bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 655: Fungal extract screening reveals malformin C to preferentially kill glioblastoma stem-like cells via concerted induction of proteotoxic stress and autophagic flux blockade
Authors: Phillips Emma L. , van Enk Sizèd , Kildgaard Sara , Schlue Silja , Göttmann Mona , Jennings Victoria , Bethke Frederic , Müller Gabriele , Herold-Mende Christel , Pastor-Flores Daniel , Schneider Martin , Helm Dominic , Larsen Thomas Ostenfeld , Goidts Violaine 
Published: March 2024

Abstract
Glioblastoma is a highly aggressive brain tumor for which there is no cure. The dire prognosis of this disease is largely attributable to a high level of heterogeneity, including the presence of a sub-population of tumor initiating glioblastoma stem-like cells (GSCs), which are refractory to chemo- and radiotherapy. Here, in an unbiased marine-derived fungal extract screen, together with bioguided dereplication based on high resolution mass spectrometry, we identified malformin C to preferentially induce cell death in patient-derived GSCs, and explore the potential of this cyclic peptide as a therapeutic agent for glioblastoma. Malformin C significantly reduced tumor growth in an in vivo xenograft model of glioblastoma. Using transcriptomics and chemoproteomics, we found that malformin C binds to many proteins leading to aggregation, and rapidly induces unfolded protein response, including autophagy, in GSCs. Malformin C also appears to accumulate in lysosomes, disrupting autophagic flux and driving cells to death. Supporting this, malformin C synergizes with chloroquine, an inhibitor of autophagy. Strikingly, we observed that autophagic flux is differentially regulated in GSCs compared with normal astrocytes. The sensitivity of GSCs to malformin C highlights the relevance of proteostasis and autophagy as a therapeutic vulnerability in glioblastoma.
Citation Format: Emma L. Phillips, Sizèd van Enk, Sara Kildgaard, Silja Schlue, Mona Göttmann, Victoria Jennings, Frederic Bethke, Gabriele Müller, Christel Herold-Mende, Daniel Pastor-Flores, Martin Schneider, Dominic Helm, Thomas Ostenfeld Larsen, Violaine Goidts. Fungal extract screening reveals malformin C to preferentially kill glioblastoma stem-like cells via concerted induction of proteotoxic stress and autophagic flux blockade [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 655.
Abstract 6584: Aberrant TRIM7 expression potentiates RACO-1 mediated proliferation and dysregulated interferon responsiveness in the setting of anti-PD-1 acquired resistance in cancer
Authors: Nguyen Thuy-Ai Tran , Morra Marc , Li Kevin , Bhatt Ulhas , Mwangi Joseph , Rivera-Molina Yisel , Oien Nathan , Medina Julio , Schreiber Taylor H. , Fromm George 
Published: March 2024

Abstract
While checkpoint inhibitor treatment has extended the survival of many cancer patients, most initial responders will later develop disease progression through a variety of poorly understood acquired resistance mechanisms (CPI-AR). One such recently described mechanism involves the transcriptional hyperactivation of genes associated with interferon (IFN) signaling, JAK/STAT, and antigen processing/presentation pathways. Aberrant IFN regulation in the setting of AR suggests that tumor cell intrinsic mechanisms have conferred a growth advantage despite the presence of immune-mediated pressure unleashed by PD-1/L1 antibody blockade. Analysis of transcripts progressively upregulated during acquisition of AR in vivo and transcripts upregulated by IFN exposure of isolated AR cell lines in vitro identified the E3 ubiquitin ligase TRIM7 as a candidate mediator of the AR phenotype. A specific pocket on the PRY/SPRY domain of TRIM7 has been shown to bind viral peptides, resulting in ubiquitination and degradation as a mechanism to mitigate viral propagation. Here we describe the evaluation of small molecule inhibitors (SMI) designed to the TRIM7 PRY/SPRY viral-pocket domain, where binding specificity was confirmed using mass spec analysis. These SMI competitively inhibited TRIM7 mediated stabilization of RACO-1, resulting in decreased cancer cell proliferation which was associated with altered c-Jun/AP-1 transcription. TRIM7 SMI also disrupted STING and MAVS ubiquitination and restored IFN responsiveness and sensitivity to PD-1 inhibitor treatment. Finally, given the position of TRIM7 downstream of growth factor receptor and kras signaling, combination of TRIM7 inhibitors with kras, braf, and/or MEK inhibitors was shown to additively suppress proliferation of tumor cells with kras mutations. These results provide evidence that upregulation of TRIM7 mediates both a pro-proliferative and IFN resistant phenotype in the setting of CPI-AR, and that inhibition of TRIM7 with small molecule inhibitors may prevent or reverse AR to PD-1/L1 blockade.
Citation Format: Thuy-Ai Tran Nguyen, Marc Morra, Kevin Li, Ulhas Bhatt, Joseph Mwangi, Yisel Rivera-Molina, Nathan Oien, Julio Medina, Taylor H. Schreiber, George Fromm. Aberrant TRIM7 expression potentiates RACO-1 mediated proliferation and dysregulated interferon responsiveness in the setting of anti-PD-1 acquired resistance in 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 6584.
Abstract 6599: 3D genomic analysis reveals novel enhancer hijacking mechanisms caused by complex structural alterations that drive oncogene overexpression
Authors: Mortenson Katelyn L. , Dawes Courtney , Wilson Emily R. , Patchen Nathan E. , Johnson Hailey , Gertz Jason , Bailey Swneke D. , Liu Yan , Varley Katherine E. , Zhang Xiaoyang 
Published: March 2024

Abstract
Enhancer hijacking, caused by structural alterations on chromosomes as well as extrachromosomal DNA (ecDNA), is a common cancer driver event. The complexity and ubiquity of structural alterations in cancer genomes make it difficult to identify enhancer hijacking with genome sequencing alone. Here we describe a 3D genomics-based analysis called HAPI (Highly Active Promoter Interactions) to characterize enhancer hijacking caused by various types of structural alterations. Applying HAPI analysis to HiChIP data from 34 cancer cell lines, we identified novel enhancers hijacked through chromosomal rearrangements to activate both known and potentially novel oncogenes such as MYC, CCND1, ETV1, CRKL, and ID4, which we validated using CRISPRi assays and RNA-seq analysis. Furthermore, we found that ecDNAs often contain multiple oncogenes from different chromosomes, which cause nested enhancer hijacking among them. For instance, we found that MYC ecDNAs relocate additional oncogenes from other chromosomes such as CDX2, ERBB2, or CD44 near the MYC locus, co-opting MYC’s enhancers for their overexpression, which we validated using dual-color DNA FISH and CRISPRi assays. This multiple oncogenes-involved enhancer hijacking mechanism may suggest novel therapeutic strategies such as targeting either the co-opting oncogenes or the hijacked enhancers for ecDNAs. Our study provides a robust strategy to detect enhancer hijacking events using our publicly available HAPI analysis tool and reveals novel mechanisms underlying oncogene activation caused by chromosomal and extrachromosomal structural alterations.
Citation Format: Katelyn L. Mortenson, Courtney Dawes, Emily R. Wilson, Nathan E. Patchen, Hailey Johnson, Jason Gertz, Swneke D. Bailey, Yan Liu, Katherine E. Varley, Xiaoyang Zhang. 3D genomic analysis reveals novel enhancer hijacking mechanisms caused by complex structural alterations that drive oncogene overexpression [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 6599.
Abstract 6607: Serine depletion promotes antitumor immunity throughmitochondrial DNA-mediated cGAS/STING1 activation
Authors: Saha Suchandrima , Ghosh Monisankar , Jinyu Li , Wen Asher , Galluzzi Lorenzo , Martinez Luis , Montrose David C. 
Published: March 2024

Abstract
Serine is critical for supporting cancer metabolism, and as such, depriving malignant cells of this non-essential amino acid exerts anticancer effects, in large part, through disrupting their metabolic pathways. However, the impact of these metabolic defects on tumor-targeting immunity remains poorly understood. Here, we show that restricting endogenous and exogenous serine in colorectal cancer (CRC) cells results in mitochondrial dysfunction coupled to cytosolic mitochondrial DNA accumulation and cGAS/STING1-dependent type I interferon secretion. Serine-deprived tumors have suppressed growth, accompanied by type I interferon signaling and tumor infiltration by immune effector cells. Blocking cGAS/STING1 signaling in tumor cells limits the immunostimulatory and anticancer effects of serine deprivation. Moreover, serine-depleted tumors exhibit increased sensitivity to a programmed cell death 1 blocker. Lastly, transcriptomic data from human CRCs suggest that malignant lesions with reduced serine abundance have higher immune infiltration. Taken together, our findings reveal a novel role for serine as a gatekeeper of mitochondrial integrity and hence a suppressor of anticancerimmunity.
Citation Format: Suchandrima Saha, Monisankar Ghosh, Li Jinyu, Asher Wen, Lorenzo Galluzzi, Luis Martinez, David C. Montrose. Serine depletion promotes antitumor immunity throughmitochondrial DNA-mediated cGAS/STING1 activation [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 6607.
Abstract 6626: Functional and molecular interrogation of a high-plasticity cell state in lung cancer
Authors: Chan Jason Earl , Pan Chun-Hao , Sussman Carleigh , Styers Hannah , Brown Emma , Hartmann Griffin , Meškauskaitė Brigita , Blum Melissa , Ding Selena , Torborg Stefan , Li Zhuxuan , Joost Simon , Rivas-Hernandez Eliud , Norman Thomas , Chaligne Ronan , Yan Yan , Tammela Tuomas 
Published: March 2024

Abstract
Despite recent advancements in lung adenocarcinoma (LUAD) treatment, mortality remains high. Thus, a need exists for novel therapeutic concepts to enhance treatment efficacy and improve patient survival. Cancer cell plasticity, the capacity for cancer cells to differentiate and adapt to cell-extrinsic pressures, drives LUAD progression and enables treatment resistance. We discovered a molecularly distinct "high-plasticity cell state" (HPCS), which emerges during the initial stages of tumor development and is maintained in established tumors, comprising 10-15% of the cancer cell pool. We hypothesized that the HPCS is critical for tumor progression and drug resistance. To functionally interrogate this cell state, we engineered a novel genetic system that enables both in situ ablation (via a suicide gene) and longitudinal lineage tracing (via secreted luciferases) of the HPCS in an autochthonous genetically engineered mouse LUAD model. Lineage-tracing revealed the HPCS harbors high differentiation potential (plasticity) and growth potential in situ. Strikingly, ablation of the HPCS led to robust tumor regression and growth suppression. Motivated by these findings, we sought to identify molecular drivers of the HPCS using an in vivo multiplexed gene perturbation approach coupled to single-cell RNA sequencing. This effort led to the identification of central transcriptional plasticity drivers. This study motivates the therapeutic targeting of the HPCS in lung cancer and uncovers candidate targets.
Citation Format: Jason Earl Chan, Chun-Hao Pan, Carleigh Sussman, Hannah Styers, Emma Brown, Griffin Hartmann, Brigita Meškauskaitė, Melissa Blum, Selena Ding, Stefan Torborg, Zhuxuan Li, Simon Joost, Eliud Rivas-Hernandez, Thomas Norman, Ronan Chaligne, Yan Yan, Tuomas Tammela. Functional and molecular interrogation of a high-plasticity cell state in lung 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 6626.
Abstract 6632: Adipocyte death drives dormant breast cancer cell reactivation
Authors: Yuan Xiaoyu , Ren Qihao , Stewart Sheila A. 
Published: March 2024

Abstract
Despite significant responses to initial treatments, upwards of 30% of breast cancer patients will experience a recurrence of their disease. Unfortunately, there are few clinical features that predict which patients will recur, relegating patients and their doctors to a wait-and-see approach where they must remain vigilant. Recent studies have reported that the presence of disseminated tumor cells (DTCs) in the bone marrow of early-stage breast cancer patients predicts a higher chance of recurrence and that obese patients experience 35%-40% higher rates of recurrence than lean patients. Interestingly, in addition to increased adipocyte size, obese patients experience higher rates of adipocyte apoptosis, macrophage recruitment to adipocyte tissue, and increased inflammation, shown as the formation of crown-like structures (CLSs). Given the rising prevalence of obesity, the need for mechanistic studies to elucidate its contribution to breast cancer dormancy and recurrence is urgent. To investigate how microenvironmental changes associated with obesity affect breast cancer dormancy, we utilized a well-established syngeneic mouse model of ER+ breast cancer dormancy (D2.0R). We found that D2.0R cells remained dormant in the visceral fat of wildtype mice but were reactivated upon adipocyte death due to obesity or genetic manipulation, and this reactivation required the recruitment of macrophages. To understand why macrophages were recruited to the adipose tissue and how they led to dormant tumor cell reactivation, we profiled the microenvironmental changes in visceral fat using single-cell RNA-sequencing and found that the infiltrating macrophages exhibited unique pro-inflammatory and lipid regulatory phenotypes. Further investigation revealed that macrophages activated the integrin-focal adhesion kinase (FAK) pathway in dormant D2.0R cells and the inhibition of integrin and FAK inhibited this activation. Given tumor cells can metastasize to visceral fat depots in breast cancer patients, our findings provide an important model to determine what drives dormant tumor cell growth in adipose tissue. Our study provides novel insights into how tumor microenvironment (TME) impacts breast cancer dormancy and also highlights the importance of adipose tissue as a unique reservoir that potentiates cancer relapse.
Citation Format: Xiaoyu Yuan, Qihao Ren, Sheila A. Stewart. Adipocyte death drives dormant breast cancer cell reactivation [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 6632.
Abstract 6640: Zap! Irreversible electroporation in pancreatic cancer cells induces proinflammatory cell death and improves progression free survival
Authors: Powar Manali , Imran Khan Mohammad , Allen Irving C. , Davalos Rafael V. , Salamah Zaid , Aycock Kenneth , Brock Rebecca M. , Coutermarsh-Ott Sheryl , Orr Katie 
Published: March 2024

Abstract
Pancreatic cancer is the third leading cause of cancer-related death due to its late diagnosis, few treatment options, and extremely low survival rates due to its immunosuppressive microenvironment. Irreversible electroporation (IRE),is a tumor non-thermal ablation technique that applies high-voltage electrical pulses to permeabilize the cell membrane that is irreversible and leads to necrotic cell death. IRE has had strong success in clinical trials nevertheless, little is known about the effect of IRE beyond the initiation of cell death in the tumor tissue. We hypothesize that IRE can not only induce cell death by membrane disruption to facilitate a proinflammatory microenvironment but also causes death via cell cycle arrest. We utilized in-vitro, and immunocompetent in-vivo murine models to investigate changes to pancreatic cancer and the tumor microenvironment. Our findings show that treating the cells with an increasing voltage of IRE induces more cell death. We observed cell cycle arrest in the G1 phase which may have been caused by DNA damage. There was upregulation of DNA damage repair machinery in the treated samples. Our histopathology data suggests increased necrosis on the tumor treated with IRE, as also PCR array analysis showed more proinflammatory cell death caused by pyroptosis. Finally, we demonstrated a reduction in the tumor size and a better survival rate aftertreatment. Our data suggest that Irreversible electroporation has a promising future in inducing proinflammatory type of cell death in the tumor and benefits increased patient survival. More investigation is needed to define ideal parameters for the electrical pulses and device development for tumor ablation in larger animals like porcine models.
Citation Format: Manali Powar, Khan Mohammad Imran, Irving C. Allen, Rafael V. Davalos, Zaid Salamah, Kenneth Aycock, Rebecca M. Brock, Sheryl Coutermarsh-Ott, Katie Orr. Zap! Irreversible electroporation in pancreatic cancer cells induces proinflammatory cell death and improves progression free survival [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 6640.
Abstract 6678: Microbial regulation of anti-tumor immunity in colorectal cancer
Authors: Chung Charlie , Ozcelik Elif , Habel Jill , Zhang Jialin , Qin Yihan , Garcia Libia , Merrill Joseph , Chung Taemoon , Lyons Scott , Shen Zeli , Fox James G. , Westcott Peter , Beyaz Semir 
Published: March 2024

Abstract
Colorectal cancer (CRC) is the 3rd leading site of cancers and cause of cancer cell death. Although Immunotherapies revolutionized cancer therapy, the majority of CRC patients, particularly with metastatic disease, do not respond to the treatments. This necessitates a better mechanistic understanding of the tumor-immune cell interactions in the context of CRC. Microbiome influences multiple biological aspects of the host including immune responses against cancers. Here, we show that the gut microbiome influences cancer MHC-I and -II expression levels and restricts tumor progression and metastasis, resulting in longer survival in 3 different CRC models and two different mouse strains. We found that the anti-tumor effects are dependent on T cells and B cells. Interestingly, depletion of B cell negated anti-metastatic effects of gut microbiome. Mechanistically, MHC-II expression in cancer cells mediates the anti-tumor effects of the microbiome. MHC-II upregulation on human CRC organoids enhances cancer-immune cell interactions and associated apoptosis, demonstrating an anti-tumor role and significance of MHC-II in human CRC. Thus, gut microbes that enhance MHC-II antigen presentation promotes anti-tumor immunity and may be utilized to enhance efficacy of immunotherapy in metastatic CRC.
Citation Format: Charlie Chung, Elif Ozcelik, Jill Habel, Jialin Zhang, Yihan Qin, Libia Garcia, Joseph Merrill, Taemoon Chung, Scott Lyons, Zeli Shen, James G. Fox, Peter Westcott, Semir Beyaz. Microbial regulation of anti-tumor immunity in colorectal 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 6678.
Abstract 6689: Modulation of MAITs by the tumor microbiome in anti-PD1 treated cancers
Authors: Birla Pakhi , Yang Lansaol , Sears Cynthia , Shaikh Fyza , Pardoll Drew , Housseau Franck 
Published: March 2024

Abstract
Mucosal associated invariant T (MAIT) cells are innate like T-cells that recognize non-peptide metabolite antigens presented on monomorphic MHC related-1 (MR1) making them an attractive off the shelf tool for cancer immunotherapy. In this study, we investigate the function of MAITs in the tumor microenvironment of neoadjuvant anti-PD1 treated lung cancer patients (NCT02259621)). Paired single cell RNA/TCR sequencing analysis revealed an oligoclonal expansion of MAITs comprising of canonical TRAV1-2+ and non-canonical MAITs TRAV1-2-. TCR capture from canonical MAIT clonotypes confirmed their in vitro recognition of 5-OP-RU, bacteria derived riboflavin derivative as well as MR1 dependent recognition of live bacteria present in the tumor. However, the nature of antigens recognized by non-canonical MAITs remains poorly understood. On mining transcriptional profiles of MAITs, we observed that canonical MAITs were characterized by high clonal amplification whereas the non-canonical clonotypes expressed a strong activation/exhaustion gene signature. This suggests that both these MAIT populations recognize different types of antigens, differentially activate, and respond to immune checkpoint blockade (ICB), the non-canonical MAITs being highly dysfunctional. Using bacterial 16S RNA amplicon and metagenomics sequencing, we seek to identify microbial and metabolomics signatures associated with MAIT activation and response to ICB. We identified MAITs to express a cytotoxic signature making them a potential target for cancer immunotherapy. Our findings will provide further insights into the nature of ligands recognized by MAITs and the mechanisms associated with MR1 dependent recognition and tumor killing. Investigating the role of unconventional T-cells in response to ICB has the potential to reveal new tumor-associated antigens which could open avenues into innovative combination immunotherapies.
Citation Format: Pakhi Birla, Lansaol Yang, Cynthia Sears, Fyza Shaikh, Drew Pardoll, Franck Housseau. Modulation of MAITs by the tumor microbiome in anti-PD1 treated cancers [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 6689.