bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2917: Purifying cancer-associated fibroblasts (CAFs) from glioblastoma and defining their role in therapeutic resistance
Authors: Sati Ankita , Mathur Aakriti , Lad Meeki , Saha Atul , Aghi Manish K. 
Published: March 2024

Abstract
Glioblastoma (GBM), a challenging brain tumor, necessitates the development of new therapies due to poor patient prognoses, with a median survival of 14-16 months. Standard of care, as established almost 20 years ago, remains to be surgical resection followed by chemotherapy and radiation and till date there is no defined standard of care for recurrent GBM, highlighting the urgent need for the development of novel therapies. Recent studies have implicated the tumor microenvironment in these poor prognoses. While cancer associated fibroblasts (CAFs) are a key cellular component of the microenvironment of many systemic tumors, their presence in GBM had been doubted until we recently developed intriguing data identifying cells in GBM that express fibroblast markers, have fibroblast-like morphology, and, most importantly, transcriptomically resemble CAFs from systemic cancers rather than other stromal cells that express similar surface markers such as pericytes (Jain et al. 2023). Similar to other solid cancers, GBM CAFs increase tumor growth and drive immunosuppression. The role of CAFs in regulating these processes could have significant implications in response to standard of care therapy as well as novel immunotherapies. While our initial CAF isolation had just 50% purity, we have developed a novel flow-sorting algorithm for CAF enrichment driven by our bioinformatic data. Through this protocol, we have successfully established, the first of its kind, a biobank of patient derived GBM CAFs with greater than 90% purity. These CAFs are now being utilized to investigate their contribution in conferring resistance to chemotherapy (Temozolomide) and radiotherapy. The CAFs are also being assessed for their role in suppressing T cell function and resistance to immunotherapies. In parallel, the origin of GBM CAFs and their development trajectory is being analyzed to find molecular markers to specifically target CAFs in the GBM microenvironment. The work put together will provide insight on mechanisms employed by CAFs in altering the GBM microenvironment and a basis for developing novel combination approaches, alleviating therapeutic resistance caused due to the presence of CAFs in the GBM microenvironment. The results of this study have the potential to significantly attenuate therapeutic resistance in GBM and provide much needed treatment options and improvement in survival, for what remains one of the most dismal diagnoses in the clinic.
Citation Format: Ankita Sati, Aakriti Mathur, Meeki Lad, Atul Saha, Manish K. Aghi. Purifying cancer-associated fibroblasts (CAFs) from glioblastoma and defining their role in therapeutic 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 2917.
Abstract 2929: Multiplexed somatic genome editing to model and investigate advanced colorectal cancer
Authors: Mastel Manuel , Jackstadt Rene , Meier Jasmin , Diamante Gabriele 
Published: March 2024

Abstract
Colorectal cancer (CRC) is among the deadliest cancers worldwide, with advanced CRC being the leading cause of death. For the development of novel therapy options, it is crucial to investigate mechanisms of advanced CRC in a bona fide way. However, little is known about the impact of distinct genomic alterations on cancer progression. The assessment of the function and role of the putative drivers in tumor progression via sequencing data remains challenging, due to the complexity and possible combinations of the candidates. Hence, genetically engineered mouse models (GEMMs) represent the mainstay for the investigation of the role of oncogenes and tumor suppressor genes in cancer progression. However, particularly in CRC, they are limited by imprecise modeling of cancer-associated changes, challenging scalability, and development of tumors in anatomically incorrect places. To tackle these issues, we developed SOmatic CRISPR-mediated genome Alterations of Tumor suppressors with Exploratory single cell Sequencing (SOCRATES) to analyze advanced CRC. We multiplexed CRISPR-Cas systems, packaged them into lentiviral particles, and delivered them to enterocytes via colonoscopy-guided submucosal injection. With this innovative approach, SOCRATES enables rapid and direct in vivo genome engineering for the modeling of advanced CRC with distinct mutational patterns and the investigation of the cancer cell states and tumor microenvironment (TME) upon editing the genes of interest. Similar to the Greek philosopher Socrates, who established a form of argumentized dialogue between individuals, SOCRATES facilitates the understanding of previously undiscovered communication between cancer cells and TME. We analyzed the influence of the most recurrent tumor suppressor mutations (Fbxw7, Ptprt, Arid1a, Atrx, Atm, Smad4, Pten) on the cancer cell state and TME in advanced CRC. Further, we created a TS-TME interaction atlas and revealed novel mechanistic insights into how the TS mutations rewire cell states and cell-cell communications. With this generated knowledge, SOCRATES will contribute to our understanding of complex tumor ecosystems and foster the improvement of diagnostic and therapeutic approaches.
Citation Format: Manuel Mastel, Rene Jackstadt, Jasmin Meier, Gabriele Diamante. Multiplexed somatic genome editing to model and investigate advanced 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 2929.
Abstract 2971: A cytosolic growth factor receptor serves as a convergent core of condensates for anabolic activity in cancer and senescence
Authors: Kim Taegyun , Choi Haebeen , Yoon Taeyoung , Kang Chanhee 
Published: March 2024

Abstract
Anabolic activity, driven by growth factor signaling, is essential for cellular activities, including cell growth, proliferation, and protein synthesis. Dysregulation of growth factor signaling has been implicated in numerous human pathological conditions, including cancer and aging. Interestingly, cancer cells and senescent cells - two completely different cell fates - are reported to have an increased anabolic activity. Here, we show endosomal condensation of a growth factor receptor as a molecular switch for such anabolic enhancement. Endosomal condensates of a growth factor receptor (ecGFR) exhibit liquid-liquid phase separation (LLPS), acting as a signaling hub locked in the ‘ON’ state by preventing their lysosomal degradation. Furthermore, we identify a regulatory circuit that operates in both cancer and senescence to facilitate the formation of ecGFR and its physicochemical properties. Pharmacological and genetic resolution of ecGFR corrects aberrant anabolism in cancer and senescence, thereby suppressing cancer growth and senescence-associated hyperinflammation in vitro as well as in vivo. Thus, our study provides a convergent anabolic core between cancer and senescence that could be exploited as a therapeutic vulnerability for human pathological conditions associated with aberrant anabolism.
Citation Format: Taegyun Kim, Haebeen Choi, Taeyoung Yoon, Chanhee Kang. A cytosolic growth factor receptor serves as a convergent core of condensates for anabolic activity in cancer and senescence [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 2971.
Abstract 2978: Extracellular ATP induced senescence in human lung cancer cells
Authors: Ward Ryan A. , Hunt Arabella , Anderson Nora , Chen Xiaozhuo 
Published: March 2024

Abstract
In tumors, extracellular ATP (eATP) concentrations are 1,000 to 10,000 times higher than is found in normal tissues and eATP is up taken through macropinocytosis leading to a large increase in intracellular ATP levels. eATP is also linked to the TGF-β signaling pathway as exocytosis of ATP is induced that is then used in an autocrine fashion activating the P2 × 7 purinergic receptor1. Through these mechanisms, eATP has also been recently shown to induce EMT, CSC formation, and drug resistance1. One of the mechanisms through which these processes may be induced is a senescent cell precursor2. Senescence is a generally irreversible epigenetically controlled process characterized by a complete exit from the cell cycle in response to either DNA damage, stressful conditions, or aging. Recent mounting evidence has shown that senescence can be a cancer promoting mechanism by entering this state in response to stress such as during chemotherapy, but they can utilize it to enhance their malignant capabilities, including the ability to escape their senescent state with heightened stem cell characteristics, which can lead to a higher chance of relapse after treatment2. Senescent cells have recently been named a hallmark of cancer3. This study shows the time dependent induction of a senescent like state in human lung cancer A549 cells after only 2 hours of treatment with 0.5mM eATP, the concentration found in the tumor microenvironment, through analysis of transcriptional markers using total polyA RNAseq as well as chromogenic and flow cytometric assays for senescence associated beta-galactosidase activity. Additionally, inhibitors of macropinocytosis and purinergic receptors have been used to gain insight into the mechanisms of action that this pathway takes. This demonstrates a novel use of ATP within the tumor microenvironment for aiding in cancer progression and drug resistance. After EMT, CSC formation, and drug resistance, senescence is added to the long list of eATP mediated cancer promoting processes.
1. Song J, Qian Y, Evers M, Nielsen CM, Chen X. Cancer Stem Cell Formation Induced and Regulated by Extracellular ATP and Stanniocalcin-1 in Human Lung Cancer Cells and Tumors. IJMS. 2022;23(23):14770. doi:10.3390/ijms232314770 2. Zhang D, Monteiro MJ, Liu J, Gu W. Mechanisms of cancer stem cell senescence: Current understanding and future perspectives. Clin Exp Pharma Physio. 2021;48(9):1185-1202. doi:10.1111/1440-1681.13528 3. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discovery. 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059
Citation Format: Ryan A. Ward, Arabella Hunt, Nora Anderson, Xiaozhuo Chen. Extracellular ATP induced senescence in human lung 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 2978.
Abstract 2990: Differential micro-RNA expression in circulating exosomes of pancreatic ductal adenocarcinoma patients
Authors: Kaur Rupinder , Bhoriwal Sandeep , Gautam Promod Kumar 
Published: March 2024

Abstract
Pancreatic ductal Adenocarcinoma (PDAC) is a highly lethal solid tumor with 5-year survival rate of 5-8%. Extracellular vesicles like exosomes circulating in the blood are crucial mediators of intracellular communication, immunomodulation and tumor progression. The microRNAs being the major cargo of exosomes, are the primary carriers of intracellular information. The role of exosomal-miRNA (exoMIR’s) in regulating the pathogenesis of tumors is well-established in oncology but its potential is still unexplored. To the best of our knowledge no study has yet explored the contrasting exoMIR expression in cancer patients before and after their surgery. In this study, differential exoMIR’s profile of three pancreatic ductal adenocarcinoma patients at three stages: pre-surgery, post-surgery, and follow-up was established using small RNA sequencing on the Illumina platform. In blood samples taken before and after surgery total of 181, 201 and 201 microRNAs were dysregulated in circulating exosomes of three different patients viz. P_1, P_9 & P_11 (Patient identifiers) respectively. Out of the total dysregulated microRNAs in post-op samples 76 were upregulated and 105 downregulated in P_1, 95 upregulated and 106 downregulated in P_9 & 69 upregulated and 132 downregulated in P_11 as compared to their Pre surgery samples. Further, when exoMIR’s of post-op samples were compared to that of follow-up samples after 6 months of surgery their expression profile changed notably such that a total of 184, 157 & 190 microRNAs dysregulated in follow-up of P_1, P_9 and P_11 respectively. Out of the total dysregulated microRNAs in follow up samples 93 were upregulated and 91 downregulated in P_1, 69 upregulated and 88 downregulated in P_9 & 96 upregulated and 94 downregulated in P_11 as compared to their post-op samples. On Venn diagram analysis 27 microRNAs were found to be commonly dysregulated in all 3 patients before surgery and 22 common micro RNAs were again dysregulated even after 6 months of surgery. Bioinformatic analysis of these
differentially expressed miRNAs and their respective protein targets revealed that their role in oncogenic molecular pathways is very prominent, thus highlighting their potential use in cancer therapeutics, diagnostics as well as prognosis.
Citation Format: Rupinder Kaur, Sandeep Bhoriwal, Promod Kumar Gautam. Differential micro-RNA expression in circulating exosomes of pancreatic ductal adenocarcinoma patients [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 2990.
Abstract 3015: HD-PTP mediates tumor suppression via modulation of anti-tumor immunity
Authors: Guo Chenxu , Sun Sheng , Thimmiah Nayana , Maccio Agustina , Koh Siang , Ellisen Leif 
Published: March 2024

Abstract
The role of circulating extracellular vesicles in cancer biology is an area of intense research interest. Here, we reveal a tumor suppressor mechanism of HD-PTP (His Domain Protein Tyrosine Phosphatase, encoded by PTPN23), a protein associated with ESCRT (endosomal sorting complex required for transport), a complex that controls endosome sorting and exosome secretion. While loss of HD-PTP is known to be tumorigenic in mice and is frequently observed in human cancers including Triple Negative Breast Cancer (TNBC), the relevant pathways have remained obscure. We find that inhibition of HD-PTP in vivo promotes tumor progression selectively in a syngeneic, immune-competent TNBC model but not in a matched immune-deficient model. Through systematic profiling of the exosomal proteome in HD-PTP proficient and deficient cells, we identify PD-L1 as a key exosomal cargo selectively enriched due to loss of HD-PTP. Mechanistically, we show that inhibition of HD-PTP results in PD-L1 stabilization, its co-localization with the exosomal marker CD63, the enrichment of endosomal PD-L1 and subsequent increase in ExoPD-L1 release. Exosomes produced post HD-PTP loss inhibits antigen-dependent T cell activity in vitro, and HD-PTP inhibition in a syngeneic TNBC model promotes non-cell-autonomous, exosome- and PD-L1-dependent tumor progression, associated with reduced T cell infiltration and altered macrophage polarization. Consistent with these findings, low HD-PTP levels in human solid tumors are associated with decreased tumor infiltrating lymphocytes, poor response to immune checkpoint inhibition and inferior overall survival. Taken together, our studies unveil a novel tumor suppressor pathway controlling PD-L1 trafficking and ExoPD-L1 secretion, highlighting the critical roles of HD-PTP and ESCRT in anti-tumor immunity.
Citation Format: Chenxu Guo, Sheng Sun, Nayana Thimmiah, Agustina Maccio, Siang Koh, Leif Ellisen. HD-PTP mediates tumor suppression via modulation of anti-tumor immunity [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 3015.
Abstract 3020: The tumor suppressive role of methylthioadenosine phosphorylase in melanoma
Authors: Hsiao Jennifer J. , Andreu-Perez Pedro , Kemény Lajos V. , Hejna Miroslav , Nsengimana Jérémie , Allouche Jennifer , Emran Abdullah Al , Bishop D. Timothy , Jönsson Göran B. , Newton-Bishop Julia , Song Jun , Fisher David E. 
Published: March 2024

Abstract
Methylthioadenosine phosphorylase (MTAP) is an enzyme that is expressed in virtually all tissues but lost in many cancers. MTAP deficiency can be due to either deletion of the MTAP gene or methylation of the MTAP promoter. In normal cells, MTAP catalyzes the conversion of methylthioadenosine (MTA), produced during polyamine biosynthesis, to adenine and 5-methylthioribose-1-phosphate, which is subsequently converted to methionine. MTAP deficiency results in intracellular accumulation of MTA. Although recent genome wide association studies (GWAS) have associated the MTAP locus with melanoma risk, the molecular mechanisms linking MTAP loss to increased tumorigenesis are not yet fully understood. In this study, we hypothesized that loss of MTAP and the resulting accumulation of MTA would dysregulate microphthalmia transcription factor (MITF), a master transcriptional regulator of melanocytes that is also an amplified or mutated oncogene in melanoma. We identify a novel signaling mechanism in which MTA accumulation from MTAP deficiency aberrantly induces MITF expression via inhibition of the cAMP phosphodiesterase PDE4D3 in melanocytes. Inhibition of PKA abolishes this MITF induction, suggesting that the PKA pathway is hyperactivated upon MTAP deficiency. Downregulation of MTAP leads to increased proliferation of melanoma cells in vitro and increased melanoma tumor growth in vivo. We also show that MTAP deficient melanoma cells are more resistant to the BRAF inhibitor vemurafenib and observe MTAP downregulation in BRAF inhibitor resistant melanoma clinical specimens. Furthermore, MTAP downregulation via decreased expression and/or genomic loss corresponds to significantly worse outcomes in early-stage cutaneous melanomas from multiple datasets, thereby identifying a clinically important sub-category of “thin-lethal” tumors.
Citation Format: Jennifer J. Hsiao, Pedro Andreu-Perez, Lajos V. Kemény, Miroslav Hejna, Jérémie Nsengimana, Jennifer Allouche, Abdullah Al Emran, D. Timothy Bishop, Göran B. Jönsson, Julia Newton-Bishop, Jun Song, David E. Fisher. The tumor suppressive role of methylthioadenosine phosphorylase in melanoma [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 3020.
Abstract 3034: Krüppel-like factors in regulation of gastric cancer progression
Authors: Kakkat Sooraj , Suman Prabhat , Goswami Sandeep , Basu Sujit , Heslin Martin J. , Turbat-Herrera Elba A. , Alcantara Veronica Ramirez , Sarkar Chandrani , Chakroborty Debanjan 
Published: March 2024

Abstract
Introduction: Gastric cancer (GC) is the third leading cause of cancer-associated mortality and the fifth most frequently diagnosed cancer worldwide. The development and progression of GC is a complicated multistage process subjected to dynamic changes in gene regulation. Investigating the effects of these changes is therefore critical for improving our knowledge about GC initiation and progression. Krüppel-like factors (KLFs) are evolutionarily conserved zinc finger-containing transcription factors with altered expressions and diverse regulatory functions in GC. We previously reported that there is loss of KLF4 in GC. Here we report that KLF4 is a crucial regulator of KLF5 expression and vice versa and together they regulate GC cell behavior.
Methods: The Cancer Genome Atlas (TCGA) and pan cancer data of differential expressions of KLFs in GC was analyzed. TCGA RNAseq and clinical data for the differential expression status of KLF genes in normal and cancerous tissues and the clinicopathological association was accessed from the UALCAN web portal. The expressions of KLF4 and KLF5 in human normal stomach and GC and orthotopic xenografts were detected by immunohistochemistry (IHC). KLF4, KLF5 cross regulation was evaluated by gene manipulation of each gene individually and checking the expression of the other factor in GC cells. The effect of KLFs on GC cell proliferation, migration, and invasion was determined by Ki67 staining of tissues, PrestoBlue cell viability assay, scratch wound and transwell cell invasion assays.
Results and Conclusion: Our results indicated that not only KLF4 and KLF5 have contrasting expressions and effects in GC but also these two factors cross regulate each other. While lower expressions of KLF4 was found in human GC and orthotopic xenografts, increased expression of KLF5 was found in both human GC tissue and orthotopic xenografts. KLF4 silencing and CRISPR/Cas9 knockdown in human GC cells resulted in increased expression of KLF5 which was associated with increased GC cell proliferation and invasiveness. Interestingly, KLF5 knockdown by CRISPR/Cas9 in human GC cells on the other hand resulted in increased expression of KLF4, which was associated with decreased GC cell growth. Our data therefore suggests that the differential expressions of KLF4 and KLF5 might serve as valuable prognostic markers in GC.
Citation Format: Sooraj Kakkat, Prabhat Suman, Sandeep Goswami, Sujit Basu, Martin J. Heslin, Elba A. Turbat-Herrera, Veronica Ramirez Alcantara, Chandrani Sarkar, Debanjan Chakroborty. Krüppel-like factors in regulation of gastric cancer progression [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 3034.