tbuckley/cabot-search huggingface dataset:
Abstract 2966: Senescent cancer cell vaccines induce cytotoxic T cell responses targeting primary tumors and disseminated tumor cells
Authors: Yue Liu, Joanna Pagacz, Donald J. Wolfgeher, Stephen J. Kron
Journal: Cancer Research (2024)

Abstract Diverse conventional cancer therapies, including genotoxic agents and cell cycle or cell division-targeting drugs, can trigger cancer cell senescence. Senescent cells (SnCs) induced by cancer therapy often display unrepaired chromosomal damage but persist indefinitely. SnCs remain metabolically active and display distinct alterations in transcription, secretion, and membrane protein expression/presentation. While initially viewed as a favorable outcome and likely tumor-suppressive mechanism, therapy-induced senescence has more recently been recognized as contributing to resistance, recurrence and metastasis. Adverse effects may be mediated in part by release of inflammatory mediators as components of the senescence-associated secretory phenotype (SASP). Recent studies have argued for reconsidering the potential benefits of therapy-induced senescence, especially in modulating the tumor microenvironment to potentiate anti-tumor immunity and potentiate immunotherapy. We have explored the potential for SnCs to serve as vaccines, building upon prior findings where we demonstrated the immunogenic senescence triggered by the combination of ionizing radiation (IR) and the PARP1/2 inhibitor veliparib. We find that SnCs are avidly taken up by type I conventional, CD11c+/CD103+ dendritic cells (DCs), promoting their activation and maturation. Thereby, SnCs promote DC function in T cell priming and stimulation. The capacity of SnCs to activate DCs depends on how the SnCs are formed, with our results confirming IR+veliparib induces high immunogenicity and implicating a distinct SASP in these effects. On the other hand, blocking STING signaling limits SnC activation of DCs. In vivo experiments with the murine tumor models CT26 and 4T1 suggest that both SnCs and SnC-pulsed DCs serve as effective anti-tumor vaccines. They not only confer protective immunity against tumor engraftment but also act as therapeutic vaccines, inhibiting both primary and disseminated tumor growth, and synergize with radiotherapy and immune checkpoint blockade. While direct administration of tumor-derived SnCs to patients may raise safety concerns, pulsing autologous DCs with tumor SnCs may help drive anti-tumor immune response, offering a promising path toward personalized cancer immunotherapy. Citation Format: Yue Liu, Joanna Pagacz, Donald J. Wolfgeher, Stephen J. Kron. Senescent cancer cell vaccines induce cytotoxic T cell responses targeting primary tumors and disseminated tumor cells [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 2966.
Abstract 485: Cancer killing effect of ultrasound-responsive mechanophore nanoparticles
Authors: Jian Wang, Shensheng Zhao, Junxi Yi, Yunyan Sun, Megha Agrawal, King Li, Jeffrey S. Moore, Michael Oelze, Yun-Sheng Chen
Journal: Cancer Research (2024)

Abstract Radiotherapy, a mainstay in cancer treatment, often inadvertently damages healthy tissues while targeting malignancies with free radicals. As an alternative, Photodynamic Therapy (PDT) employs non-ionizing photons to generate reactive oxygen species (ROS) in tumors, offering precise targeting with minimal long-term effects. However, its efficacy is constrained to superficial tumors due to the limited penetration of light. Sonodynamic Therapy (SDT), an evolution of PDT, uses ultrasound to enhance tissue penetration while maintaining its non-invasive nature. Initial SDT studies suggest that ultrasound can activate PDT's photosensitizers to produce ROS, offering a potential pathway for tumor eradication. Nevertheless, the principal mechanisms of ROS generation in SDT, namely pyrolysis and sonoluminescence, raise concerns about potential tissue injury. In our research, we introduce an innovative approach employing mechanophores into nanoparticles. Mechanophores, molecular units within polymers sensitive to mechanical stress, undergo transformations under such conditions, including the release of small molecules or free radicals. We have developed injectable nano-sized mechanophore nanoparticles, designed to respond to high-frequency ultrasound (&amp;gt;100 kHz) more efficiently and with reduced energy requirements. This study focuses on nano-engineering the echogenicity of these mechanophore nanoparticles to enhance ROS generation. When agitated with focused ultrasound (FUS), these nanoparticles successfully induced ROS, leading to significant cell death, a result not observed with FUS alone in the absence of nanoparticles. In vivo experiments using mouse orthotopic cancer models demonstrated these nanoparticles' ability to inhibit tumor growth effectively. Under biocompatible ultrasound conditions, the nanoparticles cause effective cancer cell eradication with minimal impact on surrounding healthy tissues. Our findings not only introduce a novel approach to cancer treatment but also pave the way for broader applications of mechanophore nanoparticles in biomedicine. This study underscores the potential of ultrasound-activatable mechanophore nanoparticles as a versatile, effective, and safe option for cancer therapy. Citation Format: Jian Wang, Shensheng Zhao, Junxi Yi, Yunyan Sun, Megha Agrawal, King Li, Jeffrey S. Moore, Michael Oelze, Yun-Sheng Chen. Cancer killing effect of ultrasound-responsive mechanophore nanoparticles [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 485.
Abstract 230: Deep learning embedding-based segmentation for morphological analysis in organoids
Authors: Akash Sureshkumar, Shilpa Bisht, Hariharan Easwaran
Journal: Cancer Research (2024)

Abstract Background: The organoid model is a useful tool for modeling the cellular microenvironment of the organ from which they are derived. Organoids recapitulate the self-organization of heterogenous cell types and the microenvironment. Quantifying the morphological features of organoids can provide valuable insights into cellular organizational defects and growth characteristics, which can facilitate drug discovery. Measurement of these characteristics in live organoids can be performed quickly and easily directly in culture using widefield microscopy. The current state-of-the-art method to detect and identify the shape of individual organoids in brightfield images uses the U-Net Convolutional Neural Network (CNN) with a watershed transform to label pixels. However, this method yields jagged shape proposals and cannot detect overlapping regions. We propose the use of an embedding-based segmentation network based on the Branched ERF-Net to solve these issues. Methods: Organoids were established from the proximal colon of BrafV600E heterozygous mice, and 50 phase-contrast images of the organoids were acquired at 2.5x and 4x magnification. Organoids present in acquired images were labeled manually. The network was trained on this collection of manually labeled images and validated on a separate validation dataset. Results: The network accurately labels organoids. Overlapping organoids are segmented correctly and shape proposals are smoother. Detection of overlapping organoids with the Branched ERF-Net architecture yields an accurate organoid count, verified against manual counting. Smoother shape proposals also enable the use of convexity defects to measure organoid budding. Conclusions: Deep-learning analysis of widefield images enables the rapid assessment of morphological characteristics, such as size, count, and budding, which are key to understanding proliferation and differentiation changes. The modified Branched ERF-Net architecture we propose for organoid segmentation is a robust and versatile method to quantify organoid morphology. Citation Format: Akash Sureshkumar, Shilpa Bisht, Hariharan Easwaran. Deep learning embedding-based segmentation for morphological analysis in organoids [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 230.
Abstract 2963: Dihydromyricetin is a senomorphic agent to promote therapeutic outcome of age-related conditions including cancer and Alzheimer's disease
Authors: Qixia Xu, Zi Li, Zhirui Jiang, Judith Campisi, Yu Sun
Journal: Cancer Research (2024)

Abstract Aging is characterized by a progressive decline of organ function and gradual rise of susceptibility to multiple chronic disorders, with cancer being a primary cause of human morbidity and mortality worldwide. Cellular senescence represents a state of permanent cell cycle arrest and contributes to chronological aging and age-related diseases including Alzheimer's disease (AD), mainly through development of a distinct secretome termed the senescence-associated secretory phenotype (SASP). By screening a natural medicinal agent library, we noticed Rattan tea extract (RTE) has a prominent antiaging potential, wherein dihydromyricetin (DMY), the most abundant natural flavonoid in RTE, played a central role in suppressing the SASP expression of senescent cells. DMY enhanced total antioxidant capacity (T-AOC), increased catalase (CAT) and glutathione peroxidase (GSH-Px) activity, upregulated the expression of HO-1, NQO1, nuclear Nrf2 and phospho-ERK (p-ERK), but decreased malondialdehyde (MDA) level in senescent cells. Furthermore, DMY regulates PI3K/Akt/mTOR signaling pathway, NLRP3 inflammasome formation, the NF-κB complex activity and ER stress-response, each responsible for a full spectrum SASP development. Transcriptomic profiling suggested that DMY can dampen the genome-wide upregulation of pro-inflammatory factors produced by senescent cells, resulting in abrogated progression of cancer malignancy including elevated proliferation, migration, invasion and chemoresistance. Importantly, combination of DMY with classic chemotherapy significantly enhanced therapeutic efficacy, causing remarkable tumor regression and extending posttreatment survival. Alzheimer's disease (AD) is marked by the presence of amyloid plaques, neurofibrillary tangles, damaged neuronal macromolecules and redox sensitive ions. We found that DMY restrains inflammatory injury in microglial cells, reduces their apoptosis and inflammation, and inhibits TLR4 and MD2 expression. Results of small molecule-protein docking and pull-down assays indicated that DMY binds MD2 to suppress the formation of TLR4 complex. In AD mice, DMY improved the cognitive disorder of animals, suppressed inflammatory injury in brain and reduced TLR4 expression. Together, DMY represents a valid natural candidate that has senomorphic activity and can be applied for treatment of malignancies or neurodegenerative disorders such as AD, pathologies that frequently arise in late life of humans. Citation Format: Qixia Xu, Zi Li, Zhirui Jiang, Judith Campisi, Yu Sun. Dihydromyricetin is a senomorphic agent to promote therapeutic outcome of age-related conditions including cancer and Alzheimer's disease [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 2963.
Abstract 5200: Multiparametric MRI along with machine learning informs on molecular underpinnings, prognosis, and treatment response in pediatric low grade glioma
Authors: Ali Nabavizadeh, Adam Kraya, Komal Rathi, Meen Chul Kim, Nastaran Khalili, Ariana Familiar, Varun Kesherwani, Hannah Anderson, Deep Gandhi, Aria Mahtabfar, Sina Bagheri, Xiaoyan Huang, Yuankun Zhu, Alexander Sickler, Saksham Phul, Sabine Mueller, Mateusz P Koptyra, Philip B Storm, Jeff Ware, Yuanquan Song, Michael J Fisher, Arastoo Vossough, Christos Davatzikos, Adam C Resnick, Anahita Fathi Kazerooni
Journal: Cancer Research (2024)

Abstract We report a comprehensive radiogenomic analysis, including multiparametric MRI and RNA sequencing of 502 tumors across 13 histological types of pediatric low-grade glioma (PLGG). Through an unsupervised analysis of treatment-naïve imaging, we were able to identify 3 distinct imaging clusters that were associated with different molecular pathways according to transcriptomic pathway analysis. Using xCell enrichment scores as input for clustering, we discovered three distinct immunological groups based on immune cell infiltration. The results suggested the presence of an ‘immune-hot” cluster within the tumors with a poorer prognosis, which may potentially benefit from emerging immunotherapies. We subsequently generated a radiomic signature that was able to predict immunological profiles. We also developed a clinicoradiomic predictive model that can assess patients’ risk of progression and predict treatment response. Finally, we evaluated the transcriptomic pathways that were most predictive of clinicoradiomic risk scores and identified the biological pathways most predictive of risk of progression in PLGG, when adjusting for molecular subtype, race, reported gender, age at diagnosis, and the anatomic location of the tumor. This is the first large-scale radiogenomic analysis in PLGG that can aid in prognostication, assessing patients’ risk of progression, predicting treatment response in conventional therapies, and early stratification of patients to identify potential candidates for targeted therapies. Citation Format: Ali Nabavizadeh, Adam Kraya, Komal Rathi, Meen Chul Kim, Nastaran Khalili, Ariana Familiar, Varun Kesherwani, Hannah Anderson, Deep Gandhi, Aria Mahtabfar, Sina Bagheri, Xiaoyan Huang, Yuankun Zhu, Alexander Sickler, Saksham Phul, Sabine Mueller, Mateusz P Koptyra, Philip B Storm, Jeff Ware, Yuanquan Song, Michael J Fisher, Arastoo Vossough, Christos Davatzikos, Adam C Resnick, Anahita Fathi Kazerooni. Multiparametric MRI along with machine learning informs on molecular underpinnings, prognosis, and treatment response in pediatric low grade glioma [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 5200.
Abstract 2944: A high-throughput screening system for identifying therapeutic targets in immuno-oncology
Authors: Dippal Parikh, Soon Youn Choi, Ki Eun Pyo, Hong-Pyo Lee, Kyuho Han
Journal: Cancer Research (2024)

Abstract INTRODUCTION: Over the last decade, cancer immunotherapy has revolutionized cancer treatment. However, more than half of patients don’t respond, and responders often lack lasting effects. Understanding how genetic variants in cancer cells influence their interaction with immune cells, especially T cells, is crucial to uncover underlying mechanisms. Genetic screens are powerful for uncovering responsible genes for various phenotypes, but challenges in obtaining ample samples to set up a proper immune and cancer co-culture system have limited their use for identifying immune modulators in cancer: primary mouse T cells expressing CD3 against a specific antigen (typically albumin) need to be extracted from transgenic mice and only syngeneic mouse cancer cell lines that match these T cells can be paired, restricting the utilization of human T cells and human cancer cells for this co-culture screening setup. METHODS: Here, we present a highly scalable co-culture system that enables genome-wide CRISPR screens on a pair of human primary T cells and any allogeneic human cancer cell lines. This system utilizes the expression of a membrane-targeted protein in mammalian cells, named as ImBridge, which directly engages and activates CD3+ immune cells. This mechanism bypasses the need for matched MHC on target cancer cells. RESULTS: We validated activation of CD3+ immune cells and selective cancer cell cytotoxicity by ImBridge. A genome-scale CRISPR screen utilizing the co-culture system unveiled known immune-oncology targets including PD-L1 and PTPN2 and revealed MEDiC_01 as a novel therapeutic target. Genetic loss of MEDiC_01 in cancer cells significantly sensitized them to cytotoxic cells, effectively eliminating cancers in the presence of human PBMCs. CONCLUSION: We demonstrated a scalable and efficient approach for conducting high-throughput functional screens to uncover genes that modulate interactions between effector T cells and target cancer cells. This can facilitate the identification of new immuno-oncology therapeutic targets, insights into underlying mechanisms, and genetic factors influencing immune susceptibility and evasion. Citation Format: Dippal Parikh, Soon Youn Choi, Ki Eun Pyo, Hong-Pyo Lee, Kyuho Han. A high-throughput screening system for identifying therapeutic targets in immuno-oncology [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 2944.
Abstract 2949: A flexible and efficient approach for single-cell CRISPR perturbation screens combined with targeted RNA-seq expression analysis
Authors: Donato Tedesco, Tianbing Liu, Mikhail Makhanov, Dongfang Hu, Nadya Isachenko, Paul Diehl, Alex Chenchik
Journal: Cancer Research (2024)

Abstract This study presents a novel approach for performing 10X platform-based targeted single-cell RNA-seq analysis in combination with CRISPR perturbation screens. For the analysis, we constructed a custom sgRNA library focused on a small subset of genes associated with the TNFα response (i.e., NFκB pathway). We compared analysis of two targeted gene expression panels—the first, targeting all protein-coding genes (genome-wide) and the other, targeting a selected set of genes representing key hubs in signaling pathway modules. Narrowing down the analyzed gene set enhanced the efficiency of single-cell RNA-seq by reducing the associated next-generation sequencing (NGS) depth required for readout, and significantly streamlining data analysis. Comparing the analysis of the expression panels targeting all protein-coding genes with the smaller pathway-targeted set, we were able to assess the general flexibility of the novel approach for single-cell CRISPR perturbation screens. We evaluated the specific tradeoffs with regard to the size of the CRISPR library, the size of the panel of genes targeted for expression analysis, and NGS sequencing depth. This flexible, targeted approach not only refines the precision of RNA-seq but also provides a more cost-effective solution for comprehensive genomic analyses. Citation Format: Donato Tedesco, Tianbing Liu, Mikhail Makhanov, Dongfang Hu, Nadya Isachenko, Paul Diehl, Alex Chenchik. A flexible and efficient approach for single-cell CRISPR perturbation screens combined with targeted RNA-seq expression analysis [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 2949.
Abstract 1946: Elucidating the mechanisms of acquired resistance to AMG510 in cancer models harboring KRAS G12C mutations
Authors: Ting Ni, Tongxin Huo, Yawen Zhang, Jingjing Wang, Gaoxiang Liu, Wenting Shi, Qingyang Gu
Journal: Cancer Research (2024)

Abstract GTPase KRas (KRAS), a critical oncogene, is known for its frequent mutations across a wide array of human cancers, most notably in pancreatic, lung, and colorectal cancers. Recent advancements in the field have led to the successful development of numerous inhibitors targeting the mutant KRAS. Clinical application of KRAS G12C inhibitors, such as AMG510 and MTRX849, represents major breakthroughs in addressing previously 'undruggable' cancer targets. Nevertheless, a subset of patients initially responsive to these inhibitors eventually exhibit treatment resistance. Uncovering the underlying mechanism would help to develop novel therapies that overcome the acquired drug resistance. To elucidate the underlying mechanisms, we generated AMG510-resistant tumor models, namely AMG510-R-MIA PaCa-2 and AMG510-R CT26 KRAS G12C, by continuous administration of AMG510 to tumor-bearing mice. Upon comparison of sensitive parental tumors and resistant tumors, we found that highly expressed KRAS and constant activation of RAS-MAPK signaling pathway are critical for resistant tumor progression following AMG510 treatment. In addition, resistant tumor cells are responsible for the elevated secretion of CXCL2/3/5, which dramatically reconditions the tumor immune microenvironment and recruits immunosuppressive cells. In summary, the exploration of the resistance mechanism in AMG510-induced resistant models provides insight into the development of new-generation KRAS-G12C inhibitors and novel combinatorial therapies. Citation Format: Ting Ni, Tongxin Huo, Yawen Zhang, Jingjing Wang, Gaoxiang Liu, Wenting Shi, Qingyang Gu. Elucidating the mechanisms of acquired resistance to AMG510 in cancer models harboring KRAS G12C mutations [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 1946.
Abstract 2637: Super-enhancer-related m6A modification promotes immune escape in hepatocellular carcinoma associated with metabolic dysfunction-associated fatty liver disease via CCL4 signaling pathway inhibition
Authors: Liangliang Xu
Journal: Cancer Research (2024)

Abstract The incidence and mortality rates of hepatocellular carcinoma caused by metabolic dysfunction-associated fatty liver disease (MAFLD) have been increasing in recent decades, emphasizing the urgent need for new therapeutic approaches. Emerging evidence suggests that approximately 80% of super-enhancer RNAs (seRNAs) undergo selective m6A modifications. seRNA and m6A modifications have been implicated in the progression of various cancers, making them potential targets for therapeutic intervention. Based on our previous research, we hypothesize that the lack of m6A modification on the super-enhancer of CCL4 may contribute to the reduced expression of the CCL4 gene in HCC.To validate our hypothesis, we employ nano-chromatin immunoprecipitation combined with high-throughput sequencing (nano-ChIP-seq), m6A-seq (m6A-seq), single-cell RNA sequencing (scRNA-seq) on multiple models including clinical samples, cell lines, and mouse models. Interestingly, we have made a significant discovery that overexpression of CCL4 in tumor cells enhances the infiltration of CD8+ T cells, which are crucial for anti-tumor immune responses. In contrast, normal tissue cells undergo m6A modification on the CCL4 seRNAs, while this modification is notably absent in cancerous tissue. Consequently, the reduced expression of CCL4 could impair the tumor-killing capabilities of CD8+ T cells and facilitate immune evasion by the tumor.Furthermore, our results shed light on the underlying molecular mechanisms involving super-enhancers and m6A modifications in the regulation of immune escape in MAFLD HCC. We identify the specific super-enhancer and downstream regulatory genes influenced by m6A modification in MAFLD-associated HCC, providing valuable insights and novel targets for the treatment of this condition. Citation Format: Liangliang Xu. Super-enhancer-related m6A modification promotes immune escape in hepatocellular carcinoma associated with metabolic dysfunction-associated fatty liver disease via CCL4 signaling pathway inhibition [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 2637.