bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5569: Mechano-chemical control of secretory cues regulating immune tolerance, survival and invasion in oral squamous cell carcinomas
Authors: Bareham Bethany R. , Dibble Matthew , Mouhib Leila , Arteagabeitia Aitor Bermejo , Mukhopadhyay Subhankar , Parsons Maddy 
Published: March 2024

Abstract
Tissue fibrosis and extracellular matrix (ECM) stiffening have been shown to promote tumor cell proliferation, metastasis, and chemoresistance in a range of cancers. Stiffness of the ECM can lead to changes in cancer cell behavior, including enhanced proliferation, activation of mechano-sensitive signaling pathways, and potential genomic damage, with implications for cancer progression and immune responses. Recent research suggests stiff matrix may also induce the release of tumor-derived small extracellular vesicles (sEVs) that promote tumor growth. Tumor-derived sEVs carry bioactive cargo, such as micro-RNAs (miRNAs) and DNA fragments, and function as a unique form of intracellular communication promoting cell survival, growth, and metastasis. Understanding these mechano-sensing mechanisms is essential for identifying potential targets in precision medicine for solid tumor treatment. However, the influence of tumor stiffness on secretory cues, and their subsequent role in immunomodulation and/or chemo-resistance has not been extensively studied.
This project aims to explore how tumor stiffness can alter cell responses to genotoxic stress and how these responses can perpetuate feedback to the immune system through the release of secretory cues such as sEVs. Here, we outline the isolation and characterization of tumor-derived sEVs obtained from culture media of oral squamous cell carcinoma (OSCC) spheroids, cultured at varying stiffness (0.2kPa-1.5kPa). In this project, we use OSCC lines that are either sensitive or resistant to cisplatin (HSC-3 and HN-5, respectively). To explore the immunomodulatory effects of these tumor-derived sEVs, we first established a consistent supply of CD206+ve macrophages differentiated from human induced pluripotent stem cells (iMacs), following the established protocol of Douthwaite et al (2021). iMacs were then treated with sEVs with their resulting immunophenotype, and activation assessed. These preliminary experiments provide a step towards understanding how the biophysical environment influences tumor cell resistance to therapy and how sEVs can modulate the relationship between cancer cells and macrophages.
Citation Format: Bethany R. Bareham, Matthew Dibble, Leila Mouhib, Aitor Bermejo Arteagabeitia, Subhankar Mukhopadhyay, Maddy Parsons. Mechano-chemical control of secretory cues regulating immune tolerance, survival and invasion in oral squamous cell carcinomas [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 5569.
Abstract 5584: Experimental ‘loss-of function’ annotation of STK11 mutations with prognostic and therapeutic implications (TNG260mutationfinder.com)
Authors: Ahronian Leanne G. , Shahagadkar Preksha , Flynn Lauren , Grove Lauren , Liu Shangtao , Meier Samuel R. , Shen Binzheng , Stowe Hannah , Wu Hsin-Jung , Yu Yi , Mignault Andre , Sienczylo Iga , DiBenedetto Heather , Fenoglio Silvia , Teng  
Published: March 2024

Abstract
Loss of function mutations in Serine Threonine Kinase 11 (STK11) occur in 15% of lung adenocarcinoma and have been shown to drive resistance to immune checkpoint blockade clinically, as well as in preclinical models. Though STK11 is commonly inactivated in human cancer with strong implications for treatment outcomes, few STK11 mutations identified from tumor samples have been functionally characterized.
TNG260 is an inhibitor of CoREST that is currently being investigated in combination with pembrolizumab for the treatment of STK11-mutant cancer (NCT05887492). Patients are eligible for enrollment in the TNG260 phase 1/2 trial if their tumor contains a deleterious STK11 mutation. To begin classifying non-annotated variants, over 2,000 distinct mutations in the STK11 gene were identified from STK11 literature or public repositories of tumor sequencing data such as AACR Project GENIE and ClinVar. Where possible, loss-of-function annotations were captured from literature or predictive tools such as PolyPhen-2. However, many STK11 variants, particularly missense mutations, have never been functionally characterized.
We developed a functional screening approach to characterize STK11 alterations using the lung adenocarcinoma cell line A549. A549 cells contain homozygous loss of STK11 via a truncation mutation at Q37, and re-expression of wild-type STK11 in these cells strongly impairs their growth in vitro and in vivo. We created a library of STK11 variant cDNAs, each containing a unique barcode. This library was expressed in A549, and cells were maintained in vitro or in vivo to allow for positive selection of STK11 loss-of-function variants and depletion of variants that behave like wild-type STK11. At the end of the screen, variants were quantified by NGS using each mutant cDNA’s unique barcode and compared to well-annotated controls.
These data were assembled to generate TNG260mutationfinder.com – the first website to curate STK11 variants with functional annotations.
Citation Format: Leanne G. Ahronian, Preksha Shahagadkar, Lauren Flynn, Lauren Grove, Shangtao Liu, Samuel R. Meier, Binzheng Shen, Hannah Stowe, Hsin-Jung Wu, Yi Yu, Andre Mignault, Iga Sienczylo, Heather DiBenedetto, Silvia Fenoglio, Teng. Experimental ‘loss-of function’ annotation of STK11 mutations with prognostic and therapeutic implications (TNG260mutationfinder.com) [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 5584.
Abstract 5598: Combined loss of the chromosome 7 genes CUX1 and EZH2 promotes chemotherapy resistance
Authors: Jotte Matthew R. , Stoddart Angela , Martinez Tanner C. , Xue Yuqing , Imgruet Molly K. , McNerney Megan E. 
Published: March 2024

Abstract
Monosomy 7 (-7) or del(7q) are recurrent in high-risk myeloid neoplasms, including up to 50% of myeloid neoplasms arising after prior exposure to chemotherapy and/or radiation. Although putative chromosome 7 tumor suppressor genes have been identified, the effects of combinatorial 7q gene loss remain unclear. A barrier to understanding the pathogenesis of -7/del(7q) is the challenge of modeling aneuploidy in animal models. To address this knowledge gap, we established an in vivo model of del(7q) clonal hematopoiesis and drug resistance using multiplex CRISPR-Cas9 to simultaneously target four 7q genes (Cux1, Ezh2, Kmt2c, and Kmt2e) in murine hematopoietic stem cells. After chemotherapy exposure, we observe significant myeloid expansion of clones edited for both Cux1 and Ezh2. Compared to the transcriptomes of control or single gene edited cells, Cux1;Ezh2-deficient cells fail to induce DNA damage response pathways after genotoxic stress. Cux1;Ezh2-deficient cells also display reduced deposition of γH2AX after DNA damage, as well as persistent, unrepaired DNA breaks, indicating perturbations to DNA damage recognition and repair. Collectively, our data support the concept of 7q as a contiguous gene syndrome region, in which combined loss of multiple genes drives drug resistance and disease development. This work reveals a genetic interaction between CUX1 and EZH2, and sheds light on how -7/del(7q) contributes to the development and inherent drug resistance characteristic of high-risk myeloid disease. Further, our CRISPR-based approach may serve as a framework for interrogating other recurrent aneuploid events in cancer.
Citation Format: Matthew R. Jotte, Angela Stoddart, Tanner C. Martinez, Yuqing Xue, Molly K. Imgruet, Megan E. McNerney. Combined loss of the chromosome 7 genes CUX1 and EZH2 promotes chemotherapy resistance [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 5598.
Abstract 5599: Role of HOX gene expression in differentiation of colon cancer stem cells
Authors: Osmond Brian T. , Facey Caroline O. , Opdenaker Lynn O. , Zhang Chi , Boman Bruce M. 
Published: March 2024

Abstract
HOX genes encode a highly conserved set of transcription factors critical for stem cell (SC) function and embryonic development. Several HOX genes have also been implicated in a myriad of cancers, including colorectal cancer (CRC). However, how HOX genes play a role in SC regulation and contributes to cancer development is unclear. HOX expression is regulated by WNT, FGF, and retinoic acid (RA) signaling - pathways which also become dysregulated in cancer. Goal: To determine how regulation of HOX genes specifies differentiation of colonic SCs into specialized cell lineages and how dysregulation of HOX genes contributes to CRC development. Hypotheses: i) Each of the different cell types within human colonic epithelium has a distinct HOX gene expression signature; ii) All-trans retinoic acid (ATRA) induced differentiation of CRC cells changes HOX expression that correlates with specific HOX expression signatures in normal colon and CRC cells. Results: Immunostaining shows that specific HOX proteins (e.g., HOXA9 & HOXC9) are selectively expressed in ALDH-positive SCs and expression of these HOX genes is increased in CRC tissues compared to normal epithelium. Bioinformatics analysis predicted that these HOX genes (plus HOXA4, HOXA10, HOXC8) are regulated by RA signaling. Accordingly, we studied how ATRA influences HOX expression in CRC cells (HT29 & SW480). We found ATRA treatment: 1) Decreases proliferation and increases neuroendocrine cell (NEC) differentiation; and 2). Leads to specific changes in HOX gene expression patterns. Using NanoString profiling, we also discovered that LGR5+ SCs, ALDH+ SCs and GLP2R+ NECs have unique HOX signatures. By defining how these HOX gene expression changes in response to ATRA treatment in comparison to the HOX gene signatures of different colonic cell lineages will help us understand the role that HOX genes play in SC differentiation and how dysregulation of HOX gene expression contributes to CRC development.
Citation Format: Brian T. Osmond, Caroline O. Facey, Lynn O. Opdenaker, Chi Zhang, Bruce M. Boman. Role of HOX gene expression in differentiation of colon cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5599.
Abstract 5626: Essential role of Slug during the evolution of drug-tolerance in lung adenocarcinoma
Authors: Ostendorp Jenny , Tumbrink Hannah Lea , Hunold Pascal , Hoehne Michaela , Jurmeister Philipp , Dekker Anastasia , Heisel Felix , Brägelmann Johannes , Klauschen Frederick , Haensel-Hertsch Robert , Sos Martin L. 
Published: March 2024

Abstract
A major obstacle in the efficacy of targeted therapies of oncogene-driven tumors are drug-tolerant persister cells (DTPs) that build the basis for the outgrowth of drug-resistant clones and ultimately limit patient survival. During treatment, DTPs enter a reversible senescent state to survive therapy while cell death is induced in non-DTPs. Here, using RNA-Seq and proteomic analyses, we identified drug-induced TGFβ2 secretion in DTPs derived from different oncogene-driven lung cancer cell lines. As expected, TGFβ2 induces epithelial-to-mesenchymal transition (EMT) that over time promotes the ability of cells to survive targeted therapy. Using CRISPR/Cas9-mediated loss-of-function and reconstitution experiments we show that downstream of TGFβ2, expression of the transcription factor SNAI2 (SLUG) is essential for the outgrowth of DTPs during targeted treatment. Unsupervised RNA-Seq data analyses in combination with Cut&Tag profiling revealed that EMT signaling is in part a SLUG regulated process but that is also independent of direct SLUG binding at the transcription start sites (TSS) of EMT signature genes. In contrast, we observed high occupancy of SLUG at TSS of genes involved in the regulation of cell cycle, being repressed in DTPs and at TSS of genes that regulate sphingolipid metabolism and MAPK signaling, being induced in DTPs. In line with our previous findings, a motif-based analysis of the Cut&Tag data (TOBIAS) furthermore uncovered a tight connection between DTP outgrowth and inflammatory signaling induced through IRF7, IRF4 or STAT1 activation. In vivo, EGFR-mutant SLUG deficient cells showed a significantly prolonged tumor onset and a higher response rate to osimertinib treatment. Overall, we uncover a major role of TGFβ2/SLUG-mediated EMT signaling that may be induced indirectly through SLUG-dependent reprogramming of cell cycle directed and metabolic processes in drug tolerant cells. These insights may offer unique therapeutic opportunities to limit the outgrowth of drug resistant tumors in cancer patients.
Citation Format: Jenny Ostendorp, Hannah Lea Tumbrink, Pascal Hunold, Michaela Hoehne, Philipp Jurmeister, Anastasia Dekker, Felix Heisel, Johannes Brägelmann, Frederick Klauschen, Robert Haensel-Hertsch, Martin L. Sos. Essential role of Slug during the evolution of drug-tolerance in lung adenocarcinoma [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 5626.
Abstract 564: Therapeutic targeting of JAK/STAT signaling and histone acetyltransferase activity in post-myeloproliferative neoplasm secondary AML
Authors: Bertulfo Kalay , Debackere Koen , Miller Hannah , Ma Cindy , Najac Ryan , Ferrando Adolfo , Palomero Teresa 
Published: March 2024

Abstract
Post-myeloproliferative neoplasm secondary Acute Myeloid Leukemia (Post-MPN sAML) is an aggressive and lethal hematologic malignancy arising from myeloproliferative neoplasms (MPN). Hyperactivation of JAK/STAT signaling was identified in 50-90% of MPNs - underscoring its role in driving MPN pathogenesis and transformation to post-MPN sAML. Ruxolitinib, a Type-I JAK2 inhibitor approved for the treatment of myelofibrosis, was tested in a Phase II clinical trial in post-MPN sAML. The trial revealed that ruxolitinib improved the quality of life in patients but was not disease-modifying. Thus, there is an urgent need to find synergistic drug combinations capable of complementing the therapeutic activity of JAK2 inhibitors in post-MPN sAML. Here, we demonstrate that combination treatment of ruxolitinib and CBP30, a bromodomain inhibitor of histone acetyltransferases (HAT) CBP and p300, enhances the therapeutic activity of ruxolitinib in post-MPN sAML. Genome-wide CRISPR loss-of-function screens in JAK2-mutated HEL cells determined that knockout of CBP sensitizes leukemic cells to JAK2 inhibitors. Consistently, functional validation through CRISPR/Cas9 demonstrated that genetic deletion of CBP but not of p300 renders HEL cells sensitive to ruxolitinib treatment. Pharmacologic inhibition of JAK/STAT signaling and HAT activity through ruxolitinib and CBP30 treatment in post-MPN sAML lines HEL and SET2 decreases proliferation and induces apoptosis and cell cycle arrest. Mechanistically, the synergism between ruxolitinib and CBP30 elicits a unique transcriptome profile in HEL with significant downregulation of E2F and MYC targets. In addition, epigenetic profiling revealed that the synergism induces global changes in H3K27ac signals with downregulation and upregulation of H3K27ac signals in predicted STAT5/BCL3 and GATA-bounded regions, respectively. Remarkably, combination treatment of ruxolitinib and CBP30 in HEL luciferase NSG mouse xenografts showed significant leukemia regression and decrease in spleen size compared to mice treated with vehicle or single agents. Overall, these results substantiate the potential of targeting JAK/STAT signaling and histone acetyltransferase activity in the treatment of post-MPN sAML.
Citation Format: Kalay Bertulfo, Koen Debackere, Hannah Miller, Cindy Ma, Ryan Najac, Adolfo Ferrando, Teresa Palomero. Therapeutic targeting of JAK/STAT signaling and histone acetyltransferase activity in post-myeloproliferative neoplasm secondary AML [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 564.
Abstract 5670: CRISPR-Mediated knockout of Ceruloplasmin (CP) and UCHL1 reveals angiogenic role in renal cell carcinoma (RCC) cell survival and proliferation
Authors: Caravan Wagma , Wu Yige , Lal Preet , Sato Kazu , Li Yize , Deen Nataly Naser Al , Chen Siqi , Abedin Ateih , Chen Feng , Ding Li 
Published: March 2024

Abstract
Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma, accounting for approximately 70% of all cases. Therapeutic treatment for metastatic ccRCC involve tyrosine kinase inhibitors or mTOR inhibiters. While these drugs extend patient survival, it also introduces a range of adverse side effects. Utilizing snRNA sequencing, snATACseq, and spatial transcriptomics, two potential ccRCC tumor specific markers have been identified: ceruloplasmin (CP) and UCHL1. These markers are notably overexpressed in a majority of ccRCC tumor cells and elevated CP levels have been correlated with reduced patient survival. To investigate the roles of CP and UCHL1 in ccRCC, CRISPR-based knockout experiments were conducted on two RCC cell lines, namely RCC4-VHL- and Caki-1. Through cell line characterization assays, we find that the absence of CP and UCHL1 impairs the cells' capabilities to migrate, proliferate, and adhere. Additionally, Cell-Derived Xenografts (CDX) of the knockout cell lines in nude mice revealed that cells lacking UCHL1 exhibited slower tumor growth compared to their parental lines. Bulk RNA sequencing further suggested a potential interrelationship between CP and UCHL1, as CP knockout cells showed increased UCHL1 expression relative to the parental line. These findings open new avenues for potential therapeutic strategies and biomarkers in the treatment and screening of ccRCC and further elevates our understandings of the roles of CP and UCHL1 in RCC tumor progression.
Citation Format: Wagma Caravan, Yige Wu, Preet Lal, Kazu Sato, Yize Li, Nataly Naser Al Deen, Siqi Chen, Ateih Abedin, Feng Chen, Li Ding. CRISPR-Mediated knockout of Ceruloplasmin (CP) and UCHL1 reveals angiogenic role in renal cell carcinoma (RCC) cell survival and proliferation [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 5670.
Abstract 5729: ADCK1 inhibition alters cell proliferation and cell cycle progression in liver cancer cells
Authors: Jacquet Noel A. , Zhao Yunfeng 
Published: March 2024

Abstract
In 2020, there were over 830,000 reported liver cancer deaths. Incidence rates of liver cancer have tripled, and death rates have doubled since the 1980s; giving this disease one of the highest mortality rates when compared to its incidence rate. Hepatocellular carcinoma (HCC) is derived from hepatocytes and is the main type of liver cancer in adults, accounting for 75-85% of all primary liver cancers. Current treatment options for HCC like radiation therapy and chemotherapy are imperfect and cause significant side effects. Tumorigenesis is dependent on an organism’s cellular metabolism. Metabolic reprogramming is a promising area of focus for cancer therapeutics. Cancer cells thrive in nutrient-deficient environments by hijacking and reprogramming the cells existing cellular metabolism. Metabolic reprogramming is driven by genetic alterations and environmental cues. AarF Domain Containing Kinase 1 (ADCK1) is a protein-coding gene that acts as a mitochondrial protein with putative kinase activity. The role of ADCK1 has not been well studied, particularly in liver cancer. Our group has sought to study how ADCK1 impacts the metabolism and cellular environment of HCC cells to help establish a more effective drug target. Bioinformatics performed by our lab report that ADCK1 was highly expressed in HCC tumor cells. The expression levels of ADCK1 were also correlated with a decrease in patient survival. ADCK1 knockout clones were generated; these knockout cells showed decreased proliferation and altered cell cycle progression. Proteomics analysis demonstrated that loss of ADCK1 was also seen to alter the expression of proteins involved in several cellular processes related to the cell cycle and cellular metabolism. How ADCK1 regulates these processes will be studied in the future.
Citation Format: Noel A. Jacquet, Yunfeng Zhao. ADCK1 inhibition alters cell proliferation and cell cycle progression in liver cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5729.