bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 33: Humanized MOLM-13 AML model as a versatile tool to study immune-activating agents
Authors: Castro Carla , Metzger Philipp , Obodozie Cynthia , Weber Holger 
Published: April 2023

Abstract
Acute myeloid leukemia (AML) is the most common acute leukemia and second most common form of blood cancer in children and adolescents. Despite progress in understanding the biology of AML, therapeutic intervention plans have not changed nor outcomes significantly improved over the last years. Current AML treatment consists of intensive chemotherapy followed by stem cell transplantation. While initially many patients respond well to chemotherapy, relapse rates are high and still associated with poor prognosis. Evidence suggests that chemo-resistant leukemic stem cells (LSCs) have the ability to reinitiate and sustain the disease. Therefore, novel therapies are urgently needed to improve AML treatment and well-characterized in vivo models modelling this disease are a prerequisite for improving the current state.
At Reaction Biology, we have used NOG and NOD-SCID mice to establish a humanized MOLM-13 AML model concomitantly engrafted with human T cells. Luciferase positive MOLM-13_Luc AML cells were injected both in naïve mice and mice pre-treated with Cyclophosphamide. Thereafter, tumor growth was monitored by bioluminescence measurements to track disseminated tumor burden and isolated T cells were applied upon tumor growth detection (generally observed on day 8 or 15 post-tumor cell inoculation for NOG or NOD-SCID mice, respectively). For each of the inoculations, fresh T cells were obtained by negative selection from buffy coat derived PBMCs with a purity of &gt;95 %. Following administration of human T cells, animals were monitored daily, including the collection of animal weights (3x/w), and tumor burden (2x/w) via in vivo bioluminescence imaging technique.
MOLM-13_Luc tumor cells grew rapidly in all NOG mice with termination of the last animals as early as day 17. Neither Cyclophosphamide pre-treatment, nor the addition of T cells influenced tumor growth or prolonged survival. In Cyclophosphamide pre-treated NOD-SCID mice, onset of tumor growth was observed to initiate homogenously at day 13 post inoculation (with applied T cells being ineffective in reducing tumor burden), whereas tumor growth in non-pre-treated animals was heterogenous and delayed by more than 7d. The presence of T cells affected tumor growth even further. Beside T cell addition, also the application of NK cell therapies were successfully investigated (data not shown).
Taken together, the MOLM-13_Luc AML tumor model is found to be suitable for the investigation of bi-specific engagers using isolated T or NK cells.
Citation Format: Carla Castro, Philipp Metzger, Cynthia Obodozie, Holger Weber. Humanized MOLM-13 AML model as a versatile tool to study immune-activating agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 33.
Abstract 34: A clinically-relevant orthotopic endometrial carcinosarcoma mouse model using human patient-derived organoids
Authors: Katcher Arielle , Chung Charlie , Gorman Megan , Yueh Brian , Lyons Scott , Merrill Joseph , Garcia Libia , Frimer Marina , Goldberg Gary L. , Beyaz Semir 
Published: April 2023

Abstract
Uterine carcinosarcoma (CS) is a rare but aggressive endometrial malignancy. Like the other subtypes of endometrial cancer, the incidence of CS has been increasing and it is projected to continue to rise. Additionally, there is racial disparity seen in African American women diagnosed with CS. African American women have an increased incidence of CS compared to other racial/ethnic groups. They also have an overall increased mortality related to endometrial cancer. Compared to other histologic subtypes of endometrial cancer, CS remains rare and understudied on a molecular and cellular basis. It remains under-represented in clinical trials. Therefore, the current therapies available for CS are extrapolated from those treatments used in the other subtypes of endometrial cancer. There is a paucity of data surrounding targeted therapies for CS resulting in worse outcomes for patients who are diagnosed with this aggressive and lethal cancer. We have developed a clinically relevant, orthotopic CS murine injection model by injecting human CS patient-derived organoids (PDO) from diverse ancestries into the endometrium of immunocompromised mice. Tumor progression in the mice was monitored with physical examination, PET/CT scan, contrast enhanced CT scan, and ultrasound. The tumor was established after three months and was visualized using various imaging techniques. The mice were sacrificed and the diagnosis of invasive CS was confirmed by macroscopic, histologic and genomic analyses. Our orthotopic CS PDO transplantation model has many potential applications for studying tumor biology and the response to treatment for CS in the pre-clinical setting. This may help identify targeted therapy for CS and potentially advance to Phase 1 human clinical trials.
Citation Format: Arielle Katcher, Charlie Chung, Megan Gorman, Brian Yueh, Scott Lyons, Joseph Merrill, Libia Garcia, Marina Frimer, Gary L. Goldberg, Semir Beyaz. A clinically-relevant orthotopic endometrial carcinosarcoma mouse model using human patient-derived organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 34.
Abstract 3464: Dynamics of resident memory (Trm) cell responses between skin and draining lymph nodes during primary and recall responses to melanoma
Authors: Messier Cameron , Khatwani Nikhil , Hawkes Aaron , Huang Yuyang (Poppy) , Turk Mary Jo 
Published: April 2023

Abstract
Tissue resident memory (TRM) cells reside durably in tissues where they serve as a vital component of protective anti-tumor immunity. In mice, TRM cells are defined by their expression of tissue retention markers such as CD69 and CD103, and lack of egress markers such as CD62L, CCR7 and S1PR1. We previously showed that depletion of regulatory T cells induces the generation of protective CD8 Trm cells in skin and draining LNs of B16 melanoma tumor-excised mice. While tumor specific Trm cells were shown to stably reside in tissues at steady state, little is known about their migration between tissue compartments and circulation during primary and recall responses to melanoma. Using gp100-specific transgenic pmel CD8 T cells expressing a Kaede-GFP photoconvertible marker, we investigated the trafficking patterns of tumor Ag specific CD8+ T-cells that were labeled in situ by exposure to UV light in the skin. During primary tumor growth, we observed pronounced movement of antigen-experienced pmel cells through skin to tumor-draining LNs. This trafficking behavior could be inhibited by treatment with FTY720, indicating its S1PR-dependence. Such movement was no longer evident at memory timepoints. However, re-challenge with B16 cells in the dermis induced rapid pmel T cell egress to both LNs and circulation. Recallenge-mediated Trm cell skin egress was confirmed using anti-Thy1.1 monoclonal antibody to deplete circulating and lymphoid memory, while preserving skin TRM. Here we found that skin TRM proliferate and transiently increase expression of Tbet, but go on to generate a durable secondary Trm response in lymph nodes. These data highlight T cell movement between tissues during Trm programming and recall responses to cancer, and shed light on a potential mechanism for the generation TRM populations in tumor-draining lymph nodes. Moreover, our results highlight the potential for retrograde movement of Trm responses from peripheral tissue reservoirs to participate more broadly in systemic anti-tumor immunity.
Citation Format: Cameron Messier, Nikhil Khatwani, Aaron Hawkes, Yuyang (Poppy) Huang, Mary Jo Turk. Dynamics of resident memory (Trm) cell responses between skin and draining lymph nodes during primary and recall responses to melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3464.
Abstract 3479: Modeling epigenetic lesions that cause gliomas
Authors: Rahme Gilbert J. , Javed Nauman M. , Puorro Kaitlyn L. , Xin Shouhui , Hovestadt Volker , Johnstone Sarah E. , Bernstein Bradley E. 
Published: April 2023

Abstract
Epigenetic lesions that disrupt gene regulatory elements and expression are increasingly recognized as potential drivers of human cancers. However, we currently lack the in vitro and in vivo models required to functionally validate such lesions and their tumorigenic impact. Here we model aberrations that arise in Isocitrate Dehydrogenase (IDH) mutant lower-grade gliomas, which exhibit profound DNA hypermethylation as a direct consequence of mutant IDH. DNA hypermethylation may promote gliomagenesis by silencing tumor suppressor genes or, alternatively, by activating proto-oncogenes through disruption of CCCTC-binding factor (CTCF) insulators. CTCF insulator sites define the three-dimensional shape of the genome by dictating the boundaries of topologically associated domains (TADs). Enhancers and promoters can interact when located in the same TAD but are restricted from interacting across different TADs. In IDH mutant gliomas, CpG sites around CTCF binding sites are frequently methylated, effectively compromising CTCF binding and thus TAD organization, allowing for cross-TAD interactions and aberrant activation of genes. We discovered a CTCF insulator downstream of the PDGFRA proto-oncogene that is recurrently disrupted in IDH mutant gliomas. We demonstrate that disruption of the syntenic insulator in mouse oligodendrocyte progenitor cells (OPCs) allows an OPC-specific enhancer to contact and induce Pdgfra, thereby increasing proliferation. In contrast, insulator disruption did not affect Pdgfra expression in neural progenitor cells (NPCs), which lack the enhancer. We also model a second recurrent epigenetic lesion in IDH mutant gliomas, the methylation-dependent silencing of the CDKN2A tumor suppressor. We show that inactivation of Cdkn2a/p19ARF by de novo promoter methylation or mutation drives OPC proliferation and cooperates with Pdgfra insulator loss. Finally, we use lentiviruses to coordinately inactivate the Pdgfra insulator and Cdkn2a in mouse corpus callosum, resulting in low-grade gliomagenesis in vivo with histological features reminiscent of human IDH mutant gliomas. Our study recapitulates recurrent epigenetic lesions in mouse models and demonstrates that the combination of Pdgfra activation and Cdkn2a silencing can transform OPCs in vitro and drive gliomagenesis in vivo.
Citation Format: Gilbert J. Rahme, Nauman M. Javed, Kaitlyn L. Puorro, Shouhui Xin, Volker Hovestadt, Sarah E. Johnstone, Bradley E. Bernstein. Modeling epigenetic lesions that cause gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3479.
Abstract 3485: Intrinsically disordered regions of the ARID1A/B tumor suppressors encode an interaction network within biomolecular condensates that directs mSWI/SNF chromatin remodeler complex activity
Authors: Patil Ajinkya , Strom Amy R. , Collings Clayton K. , Paulo Joao A. , Wauer Tobias , Sankar Akshay , St.Laurent Jessica D. , Cervantes Kasey S. , Gygi Steven P. , Brangwynne Clifford P. , Kadoch Cigall 
Published: April 2023

Abstract
The mammalian SWI/SNF (mSWI/SNF or BAF) ATP-dependent chromatin remodeling complexes collectively represent one of the most frequently mutated cellular entities in cancer, second only to TP53. Mutations across the 29 human genes that encode mSWI/SNF complex subunits occur in over 20% of human cancers, with mutations affecting ARID1A and ARID1B, the largest BAF subunits, being the most frequent. However, the functional contributions of these subunits, particularly their commonly mutated N-terminal intrinsically disordered regions (IDRs) and a highly conserved ARID DNA-binding domain, to BAF function remain poorly understood. Here, we demonstrate that the IDRs of ARID1A/B, coupled with the ARID domain, drive biomolecular condensate formation and BAF chromatin localization in cells. We define ARID1A/B IDRs as two-part systems, facilitating homotypic BAF complex interactions (i.e., valence generated by localized condensation) and heterotypic complex interactions, that together establish a highly specific, sequence-encoded protein interaction network within condensates. Both types of interactions are required for appropriate genome-wide targeting of BAF complexes, DNA accessibility generation, and appropriate gene expression. Replacement of the ARID1A N-terminal IDR with IDRs derived from two unrelated proteins FUS and DDX4, rescues generic condensation of BAF but not chromatin occupancy, DNA accessibility, and heterotypic interactions, highlighting the sequence-specificity embedded in the IDR of ARID1A. Taken together, these data establish a role for the largest and most frequently perturbed IDRs within a major chromatin remodeler and explain how biomolecular condensate formation enables both genomic localization and functional partner recruitment. Furthermore, these findings lay the groundwork for mapping IDR sequence specificity or “grammar”, that dictates the co-condensation network formation, and suggests that targeted disruption of these mechanisms may represent new targeted therapeutic opportunities across multiple cancers.
Citation Format: Ajinkya Patil, Amy R. Strom, Clayton K. Collings, Joao A. Paulo, Tobias Wauer, Akshay Sankar, Jessica D. St.Laurent, Kasey S. Cervantes, Steven P. Gygi, Clifford P. Brangwynne, Cigall Kadoch. Intrinsically disordered regions of the ARID1A/B tumor suppressors encode an interaction network within biomolecular condensates that directs mSWI/SNF chromatin remodeler complex activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3485.
Abstract 3500: A noncatalytic role for mettl1 in oncogenic translation in soft tissue sarcoma
Authors: Ali Raja Hussain , Silverman Brianna , Orellana Esteban A. , Kennedy Alyssa , Bowers Caitlin , Gutierrez Ashley , Papke David , Fletcher Christopher D. , Atayde Antonio P. , Shimamura Akiko , Gregory Richard I. , Gutierrez Alejandro 
Published: April 2023

Abstract
Amplification of chromosomal material derived from 12q is pathognomonic in a subset of soft tissue sarcomas (STS), including well-differentiated and dedifferentiated liposarcoma. However, it remains unclear which of the amplified genes are oncogenic drivers, obstacles to rational therapeutic development. We defined a minimal 12q amplicon in human liposarcoma, and tested the oncogenic activity of each recurrently amplified gene to accelerate the onset of AKT-induced STS in a genetically engineered zebrafish model of the disease. This revealed several genes whose overexpression accelerated the onset of AKT-induced STS, including METTL1, best-known for its ability to catalyze methylation of tRNAs. Surprisingly, catalytically defective mutants of METTL1 exhibited oncogenic activity that was at least as potent as the wild-type gene in zebrafish and human STS, indicating enzyme-independent oncogenic functions. We found that METTL1 promotes ribosome assembly and oncogenic translation independent of its enzymatic activity. In human liposarcoma cells and mouse embryonic fibroblasts, METTL1 overexpression was sufficient to stimulate polysome formation, and this effect was phenocopied by catalytically dead mutants of METTL1. METTL1 overexpression also robustly stimulated the rate of protein synthesis in cells (P &lt; 0.0001), and in a cell-free biochemical assay for translation of a reporter mRNA (P &lt; 0.001). The ability of METTL1 to stimulate ribosomal function triggered a therapeutically targetable dependency, because small molecule inhibitors of ribosome biogenesis had potent therapeutic activity against METTL1-amplified (P &lt; 0.0001), but not METTL1 wild-type, sarcoma cells. Thus, METTL1 is a soft tissue sarcoma oncogene that stimulates oncogenic translation independent of its enzymatic activity, an oncogenic function that can be targeted therapeutically.
Citation Format: Raja Hussain Ali, Brianna Silverman, Esteban A. Orellana, Alyssa Kennedy, Caitlin Bowers, Ashley Gutierrez, David Papke, Christopher D. Fletcher, Antonio P. Atayde, Akiko Shimamura, Richard I. Gregory, Alejandro Gutierrez. A noncatalytic role for mettl1 in oncogenic translation in soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3500.
Abstract 3789: Circular RNA expression is enriched in breast cancer extracellular vesicles and is associated with chemotherapy resistance
Authors: Ngue Harrison , Shrestha Jitendra , Kim Hyejin , Vasudevan Shobha 
Published: April 2023

Abstract
Up to 90% of failures in chemotherapy treatment are associated with metastatic-related drug resistance. Extracellular vesicles (EVs) are believed to play a role in the spread of chemotherapy resistance through the horizontal transfer of oncoproteins and noncoding RNA species, but the underlying mechanisms for this are not fully understood. Here, we study EV biogenesis, release, and uptake in the context of breast cancer chemoresistance. Specifically, we characterized the bioactive cargoes in EVs secreted by chemoresistant triple negative breast cancer cells and chemoresistant estrogen receptor-positive breast cancer cell lines. Preliminary data show that these EVs contain unusually high levels of circular RNAs, small RNA species formed covalently through backsplicing and are typically noncoding. When chemosensitive cells absorb these circRNA-enriched EVs, they experience a significant increase in resistance phenotypes. Moreover, knockdown of the circRNAs via antisense oligonucleotides results in decreased chemoresistance, suggesting a role of circRNAs in the development of chemotherapy resistance. Previous studies have shown that tumor-derived exosomal circRNAs may confer resistance by sponging microRNAs. We are exploring what the circRNAs do mechanistically to promote tumor survival, and clarifying these mechanisms as a whole will serve to potentially provide therapeutic targets against chemotherapy resistance and cancer recurrence.
Citation Format: Harrison Ngue, Jitendra Shrestha, Hyejin Kim, Shobha Vasudevan. Circular RNA expression is enriched in breast cancer extracellular vesicles and is associated with chemotherapy resistance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3789.
Abstract 3793: Regulation of miR-124 expression by promoter methylation in CRC and its relationship with KITENIN expression
Authors: Park So-Yeon , Zhou Rui , Gamage Chathurika D. B. , Pulat Sultan , Varlı Mücahit , Kim Hangun 
Published: April 2023

Abstract
The mechanisms that regulate microRNA expression in cancer are not fully understood. However, recently reported data show that the epigenetic mechanism plays an important role in the regulation of microRNA expression. In in this study, we investigated the relationship between miR-124 promoter methylation and target genes in CRC. The expression of miR-124 was increased by Aza treatment and the expression of KITENIN was decreased in CRC cells. First, we examined the methylation status of miR-124 promoter in two normal cell lines and seven CRC cell lines using pyrosequencing assay. As a result, miR-124 promoter was hypermethylated in CRC cells and low in normal cells. Next, we evaluated the DNA methylation status for a miR-124 promoter in paired colorectal normal tissues and colorectal cancer tissues specimens from 10 patients. Overall, methylation of the miR-124 promoter was high in cancer among clinical tissues, and the expression of miR-124 was low in cancer tissues. The expression of the KITENIN was also higher in cancer tissues than in normal tissues. These results prove that DNA hypermethylation contributes to the transcriptional down-regulation of miR-124 in colon cancer, and that the epigenetic silencing of miR-124 in cancer cells modulate the activity of KITENIN. Our findings provide basic data that can be useful for clinical treatment of CRC patients through the mechanism of miR-124 regulation identified as a regulator of KITENIN.
Citation Format: So-Yeon Park, Rui Zhou, Chathurika D. B. Gamage, Sultan Pulat, Mücahit Varlı, Hangun Kim. Regulation of miR-124 expression by promoter methylation in CRC and its relationship with KITENIN expression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3793.
Abstract 3885: A secondary Gαq mutation confers resistance to Gαq inhibitors in uveal melanoma
Authors: Ma Jiafang , Wang Meng , Manglik Aashish , Bastian Boris C. , Chen Xu 
Published: April 2023

Abstract
Uveal melanoma (UM) is a rare subtype of melanoma that originates from melanocytes of the choroidal plexus, ciliary body and iris. Despite successful treatment of the primary by radiation or surgery, 50% of UM patients develop metastases, mostly in the liver, as an invariably lethal complication. Over 90% of UM harbor activating mutations in the closely related GNAQ or GNA11 genes, mainly at codons Q209, compromising the GTPase activity. Mutant GNAQ and GNA11 can be successfully targeted by the cyclic depsipeptide YM-254890. To anticipate mechanisms of resistance that might arise under treatment with this novel class of Gαq inhibitors, we generated UM cell lines resistant to YM-254890 using an in-vitro cell culture system. Upon chronic growth suppression of a GNA11Q209L mutant UM cell line, we established 12 YM-254890 resistance clones. We identified a secondary GNA11F75Y mutation in one clone and GNA11Y192H mutations in the other 11 clones. The secondary mutations were present in cis with the original GNA11 Q209L mutations. To validate the functional role of these secondary mutations in conveying resistance, we engineered two double mutants, GNA11Q209L/F75Y and GNA11Q209L/Y192H, and introduced them into 293FT cells respectively and confirmed that both F75Y and Y192H convey resistance to YM-254890 treatment. The proliferation of YM-254890-resistant cell lines was still dependent on GNA11 and downstream PKC/MAPK signaling. Combined inhibition of PKC and MEK synergistically reduced cell viability in YM-254890 resistant UM cells. Analysis of the crystal structure of YM-2548890 in complex with GNAQ predicts both F75Y and Y192H mutations directly affect the binding of YM-254890 to Gαq. Our data suggest that direct targeting mutant GNAQ/11 is promising but will select for secondary mutations within GNAQ/11 that will result in resistance. Combinatorial targeting of other components in the Gαq signaling pathway will increase clinical efficacy.
Citation Format: Jiafang Ma, Meng Wang, Aashish Manglik, Boris C. Bastian, Xu Chen. A secondary Gαq mutation confers resistance to Gαq inhibitors in uveal melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3885.