tbuckley/cabot-search huggingface dataset:
Abstract LB445: USP24 suppresses T cell anti-tumor activity by enhancing the stability of the PD-1 protein
Authors: Hung-Chia Hsieh, Jan-Jong Hung, Yi-Ching Wang
Journal: Cancer Research (2024)

Abstract Persistent programmed cell death-1 (PD-1)/PD-L1 inhibitory signaling disrupts T cell cytotoxic function, leading to T cell exhaustion—a phenomenon strongly associated with advanced cancer progression and immunotherapy failure. Deciphering the mechanisms behind dysregulated PD-1 expression and reactivating tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment (TME) is crucial. Our previous research established that tumor-associated macrophage-derived IL-6 promotes STAT3-dependent PD-1 transcriptional activity and immunotherapy resistance. The current study further explores whether IL-6 abundance in the TME contributes to PD-1 protein stability. Results indicate that IL-6 extended PD-1 protein half-life in T cells, suggesting its role in modulating PD-1 protein stability. Furthermore, analysis of the GEO database showed a positive correlation between the expression of ubiquitin-specific-processing protease (USP) family enzymes and PD-1 in non-responding patients receiving anti-PD-1 therapy. Knockdown experiments revealed that USP24 strongly downregulated PD-1 protein expression and stability. USP24 depletion reversed IL-6-induced PD-1 expression and stability, with USP24 colocalizing with PD-1 at the plasma membrane upon IL-6 stimulation. Immunoprecipitation-Western blot assays confirmed that USP24 directly interacted with PD-1 and countered E3 ligase c-Cbl-mediated ubiquitination. Depleting USP24 suppressed PD-1-mediated immunosuppression both in vitro and in vivo. In lung-specific EGFRL858R/USP24C1698A functional knockout mice, tumor progression was slower, and exhausted tumor-infiltrating PD-1+ TIM-3+ CD8+ T cells reduced compared to EGFRL858R mice. Inhibiting PD-1 stability with an IL-6 neutralizing antibody or the novel inhibitor USP24-i-101 decreased tumor volume and increased activated cytotoxic T cell infiltration in vivo. Moreover, USP24-i-101 enhanced therapeutic effects in combination with anti-CTLA4 immunotherapy. Clinically, our in-house cohort revealed elevated USP24 expression in tumor-infiltrating lymphocytes or peripheral T cells, correlating with worse clinical outcomes and unfavorable responses to immunotherapy in lung cancer patients. This study uncovers USP24 as a novel PD-1 regulator, deubiquitinating PD-1 to enhance protein stability and suppress T cell function. In conclusion, USP24 emerges as a potential target for enhancing anti-tumor immunity and as a biomarker predicting clinical responses to immunotherapy in lung cancer. Citation Format: Hung-Chia Hsieh, Jan-Jong Hung, Yi-Ching Wang. USP24 suppresses T cell anti-tumor activity by enhancing the stability of the PD-1 protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB445.
Abstract LE21: Mechanisms of gene regulation by chromatin adaptors in development and disease
Authors: Yadira Marie Soto-Feliciano
Journal: Cancer Research (2024)

Abstract Complex biological processes, such as organismal development, are directly influenced by the interplay between genes and the cellular structures and environmental factors that regulate them. Key players in this regulation are chromatin adaptor proteins, which can impact the genetic and epigenetic programs of cells. However, our understanding of how these proteins interact with chromatin - the physiological form of our genomes - and regulate gene activity is limited, especially in the context of diseases like cancer. To test our central hypothesis and to understand how chromatin adaptors contribute to cell function, we are developing innovative high-throughput and biochemical approaches. These will help us systematically identify specific histone modifications that affect the binding of Menin and other adaptors to chromatin. Our experimental approach includes profiling, validation, and functional characterization using advanced genomic and epigenomic technologies, transcriptional profiling, and CRISPR gene editing. The application of these techniques will reveal, for the first time, the molecular mechanisms by which these proteins bind to specific parts of the genome and regulate gene activity. Our findings will enhance our understanding of how chromatin adaptors, like Menin, interact with chromatin and regulate gene activity in different tissues, and how these functions are disrupted by cancer-associated mutations. This will also contribute to the development of potential new therapies that target these altered mechanisms. Furthermore, our findings can be extended to other proteins involved in chromatin and epigenetic regulation, enabling a broader application in understanding and treating cancer and other human diseases. Citation Format: Yadira Marie Soto-Feliciano. Mechanisms of gene regulation by chromatin adaptors in development and disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LE21.
Abstract SY07-01: p53-mediated stem cell competition: Insights into mechanisms of clonal dominance
Authors: Eugenia Piddini
Journal: Cancer Research (2024)

Abstract TP53 Mutations confer clonal advantage in several tissues contributing to tumorigenesis. It has traditionally been proposed that heightened resistance to apoptosis/cell cycle arrest can account for clonal advantage. P53 mediated clonal dominance has also been observed in cultured embryonic stem (ES) cells, though it is not clear how this is established. Using live cell imaging we show that human ES cells (hESCs) mutant for TP53 induce death of hES-WT cells and outcompete them. Competition is mediated by apoptosis induction and requires direct cell contact, as in co-cultures of hES-P53KO and hES-WT cells where contact is prevented competition is not observed. To ask if hES-P53KO competition is mediated by mechanical interactions, we cultured cells on deformable membranes to measure their resistance to cell compaction. Interestingly, while hES-WT cells displayed apoptosis induction upon cell compaction, hES-P53KO cells were resistant to compaction-induced apoptosis. We suggest that differential sensitivity to compaction in crowded cultures/tissues can drive p53-induced competitive cell elimination. Identifying the mechanisms by which p53 confers resistance to cell compaction could lead to novel actionable targets to prevent the expansion of p53 mutant stem cells in cancerous and pre-cancerous lesions. Citation Format: Eugenia Piddini. p53-mediated stem cell competition: Insights into mechanisms of clonal dominance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY07-01.
Abstract LB256: New mechanistic insights into cisplatin resistance in muscle-invasive bladder cancer
Authors: Lily Elizabeth R. Feldman, Saswat Mohapatra, Robert Jones, Charlene Tilton, Tahlita Zuiverloon, James Costello, Dan Theodorescu
Journal: Cancer Research (2024)

Abstract The standard of care for eligible patients with muscle-invasive bladder cancer (MIBC) is cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy. However, platinum-based treatments leave up to 70% of MIBC patients with residual disease, and the 5-year survival rate for these individuals is under 30%. Understanding cisplatin resistance mechanisms will improve MIBC treatment by developing more effective therapeutics and precision medicine strategies. We previously identified NPEPPS, an M1 aminopeptidase, as a novel and potentially targetable mediator of platinum drug response. Recently, we have established that NPEPPS controls platinum drug import through its interactions with volume regulated anion channels (VRACs), which have been shown to import cisplatin to cells directly. We have shown that NPEPPS interacts with key VRAC subunit SWELL1 at the cell membrane and that intact SWELL1 is required for NPEPPS-mediated platinum resistance. We further discovered that NPEPPS cannot bind SWELL1 when its enzymatic aminopeptidase function is disrupted genetically or pharmacologically. In vivo studies showed that catalytic-dead NPEPPS-mutant MIBC xenografts were sensitive to cisplatin treatment compared to NPEPPS-wildtype xenografts. Patient cohort data analysis supported the model that the expression of NPEPPS and its relative expression with VRAC proteins are associated with overall survival in treatment-resistant MIBC patients. These findings shed light on how bladder cancer cells resist chemotherapy by disrupting the transport of drugs into cells and suggest new ways to target NPEPPS to enhance the effectiveness of platinum-based therapeutics in treating bladder cancer. Citation Format: Lily Elizabeth R. Feldman, Saswat Mohapatra, Robert Jones, Charlene Tilton, Tahlita Zuiverloon, James Costello, Dan Theodorescu. New mechanistic insights into cisplatin resistance in muscle-invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB256.
Abstract LB258: ZDHHC20 is a potential target for overcoming ABCB1-mediated multidrug resisance (MDR) in cancer
Authors: Ning Ji, Xin Peng, Yi-nan Liu, Yuqi Yang, Zhe-Sheng Chen, Dexin Kong, Yueguo Li
Journal: Cancer Research (2024)

Abstract ABCB1-mediated multidrug resistance (MDR) in cancer cells is an increasingly important cause of anticancer drug treatment failure. The occurrence of MDR in cancer reduces the effectiveness of antitumor drugs, which results in poor quality of life and increased mortality of patients, and creates a heavy burden for the patient's family and society. Hence, the reversal of ABCB1-mediated MDR in cancer is a highly urgent clinical need. Although reversal agents targeting ABCB1 have been developed and partially tested in clinical trials, their main mechanism limits to inhibit the function of ABCB1 efflux pumps, which lacks tumor tissue specificity and has poor clinical effects, and the development of ABCB1-based resistance reversal strategies has entered a bottleneck. ABCB1 mediates tumor MDR through drug efflux and lysosomal segregation, and intervention in the plasma membrane/lysosomal membrane localization of ABCB1 is a potential strategy to reverse drug resistance. Palmitoylation, as a post-translational lipid modification, plays an important role in protein anchoring, transport, and functional regulation, and is highly relevant to human tumors. In the present study, palmitoylation modification was first identified as a key post-translational lipid modification of ABCB1. ABCB1 is palmitoylated in its cytoplasmic domain, which is further stabilized by blocking its ubiquitination, consequently suppressing ABCB1 degradation by lysosomes. We identified palmitoyltransferase ZDHHC20 (DHHC20) as the main acetyltransferase required for the palmitoylation of ABCB1, and show that the inhibition of ABCB1 palmitoylation via 2-bromopalmitate (2-BP), or the silencing of DHHC20, decreases ABCB1 expression and overcomes MDR in vitro as well as in mice bearing SW620/Ad300 resistance cells. Moreover, Cysteine residues C787 was identified as the main palmitoylation cite in human ABCB1. Database and RNAseq analyses revealed that ZDHHC20 is highly expressed in tumor tissues and tumor MDR cells, which makes it a potential tumor tissue-specific target for overcoming ABCB1-mediated MDR in cancer. Our results firstly identified the novel post-translational modification (palmitoylation) of ABCB1 and provide a new research direction and theoretical basis for breaking through the bottleneck of the development of reversal agents for ABCB1-mediated MDR in cancer. Citation Format: Ning Ji, Xin Peng, Yi-nan Liu, Yuqi Yang, Zhe-Sheng Chen, Dexin Kong, Yueguo Li. ZDHHC20 is a potential target for overcoming ABCB1-mediated multidrug resisance (MDR) in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB258.
Abstract LB451: Targeting oncogenic transcription and signaling crosstalk fueling drug resistance in lung cancer
Authors: Nilanjana Chatterjee, Victor Olivas, Wei Wu, Tracy Tang, Ben Powell, Trever Bivona
Journal: Cancer Research (2024)

Abstract Lung cancer is the leading cause of all cancer-related mortality worldwide. The RAS-RAF-MEK-ERK (RAS-MAPK) signaling pathway is critical for maintaining cell survival and proliferation. Somatic mutations in the RAS or RAF genes are associated with frequent hyper-activation of RAS-MAPK pathway in non-small cell lung cancer or NSCLC. While direct inhibitors of KRAS G12C are emerging with promising efficacy, resistance to these agents as well as to inhibitors of RAF and MEK remains an obstacle to long-term patient survival. Therefore, it is essential to understand how drug resistance emerges in lung cancer and to identify bypass survival pathways or compensatory mechanisms that limit the response to RAS-MAPK targeted therapies in lung cancer. Emerging literature indicates a critical role of bromodomain and extra-terminal domain (BET) family of bromodomain proteins (BRD4, BRD3, BRD2) in various human malignancies and provides the rational for targeting BET proteins as a strategy for the development of new anticancer drugs. Using combinatorial drug screens in a panel of NSCLC cell lines, we found that BET proteins act in parallel to the RAS-MAPK pathway to promote drug resistance in lung cancer. Combination of BET and RAS-MAPK inhibitors caused pronounced cell death and potent tumor regression/stasis in several KRAS or BRAF mutant models of NSCLC with synergistic apoptosis induction and downregulation of MYC, a transcriptional target of BET proteins. However, concurrent loss of the tumor suppressor STK11 (aka LKB1) in NSCLC cells induced activation of the Hippo pathway effector and transcriptional co-activator, YAP and conferred resistance to the BET and RAS-MAPK inhibitors combination in NSCLC cells and tumors.These findings suggest an unprecedented functional interplay between BET chromatin regulators, Hippo-YAP and RAS-MAPK signaling in lung cancer and therapy resistance. Further, this study identified STK11 as a modifier of sensitivity to the BET and RAS-MAPK inhibitors combination in NSCLC cells and tumors. Citation Format: Nilanjana Chatterjee, Victor Olivas, Wei Wu, Tracy Tang, Ben Powell, Trever Bivona. Targeting oncogenic transcription and signaling crosstalk fueling drug resistance in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB451.
Abstract LB253: Crafted experiments to evaluate feature selection methods for single cell RNA-seq data
Authors: Siyao Liu, David Corcoran, Susana Garcia-Recio, Charles Perou, J.S. Marron
Journal: Cancer Research (2024)

Abstract Single-cell RNA sequencing (scRNA-seq) technologies have revolutionized our understanding of cellular compositions and tumor behavior at the single-cell level, and have been widely used in many biomedical applications, such as identifying and characterizing novel cell types/states. While numerous computational methods have been developed for analyzing scRNA-seq data, benchmarking various analytical methods remains a key challenge for two reasons. First, there is a lack of ground truth datasets where unambiguous cell type identities are known using external information. Second, simulation of scRNA-seq data tends to be overly artificial and simplistic, which may not well mimic the underlying biological complexity as well as high level of technical variability. Here, we propose the use of crafted experiments, a new approach based upon perturbing signals in a real dataset for comparing different scRNA-seq analytical methodologies. We demonstrate the effectiveness of crafted experiments in the context of a novel univariate distribution-oriented suite of feature selection methods, called GOF (Goodness of Fit). We show that GOF more frequently selects features that robustly identify crafted artificial clusters in crafted experiments and achieves similar performance compared to the field standard method using real datasets. Importantly, we show the use of crafted experiments for identifying the contexts in which each method performs the best. Crafted experiments offer valuable comparisons of scRNA-seq analysis methods, and the crafted datasets generated from this study provide a useful resource for the single-cell community. Citation Format: Siyao Liu, David Corcoran, Susana Garcia-Recio, Charles Perou, J.S. Marron. Crafted experiments to evaluate feature selection methods for single cell RNA-seq data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB253.
Abstract SY19-03: Mechanisms of sensitivity and resistance to CDK2 inhibitors
Authors: Sabrina L. Spencer
Journal: Cancer Research (2024)

Abstract CDK2 is a core cell-cycle kinase that phosphorylates many substrates to drive progression through the cell cycle. We used several CDK2 inhibitors in clinical development to interrogate CDK2 substrate phosphorylation, cell-cycle progression, and drug adaptation in preclinical models. In normal mammary cells and estrogen receptor-positive breast cancer cells, CDK2 inhibition causes a rapid loss of substrate phosphorylation that is rapidly restored by a hard-wired cell-cycle buffering mechanism. In this mechanism, CDK4/6 backstops Rb1 hyper-phosphorylation to maintain Cyclin A2 expression, enabling re-activation of CDK2 in the presence of CDK2 inhibitor. By contrast, CCNE1-amplified ovarian cancers do not exhibit this rapid rebound. Our results augment our understanding of CDK plasticity and CDK dependencies, delineate the genetic backgrounds in which this adaptive rebound upon CDK2 inhibition can occur, and suggest contexts in which CDK2 inhibition will be most effective as a cancer therapy. Citation Format: Sabrina L. Spencer. Mechanisms of sensitivity and resistance to CDK2 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY19-03.
Abstract LB251: Widespread epigenetic deregulation and its dependency on tumor sidedness in colorectal cancer
Authors: Brandon Burgman, Xingxin Pan, Anjali Agrawal, Nidhi Sahni, S. Stephen Yi
Journal: Cancer Research (2024)

Abstract Clinical evidence suggests that right-sided colorectal cancer (CRC) tends to have a worse prognosis compared to left-sided CRC. The distinct functional mechanisms underlying this “sidedness” remain cryptic and poorly understood. Thus, molecular classification of CRC is of paramount in targeting specific subtypes and personalizing treatment for patients. To identify targetable molecular features to improve treatment regimens, we performed multi-faceted network analyses of a large number of CRC patients. In our network model, differential expression of transcript abundance, epigenetic features, and mutational frequency were used to identify widespread gene dysregulation and perturbed pathways to reveal disrupted networks distinct to right or left sided colorectal cancer. We discovered histone related genes and distinct epigenetic signals are at play in right-sided CRC. Additionally, our studies reveal “at risk” patient characteristics suggestive of survival differences, to improve diagnostic predictors based on CRC sidedness. Overall, our integrative approach serves to link molecular profiles distinct between left and right sided colorectal cancer, while paving the way towards identifying more effective treatment alternatives from a previously overlooked, readily characterized subtype of colorectal cancer. Citation Format: Brandon Burgman, Xingxin Pan, Anjali Agrawal, Nidhi Sahni, S. Stephen Yi. Widespread epigenetic deregulation and its dependency on tumor sidedness in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB251.
Abstract SY22-01: A strategy to intervene mitotic kinases to induce mitotic catastrophe in cancer cells
Authors: Motoko Takahashi, Minji Jo, Nana Kamakura, Chang Liu, Utako Kato, Toru Hirota
Journal: Cancer Research (2024)

Abstract Chromosomal instability (CIN) is an outstanding feature of cancer, which relates to intratumor heterogeneity, therapeutic resistance, and poor prognosis. While cancer cells can proliferate with CIN, experimentally induced aneuploidy is known to suppress cell growth, leading to the idea that extreme ploidy changes are detrimental to cancer cells. One of the major etiologies of CIN is abnormal kinetochore microtubule attachments, followed by chromosome missegregation. To avoid this, cells have evolved a robust system including two molecular networks for stabilizing and destabilizing microtubule attachments. Two mitotic kinases are involved in this system which have opposite but balanced mode of actions. We previously found that a wide range of cancer cells are defective for destabilization and results in an elevated rate of missegregation. In this study, we aimed to manipulate this kinase balance and found that weighing the balance to stabilizers can cause catastrophic chromosome segregation in mitosis, and such effect could be induced predominantly in cancer cells. These findings prompted us to undertake a screen for small molecules targeting the balanced activity of mitotic kinases. Citation Format: Motoko Takahashi, Minji Jo, Nana Kamakura, Chang Liu, Utako Kato, Toru Hirota. A strategy to intervene mitotic kinases to induce mitotic catastrophe in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY22-01.