bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6909: KRASG12C inhibitor resistance in patient-derived non-small cell lung cancer models
Authors: Rosen Joshua C. , Pham Nhu-An , Li Quan , Cao Pinjiang , Hueniken Katrina , Koga Takamasa , Radulovich Nikolina , Koers Alex , Niedbala Michael , Ross Sarah , Sacher Adrian , Tsao Ming-Sound 
Published: March 2024

Abstract
Introduction: One quarter of lung adenocarcinomas (LUAD) harbor KRAS-mutations, with KRASG12C accounting for the majority (40%). GDP-KRASG12C inhibitors (G12Ci) have been developed for this patient cohort, and two of these are approved for clinical use in the US. While response rates to G12Ci tested in clinical trials have been between 35-50%, studies have identified mechanisms of adaptive resistance to these novel agents, limiting their use as monotherapies. However, primary (intrinsic) resistance to these compounds has not been explored extensively. We leveraged our patient-derived xenograft (PDX) and xenograft-derived organoid (XDO) development programs to study primary resistance to the novel G12Ci, AZD4625.
Methods: Twelve KRASG12C PDX models were established which recapitulated patient tumor histology, and genomic, transcriptomic, and methylome profiles. From these 12 PDX, six long-term (passage &gt;10) XDO were generated. PDX were treated with AZD4625 chronically for four weeks as well as in an acute dosing pharmacodynamic study, where tumors were harvested for further analysis.
Results: The AZD4625 drug screen in our PDX models reproduced the G12Ci response rate observed in clinical trials. Four of twelve tumor models reduced in size on treatment, while the remainder were considered resistant as these tumors increased in size on treatment. Sensitive tumors became necrotic while those resistant remained proliferative. XDO models recapitulated their originating PDX genomic alterations, histology, as well as responses to AZD4625. During the acute pharmacodynamic screen in our PDX models, we observed a decrease in pERK1/2 and pS6 protein expression in sensitive but not resistant models, despite acute DUSP6 gene expression decreases in every model. Global proteomic analysis highlighted differences between each model.
Conclusion: PDX and XDO are useful models to study resistance to this novel class of inhibitor, with the KRASG12C NSCLC PDX models exhibiting a treatment response rate that is similar to those observed in clinical trials. Global proteomics suggests uniqueness of each model in our cohort, hinting that a universal combination of specific targeted agents to treat KRASG12C LUAD tumors may be insufficient.
Citation Format: Joshua C. Rosen, Nhu-An Pham, Quan Li, Pinjiang Cao, Katrina Hueniken, Takamasa Koga, Nikolina Radulovich, Alex Koers, Michael Niedbala, Sarah Ross, Adrian Sacher, Ming-Sound Tsao. KRASG12C inhibitor resistance in patient-derived non-small cell lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6909.
Abstract 6911: Expanding reported molecular characteristics for the NCI Patient-Derived Models Repository
Authors: Timme Cindy R. , Evrard Yvonne A. , Das Biswajit , Chang Ting-Chia , Chen Alice , Chen Li , Crespo-Eugeni Michelle A. , Jiwani Shahanawaz , Karlovich Chris A. , Pauly Rini , Wu Peter I-Fan , Newton Dianne L. , Williams P. Mickey , Hollingshead Melinda G. , Doroshow James H. 
Published: March 2024

Abstract
The National Cancer Institute’s Patient-Derived Models Repository (NCI PDMR; https://pdmr.cancer.gov) has developed a national repository of Patient-Derived Models (PDMs) comprised of patient-derived xenografts (PDXs), in vitro patient-derived tumor cell cultures (PDCs) and cancer associated fibroblasts (CAFs) as well as patient-derived organoids (PDOrg). These PDMs are clinically annotated with molecular information available in an easily accessible database for the extramural community. To ensure the data and models remains pertinent to current translational efforts, NCI actively reviews and adds new molecular features to the public database for researchers to use. While these data could be obtained through analysis of the available NextGen sequencing files in the PDMR database, many laboratories do not have the bioinformatics support to run these assessments for models that are of research interest. Therefore, new pipelines for an array of additional model and molecular characteristics present in PDX, PDOrg, and PDC models have been validated and are reported in the public database in a searchable format. Current model characteristics include addition of OncoTree Codes as a second histologic classifier, use of the PDXNet Consortium’s inferred ancestry caller to better represent Native/Latin American populations, human leukocyte antigen (HLA) typing, molecular classification of tumors (e.g. CMS subtyping of colorectal adenocarcinoma, PAM50 signature based subtyping of breast carcinoma), microsatellite instability (MSI) assessment, and identification of clinically relevant fusions. SOPs for the pipelines used are available on the public website to allow for independent validation and use by other laboratories. Funded by NCI Contract No. HHSN261200800001E
Citation Format: Cindy R. Timme, Yvonne A. Evrard, Biswajit Das, Ting-Chia Chang, Alice Chen, Li Chen, Michelle A. Crespo-Eugeni, Shahanawaz Jiwani, Chris A. Karlovich, Rini Pauly, Peter I-Fan Wu, Dianne L. Newton, P. Mickey Williams, Melinda G. Hollingshead, James H. Doroshow. Expanding reported molecular characteristics for the NCI Patient-Derived Models Repository [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 6911.
Abstract 6943: Evolutionary dynamics under chemotherapy in small cell lung cancer: Insights from patient-derived xenotransplant models
Authors: Kaiser Laura C. , Schmiel Marcel , Ruminska Agnieszka , Alavinejad Nazanin , Müller Christian , Valiulis Justinas , Peifer Martin , Cartolano Maria , Thomas Roman K. , George Julie 
Published: March 2024

Abstract
Introduction: The treatment of patients with small cell lung cancer (SCLC) represents a major medical challenge due to aggressive tumor growth and the poor 5-year overall survival rate of only 5%. SCLC tumors typically are remarkably sensitive to chemotherapy at the beginning; however, the subsequent rapid relapse of therapy-resistant tumors is a severe obstacle. We therefore aimed to decipher the molecular patterns guiding processes of evolutionary adaptation in SCLC as a consequence of therapeutic interventions.
Methods: Over 100 patient-derived xenotransplant models were generated from clinical SCLC specimens capturing a wide range of genetic and molecular features as well as clinical phenotypes with regard to chemotherapy response. We recapitulated chemotherapy response in vivo for 32 models, and performed in-depth genome and single-cell transcriptome sequencing to thus dissect genomic evolutionary trajectories and transcriptional plasticity of therapy-naïve and relapsed tumors, which includes the study of multiregional and longitudinal samples.
Results: The response to chemotherapy in vivo reflected the clinical response of the patients; however, several models of relapsed patients remained sensitive to treatment. Genomic studies of clonal dynamics indicated selection of subclones as a result of therapeutic pressure. In contrast, chemo-refractory tumors maintained their clonal composition after therapy. In agreement with genomic profiles, single-cell transcriptome data revealed a tremendous shift in expression profiles and composition of subpopulations. Furthermore, subclonal genomic events including copy number alterations were found to shape the transcriptional heterogeneity in tumors.
Conclusion: Here, we demonstrate a comprehensive functional characterization of multi-regional tumor sites and longitudinal specimens acquired from patients with SCLC, in which we elucidate genomic and transcriptional heterogeneity as a consequence of therapy response. Overall, our data points to a complex interplay between sub-clonal genomic changes and transcriptional plasticity shaping therapy response in which pre-existing genomic alterations impact selection under therapy.
Citation Format: Laura C. Kaiser, Marcel Schmiel, Agnieszka Ruminska, Nazanin Alavinejad, Christian Müller, Justinas Valiulis, Martin Peifer, Maria Cartolano, Roman K. Thomas, Julie George. Evolutionary dynamics under chemotherapy in small cell lung cancer: Insights from patient-derived xenotransplant models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6943.
Abstract 6980: GOLGA7 is essential for NRAS trafficking from the Golgi to the plasma membrane but not for its palmitoylation
Authors: Liu Chenxuan , Jiao Bo , Wang Peihong , Zhang Baoyuan , Gao Jiaming , Li Donghe , Xie Xi , Yao Yunying , Yan Lei , Qin Zhenghong , Liu Ping , Ren Ruibao 
Published: March 2024

Abstract
RAS GTPases play a crucial role as oncogenic drivers in multiple cancer types. Targeting their localization to the plasma membrane (PM) is a promising strategy for cancer therapy, as RAS signaling requires PM localization. While KRAS traffics through a Golgi-independent route, palmitoylated RAS isoforms are transported to PM from the Golgi via a secretory pathway that is not yet fully understood. GOLGA7 is a Golgi-resident protein known as an accessory protein stabilizing the palmitoyltransferase ZDHHC9 for the palmitoylation of NRAS and HRAS. In this study, we found that among all four RAS isoforms, NRAS uniquely requires GOLGA7 for its association with the PM. Interestingly, the mislocalization of NRAS is achieved without detectable changes in its palmitoylation level in GOLGA7 deficient cells. We further observed that loss of GOLGA7 inhibit the anterograde trafficking of GFP-NRASG12D proteins and result in the accumulation of NRAS in the cis compartment of the Golgi apparatus. Moreover, targeting GOLGA7 suppresses cell proliferation by downregulating RAS signaling in a variety of NRAS-mutant cancer cells. Finally, GOLGA7 depletion attenuated the oncogenic transformation induced by NRASG12D in mice. These findings reveal a specific intracellular trafficking route mediated by GOLGA7 and have identified GOLGA7 as a potential therapeutic target for NRAS-driven cancers.
Citation Format: Chenxuan Liu, Bo Jiao, Peihong Wang, Baoyuan Zhang, Jiaming Gao, Donghe Li, Xi Xie, Yunying Yao, Lei Yan, Zhenghong Qin, Ping Liu, Ruibao Ren. GOLGA7 is essential for NRAS trafficking from the Golgi to the plasma membrane but not for its palmitoylation [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 6980.
Abstract 6984: Investigating the function of the OSM-OSMR axis in pancreatic ductal adenocarcinoma (PDAC)
Authors: Sui Yuan , Hunter Tony 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, characterized by a low survival rate and a significant global mortality impact. The interaction between PDAC and the immune system is complex and plays a crucial role in the progression of the disease. PDAC creates an immunosuppressive tumor microenvironment, which hampers the ability of immune cells to effectively infiltrate the tumor and mount an anti-cancer immune response. Additionally, there is an imbalance of cytokines, with an overabundance of immunosuppressive factors and a deficiency in pro-inflammatory cytokines. This hostile immunological landscape contributes to the aggressive nature of PDAC and hinders the success of immunotherapies and adjuvant treatments. One cytokine of particular interest is oncostatin M (OSM), a member of the interleukin-6 (IL-6) family. OSM has been implicated in the regulation of cancer and has been associated with poor overall survival in pancreatic cancer and other malignancies. Similar to other cytokines, OSM is secreted by immune cells and acts as a regulator of the inflammatory microenvironment surrounding the tumor. The levels of OSM in this milieu can potentially influence cancer development and regulation through multiple mechanisms. Despite the growing understanding of cytokines in cancer, research on the role of OSM in PDAC is still limited and requires further investigation to identify potential therapeutic targets. Therefore, there is a critical need to delve deeper into the functions of OSM and its receptor, oncostatin M receptor (OSMR), in the initiation and progression of pancreatic cancer. As such, our goal is to examine the functions of OSM and its receptor (OSMR) in initiating and advancing pancreatic cancer to better comprehend the role of the OSM-OSMR axis in PDAC, both in vivo and in vitro.
Citation Format: Yuan Sui, Tony Hunter. Investigating the function of the OSM-OSMR axis in pancreatic ductal adenocarcinoma (PDAC) [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 6984.
Abstract 6985: The oncogenic functions and action mechanism of UTP14A, a subunit required for 18S rRNA synthesis, in head and neck cancer
Authors: Wu Li-Wha , Chang Chen-Ni , Biswas Pulak K. , Tsai Sen-Tien 
Published: March 2024

Abstract
Head and neck cancer (HNC) is the sixth common malignancy in the world and &gt; 90% of HNC cases are squamous cell carcinoma in origin. Oral cancer is one major HNC subtype. Despite the recent advancements in cancer diagnostics and therapeutics, the 5-yr survival rate of advanced HNC patients remains &lt;50%. Ribosomes are the cellular factories responsible for making proteins. The hyper-activation of ribosome biogenesis initiated by oncogene gain or tumor suppressor gene loss plays a critical role in cancer initiation and progression. Ribosome biogenesis is a complex and energy intensive process that involves hundreds of factors. UTP14A gene encodes a member of the uridine triphosphate 14 family and is an essential component of a large ribonucleoprotein complex bound to the U3 small nucleolar RNA. Previous studies have demonstrated that UTP14A plays a key role in the synthesis of ribosomes and 18S rRNA, and is overexpressed in several malignancies. However, the biological functions and underlying mechanisms of UTP14A in HNC remain elusive. We found not only the increase of UTP14A mRNA expression in TCGA-HNC database but also its negative impact on patient clinical outcome. UTP14A depletion significantly impaired HNC cell proliferation, migration and invasion in vitro. Ectopic overexpression had the opposite effect, suggesting an oncogenic role for UTP14A in HNC. Through gene set enrichment analysis of pairwise RNA sequencing results, several genes involved in the process of epithelial mesenchymal transition (EMT) were potentially associated with manipulated UTP14A expression. We also detected a concordant change of lipid droplet numbers and its surface marker expression in UTP14A-manipulated cells, respectively, by BODIPY staining and immunhistochemical staining. Western blot analysis validated a positive relationship of EMT markers and COX-2, a potential mediator of lipid metabolism and EMT, with altered UTP14A expression. The involvement of COX2 in UTP14A mediation was confirmed by using both pharmacological inhibition and genetic manipulation. We also identified p38 as a central downstream effector but acting upstream from COX-2 in UTP14A mediation in oral cancer cells. We believe that our study of UTP14A-mediated oncogenic signaling axis can potentially be harnessed as a novel therapeutic target against HNC although more mechanistic studies may be needed.
Citation Format: Li-Wha Wu, Chen-Ni Chang, Pulak K. Biswas, Sen-Tien Tsai. The oncogenic functions and action mechanism of UTP14A, a subunit required for 18S rRNA synthesis, in head and neck 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 6985.
Abstract 7022: Whole genome and reduced representation enzymatic methyl-seq enable cost effective methylomes
Authors: Panchapakesa Vaishnavi , Ponnaluri Chaithanya , Evanich Daniel , Erijman Ariel , Langhorst Bradley , Williams Louise 
Published: March 2024

Abstract
DNA methylation is an epigenetic regulator of gene expression with important functions in development and diseases such as cancer. Traditionally, sodium bisulfite conversion was used to distinguish 5-methylcytosines (5mC) and 5-hydroxymethylcytosines (5hmC) from cytosines. However, this method damages DNA and introduces significant sequencing bias. NEBNext® Enzymatic Methyl-seq (EM-seq™) is an enzymatic conversion approach that minimizes DNA damage therefore enabling longer insert sizes, lower duplication rates and a more accurate quantification of methylation in DNA samples with inputs ranging from 10 ng to 200 ng. An improved enzymatic conversion method, EM-seq v2, has a more streamlined workflow and an expanded DNA input range of 100 pg to 200 ng. Libraries made using NA12878 genomic DNA show improved yields, consistent global methylation and an even GC bias representation. The increased library yields subsequently reduces sequencing duplications and costs. Sequencing costs are an important consideration when performing whole genome methylome analysis as this often needs high sequencing depth to attain meaningful coverage to accurately call methylation. Reduced representation libraries, a commonly used method to investigate DNA methylation, relies on enrichment of CpGs within libraries digested using MspI. These CpGs are commonly found in regulatory regions. Although lacking comprehensive CpG coverage, for many researchers this method provides enough cost effective CpG methylation coverage for their studies. Reduced Representation EM-seq libraries (RREM-seq) and Reduced Representation Bisulfite libraries (RRBS) were made using 200 ng to 100 pg of NA12878 DNA. EM-seq adaptors were ligated to MspI digested DNA followed by conversion using either EM-seq v2 or sodium bisulfite. Libraries were PCR amplified and sequenced on an Illumina NovaSeq platform. RREM-seq resulted in higher yields and reproducible results regardless of input amounts compared to RRBS libraries. RREM-seq libraries also identified a higher number of CpGs with even coverage facilitating accurate methylation calling. RREM-seq libraries have superior sequencing metrics resulting in robust methylation profiling. Focusing on a subset of the genome generates higher coverage DNA methylation data at a lower DNA sequencing cost.
Citation Format: Vaishnavi Panchapakesa, Chaithanya Ponnaluri, Daniel Evanich, Ariel Erijman, Bradley Langhorst, Louise Williams. Whole genome and reduced representation enzymatic methyl-seq enable cost effective methylomes [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 7022.
Abstract 7041: Tumor-immune interactions and cisplatin resistance in localized muscle-invasive bladder cancer
Authors: De Carvalho Filipe La Fuente , Lee Jihyun , Bi Kevin , Titchen Breanna , Stawiski Konrad , Park Jihye , Garza Amanda , Michaud Daniel , Guerriero Jennifer , Mittendorf Elizabeth , Mouw Kent , Van Allen Eliezer 
Published: March 2024

Abstract
Background: Cisplatin-based chemotherapy followed by radical cystectomy remains the standard-of-care treatment for patient with localized muscle-invasive bladder cancer (MIBC). Neoadjuvant clinical trials studying the combination of cisplatin-based chemotherapy and immune checkpoint blockade (ICB) in MIBC reported encouraging pathologic complete response rates. However, the molecular mechanisms and cellular programs involved in response and resistance to cisplatin and ICB in MIBC remain incompletely characterized. Our goal is to define cellular transcriptional programs and chromatin accessible regions in cancer cells and infiltrating immune cells associated with response and resistance to neoadjuvant systemic therapy.
Methods: We performed single-cell Multiome ATAC and Gene expression sequencing (simultaneous identification of gene expression and open chromatin regions within the same cell) of tumors that had a complete response – “responders” – and tumors that had no response or progressed – “non-responders” – through neoadjuvant cisplatin-based chemotherapy (n=15). Single cell suspensions were prepared following the 10x Genomics protocol. Cell Ranger ARC was used for sequence alignment, peak calling, and generation of count matrices. Downstream single-cell gene expression analysis was performed with Scanpy and ATAC-seq with Seurat.
Results: We identified two distinct urothelial cell populations in "responders" vs "non-responders" based on single cell gene expression and genome wide chromatin accessibility regions. Cancer cells in “non-responders” preferentially express basal cell gene expression signatures. “Non-responders” were significantly enriched in suppressive tumor-associated macrophages (TAMs). Interestingly, SPP1+ TAMs known to have a pro-tumoral role and promote resistance to ICB were exclusively identified in “non-responders”.
Conclusion: Single cell and genome wide chromatin accessibility regions identify heterogenous urothelial cell populations expressing basal cell markers in tumors resistant to neoadjuvant cisplatin-based chemotherapy. “Non-responders” are significantly enriched with TAMs implicated in resistance to ICB. Future studies will better define the implications of these findings in cancer therapeutics for patients with MIBC.
Citation Format: Filipe La Fuente De Carvalho, Jihyun Lee, Kevin Bi, Breanna Titchen, Konrad Stawiski, Jihye Park, Amanda Garza, Daniel Michaud, Jennifer Guerriero, Elizabeth Mittendorf, Kent Mouw, Eliezer Van Allen. Tumor-immune interactions and cisplatin resistance in localized muscle-invasive bladder 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 7041.