in cancer model can be an invaluable assessment method to explain the detailed cellular/molecular mechanism of immune response to cancer involved with T lymphocytes, dendritic cells, and immune checkpoint inhibitors to accelerate the efficiency of cancer immunotherapy. Citation Format: Soyeon Ahn, Kubra Akyildiz, Hyunseok Kim, Pilhan Kim. Real-time intravital trafficking of tumor infiltrating lymphocytes in breast cancer models [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 4149.
Abstract 4165: Influence of halogens in squaraine dye on optoacoustic signal
Authors: Kavita Belligund, William MacCuaig, Carly Wickizer, Yihan Shao, Lacey R. McNally
Journal: Cancer Research (2024)

Abstract Optoacoustic imaging has grown in clinical relevance due to inherent advantages in sensitivity, resolution, and contrast, compared to standard modalities, such as fluorescence. However, guiding principles for development of small molecule contrast agents specific for optoacoustic imaging is lacking. This study assesses the influence of specific structural features of small molecule dyes, specifically squaraine dyes, that result in optoacoustic activity. Through computational models, in vitro testing, and in vivo experimentation this study assesses the effects of halogens on small molecule squaraine dyes to increase optoacoustic signal. By using the aid of our computational model, we decorated the squaraine scaffold with heavy halogenation of squaraines increased optoacoustic activity (2.12 a.u. vs. 0.21 a.u., p&amp;lt;0.001). Density functional theory models suggest the origin of increased optoacoustic signal is due to increases in transition dipole moment which manifested experimentally as increased absorbance in the NIR wavelength range and decreased fluorescence quantum yield, respectively. This study provides an insight into the structure-function relationships that lead to guiding principles for designing optoacoustic-specific contrast agents. Further developments of squaraines and other types of optoacoustic agents will further increase relevance of optoacoustic imaging in a clinical setting. Citation Format: Kavita Belligund, William MacCuaig, Carly Wickizer, Yihan Shao, Lacey R. McNally. Influence of halogens in squaraine dye on optoacoustic signal [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 4165.
Abstract 2326: Integrating single nucleotide variants (SNVs), copy number alterations (CNAs), and structural variants (SVs) into single-cell clonal lineage inference
Authors: Nishat Bristy, Xuecong Fu, Russell Schwartz
Journal: Cancer Research (2024)

Abstract Background: We extend algorithms for clonal lineage inference (``tumor phylogenetics'') from single-cell DNA sequence (scDNA-seq) data to accommodate broader classes of genetic variants, including single nucleotide variants (SNVs), copy number alterations (CNAs), and structural variants (SVs). Methods: We develop a computational method based on constrained optimization, posing a problem of inferring cellular lineage trees consistent with a given scDNA-seq data set constrained to follow a Dollo parsimony model for SNVs and SVs. We then seek an optimal tree consistent with these constraints so as to optimize for a CNA minimum evolution model balanced against measure of consistency of the different data types with one another relative to the reconstructed set of clones. We pose this problem as an integer linear program (ILP) that we solve heuristically via a coordinate descent algorithm. We tested the resulting method on a combination of synthetic scDNA-seq data and publicly available real data. Results: Results on synthetic data show the method to be effective at constructing lineage trees under a variety of parameter domains, including variations in noise levels, clone numbers, single cells, and mutation rates. We further show it to yield improved accuracy over widely used prior models that operate on only subsets of these variant types. Application to previously published scDNA-seq data demonstrate the method to be effective at inferring clonal lineage trees incorporating all three variant types. The results further show how the different kinds of variants can contribute in tandem to progression along single cell lineages or to the emergence of clones exhibiting hallmarks of distinct mechanisms of progression. Conclusion: The results support the effectiveness of our method in resolving accurate trees from scDNA-seq data including diverse variant types, as well as the value of considering these mutation types collectively in developing a comprehensive understanding of how various forms of somatic mutability together shape clonal evolution in cancers. Citation Format: Nishat Bristy, Xuecong Fu, Russell Schwartz. Integrating single nucleotide variants (SNVs), copy number alterations (CNAs), and structural variants (SVs) into single-cell clonal lineage inference [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 2326.
Abstract 4758: Targeting cellular pH as a novel therapeutic strategy in CDK4/6 inhibitor resistant breast cancer
Authors: Erin R. Scheidemann, Diane M. Demas, Ayesha N. Shajahan-Haq
Journal: Cancer Research (2024)

Abstract Cyclin dependent kinase 4 and 6 inhibitors (CDK4/6i) are part of standard of care therapy in combination with antiestrogens for the treatment of metastatic estrogen receptor positive (ER+) breast cancer. Of the three major CDK4/6i, only ribociclib and abemaciclib, but not palbociclib, have shown significant improvement in overall survival in the clinic. However, resistance to CDK4/6i is prevalent and advanced metastatic ER+ breast cancer remains incurable. Other studies have focused on cell cycle or growth factor alterations in resistant tumors but targeting these pathways have not been clinically validated. Beside inhibiting the cell cycle, CDK4/6i are known to induce lysosomes in sensitive cells but the role of lysosomes in CDK4/6i resistance remains elusive. Recently, we have shown that CDK4/6i resistant breast cancer cells gain metastatic potential relative to sensitive cells and this is potentially due to deregulated lysosomes, which can be targeted with lysosome destabilizers. Here we show that all three CDK4/6i induce rapid lysosomal acidification in sensitive cells, which suggests a role of cellular pH in CDK4/6i-mediated cell death. However, in resistant cells, lysosomal acidification following CDK4/6i treatment was diminished. Therefore, we hypothesize that cellular pH is tightly regulated in CDK4/6i resistant cells and this pathway can be targeted to inhibit cell viability. Interestingly, protein levels of carbonic anhydrase IX (CA9), an important regulator of cellular pH, is significantly elevated in resistant cells. Increased CA9 levels correlate with impaired overall survival in breast and other cancers. Small molecule inhibitor of CA9, S4 or clinical-grade SLC-0111, inhibits growth of resistant cells when combined with CDK4/6i plus antiestrogens. Thus, our study highlights the role of pH changes in CDK4/6i resistant breast cancer and offer therapeutic strategies to treat this incurable disease. Citation Format: Erin R. Scheidemann, Diane M. Demas, Ayesha N. Shajahan-Haq. Targeting cellular pH as a novel therapeutic strategy in CDK4/6 inhibitor resistant breast cancer [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 4758.
Abstract 2328: Next-generation sequencing-based regression algorithm to determine homologous recombination deficiency scores in a pan-cancer cohort
Authors: Boram Choi, Youn Jin Choi
Journal: Cancer Research (2024)

Abstract Background: Homologous recombination deficiency (HRD) inhibits double strand breaks from being repaired in DNA, leading to cancer cells failing to recover themselves and cell death. Previous studies found that HRD-positive ovarian cancer patients had more significant clinical benefits from poly ADP-ribose polymerase inhibitors (PARPi) treatment. For accurate detection of HRD, next-generation sequencing (whole exome, whole genome) was used to identify large-scale genomic aberrations including telomeric allelic imbalance (HRD-TAI score), loss of heterozygosity profiles (HRD-LOH score), and large-scale state transitions (HRD-LST score). So far, many studies (HRDetect, SigMA, CHORD and shallowHRD) have been conducted to accurately determine HRD in a pan-cancer cohort. As the study progressed, it has been revealed that PARPi is effective when applied to patients with HRD in not only ovarian cancer but also breast cancer, prostate cancer, and pancreatic cancer. Purpose: To develop an algorithm that accurately predict HRD score in patients with ovarian cancer, breast cancer, prostate cancer, and pancreatic cancer utilizing a machine learning algorithm. Methods: We used whole-genome sequencing (WGS) data of 710 samples from 309 patients, whole-exome sequencing (WES) data of 4,650 samples from 2,193 patients from the pan-cancer cohort of the TCGA (TCGA-OV, TCGA-BRCA, TCGA-PRAD, and TCGA-PAAD). The HRD-TAI/HRD-LST/HRD-LOH scores were calculated through structural variation analyses. After data cleaning processes, machine-learning models were trained and tested on 228 out of 2,502 samples, and validation was performed on 1,248 out of 2,502 samples from the TCGA dataset. Results: To assess the performance of the machine-learning regressor, the concordance between predictions and annotations was quantified by calculating the R squared (𝑅;;;^2). As a result of training using machine learning algorithm, we achieved a high 𝑅;;;^2 (0.904) with a RMSE (root mean squared error) score (7.649) for a pan-cancer cohort. Conclusions: Our regressor was robust and accurate when applied to 4 cancer types. Using our systematic pan-cancer analysis, we found novel insights into the mechanisms of HRD across cancer types with potential contribution to clinical practice. Citation Format: Boram Choi, Youn Jin Choi. Next-generation sequencing-based regression algorithm to determine homologous recombination deficiency scores in a pan-cancer cohort [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 2328.