bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1671: Exploring the mechanism of PP2A regulated cell death via macropinocytosis in pancreatic cancer
Authors: Doraivel Indiraa , Baral Garima , Pfeffer Claire M. , Allen-Petersen Brittany L. 
Published: March 2024

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is the 4th leading cause of cancer-related death in the United States. KRAS is an oncogene mutated in 90% of PDAC patients. Oncogenic KRAS leads to aberrant cell proliferation and survival. KRAS is considered hard to target because resistance mechanisms to KRAS inhibitors are common highlighting the need to understand alternative strategies. PDAC tumor microenvironment evolves with cancer cell progression leading to vascular remodeling and blood vessel collapse. This makes the tumors nutrient deplete. To circumvent this, cells employ KRAS-dependent macropinocytosis- a nutrient scavenging pathway. Macropinocytosis is the process by which cells take up extracellular material by membrane ruffling to form vesicles which then fuse with lysosomes to release nutrients. Targeting KRAS-driven macropinocytosis can be crucial to limiting nutrients to the cell to prevent tumor growth. Protein Phosphatase 2A (PP2A), a heterotrimeric Serine/Threonine phosphatase, is a downstream regulator of KRAS. Its activity is repressed by mutated KRAS. We have seen that the activation of PP2A with small molecular activator, DT061, prevents macropinosomes from fusing with lysosomes which leads to cell death. But how DT061 regulated PP2A activity affects the macropinocytosis pathway is still unknown. The purpose of this study is to understand the mechanism of cell death brough upon by the activation of PP2A with DT061. Membrane ruffling is critical for the initiation of macropinocytosis. Rac is a GTPase usually involved with membrane ruffling. To show that Rac is needed for DT061 mediated macropinocytosis, we used EHT 1864, a Rac family inhibitor. Cells were treated with EHT 1864 before being treated with DT061 and stained with crystal violet. The inhibition of Rac prevented DT061 driven cell death, indicating that Rac is crucial to DT061 driven cell death. High molecular weight TMR-Dextran can only be taken up by the cells through macropinocytosis. Cells were treated with TMR-Dextran and EHT 1864. Cells with Rac inhibition showed lower uptake of TMR-Dextran than cells that were treated with DT061. Together these findings indicate to us that Rac plays a crucial role in the initiation of macropinocytosis and the regulation of cell death caused by the activation of PP2A. Understanding the pathway of DT061 mediated cell death can be vital to developing this concept as a therapeutic method of treatment for PDAC patients who currently have the lowest 5-year survival rate (12%) of all cancers.
Citation Format: Indiraa Doraivel, Garima Baral, Claire M. Pfeffer, Brittany L. Allen-Petersen. Exploring the mechanism of PP2A regulated cell death via macropinocytosis in pancreatic 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 1671.
Abstract 1677: The emerging role of the Plasminogen-Apple-Nematode (PAN) domain in cancer therapy
Authors: De Kuntal , Pal Debjani , Muchero Wellington 
Published: March 2024

Abstract
The Plasminogen-Apple-Nematode (PAN) domain, with a core of four to six cysteine residues, is found in more than 28,000 proteins across 959 genera. However, its role in protein function still needs to be elucidated. Numerous proteins initially characterized the PAN domain, including a well-known master regulator for cancer cell proliferation, HGF (Hepatocyte growth factor). Abnormal regulation of HGF-mediated signaling results in multiple deadly cancers. The binding of HGF to its cell surface receptor, c-MET, triggers signaling pathways, which leads to cancer. Here, we show that mutating four core cysteine residues in the HGF PAN domain reduces c-MET interaction, subsequent c-MET autophosphorylation, and phosphorylation of its downstream targets, perinuclear localization, cellular internalization of HGF and its receptor, c-MET, and c-MET ubiquitination. Furthermore, transcriptional activation of HGF/c-MET signaling-related genes involved in cancer progression, invasion, metastasis, and cell survival was impaired. Thus, targeting the PAN domain of HGF may represent a mechanism for selectively regulating the binding and activation of the c-MET pathway. Additionally, we found this domain in the tumor suppressor gene, MST1 (macrophage stimulating 1), and mutating the domain altered the protein function through protein stability and ubiquitination. In another study, we show that cysteine residues in the vestigial plasminogen-apple-nematode (PAN) domain of NRP1 are necessary for SARS-CoV-2 spike protein internalization. Mutating novel cysteine residues in the PAN altered NRP1 stability and downstream activation of the extracellular signal-regulated kinase (ERK) signaling pathway, impairing its interaction with the spike protein. These results show the diverse critical role of the PAN domain beyond cancer therapy.
Citation Format: Kuntal De, Debjani Pal, Wellington Muchero. The emerging role of the Plasminogen-Apple-Nematode (PAN) domain in cancer therapy [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 1677.
Abstract 1699: Defining the impact of aberrant transcription on the chromatin structure
Authors: Thomas Naiju , Reznicek Timothy E. , Aiden Erez Lieberman , Rowley M. Jordan , Wagner Eric , Nir Guy 
Published: March 2024

Abstract
Genome organization in humans is governed by two major mechanisms: loop extrusion by cohesin and CTCF and the spatial compartmentalization of the chromosomes. These folding mechanisms have been shown to regulate several genomic functions, including gene expression. However, how transcription might regulate the chromatin structure remains a subject of many ongoing investigations. In this study, we use the Integrator protein complex as a tool to understand the impact of aberrant transcription on the 3D structure of the genome. During transcription initiation, RNA Polymerase-II (Pol-II) often pauses proximally to the promoter before further elongating transcripts. The Integrator protein complex regulates this checkpoint by its endonuclease and phosphatase activity. This protein complex is essential in premature transcription termination in hundreds of protein-coding genes. It also facilitates the synthesis of non-coding (ncRNA), such as enhancer RNAs (eRNAs) and long non-coding RNAs (lncRNAs), which have been shown to support loop extrusion domains, and their absence may disrupt these domains. Using HiC sequencing, we found that depleting Integrator proteins can interfere with forming and maintaining loop domains. This study aims to be the first to decipher the relationship between chromosome structure and Integrator protein activity and address our very little knowledge of how misregulation of transcription termination may influence the folding of chromosomes.
Citation Format: Naiju Thomas, Timothy E. Reznicek, Erez Lieberman Aiden, M. Jordan Rowley, Eric Wagner, Guy Nir. Defining the impact of aberrant transcription on the chromatin structure [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 1699.
Abstract 175: Tumor-associated monocytes and neutrophils: Targets for immunotherapy
Authors: Jung Keehoon 
Published: March 2024

Abstract
Cancer is the leading cause of deaths worldwide. However, current anti-VEGF therapies for solid cancers provide limited survival benefit as tumors rapidly develop resistance to these agents.We have uncovered an immunosuppressive role for non-classical Ly6Clow monocytes that mediates resistance to anti-VEGFR2 treatment. We found that the chemokine CX3CL1 was upregulated in both human and murine tumors following the VEGF signaling blockade, resulting in recruitment of CX3CR1+ Ly6Clow monocytes into the tumor. We also found that treatment with VEGF-A reduced expression of CX3CL1 in endothelial cells. Intravital microscopy revealed that CX3CR1 is critical for Ly6Clow monocyte transmigration across the endothelium in tumors. Moreover, Ly6Clow monocytes recruit Ly6G+ neutrophils via CXCL5 and produce IL-10, which inhibits adaptive immunity. Preventing Ly6Clowmonocyte or Ly6G+ neutrophil infiltration into tumors enhanced inhibition of tumor growth with anti-VEGFR2 therapy. Furthermore, we developed a gene therapy using a nanoparticle formulated with a siRNA against CX3CL1, which reduced Ly6Clow monocyte recruitment and improved outcome of anti-VEGFR2 therapy.Taken together, we identified immunosuppressive non-classical Ly6Clow monocytes as key players in tumor resistance to anti-angiogenic therapy in cancers. We also revealed molecular mechanisms underlying anti-angiogenic treatment resistance, suggesting potential immunomodulatory strategies to enhance the long-term clinical outcome of anti-VEGF therapies, proven by state-of-the-art in vivo imaging modalities.
Citation Format: Keehoon Jung. Tumor-associated monocytes and neutrophils: Targets for immunotherapy [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 175.
Abstract 1802: Melanoma addiction to GCDH
Authors: Nadig Namratha , Verma Sachin , Ronai Ze'ev A. 
Published: March 2024

Abstract
Rewiring of metabolic pathways often underlies the malignant state, including melanoma. In our previous studies we have demonstrated melanoma addiction to Gutaryl Co-dehydrogenase (GCDH), an enzyme in the lysine catabolism pathway. Our studies revealed that blocking GCDH activity in melanoma, but not colon, lung or breast cancer cells, led to cell death which abolished growth both in culture and in vivo. Important cellular component which was found to mediate melanoma addiction to GCDH was the transcription factor NRF2, which exhibited tumor suppressor function upon GCDH inhibition. Notably, coinciding with NRF2 tumor suppressor role seen upon GCDH inhibition was its glutarylation, a post translational modification which acquired NRF2 stability and ability to induce transcription of ATF4, ATF3 and CHOP which led to extensive cell death program. Knockdown of NRF2, ATF3 or DTHDK-1 effectively blocked the cell death phenotype seen upon GCDH knockdown. Analyses of patient data confirmed that low GCDH expression coincided with prolonged survival of melanoma but not colon, breast or prostate cancer patients. These findings led us to perform an unbiased screen to identify cellular components, which underlie melanoma addiction to GCDH. The results of this analysis will be discussed.
Citation Format: Namratha Nadig, Sachin Verma, Ze'ev A. Ronai. Melanoma addiction to GCDH [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 1802.
Abstract 1806: Induction of KRAS G13D dimers as a therapeutic strategy for colorectal cancer
Authors: Angira Deekshi , Li anbo , Zhou Zhiwei , Lee Seungheon , Ready Joseph , Westover Kenneth 
Published: March 2024

Abstract
Colorectal cancer (CRC) is the third leading cause of cancer deaths. Most CRCs arise from polyps in the colon/rectum that acquire gene mutations, including frequent activation of the oncogene Kirsten rat sarcoma virus (KRAS) observed in 40% of cases, particularly at codons 12, 13, and 61. KRAS oligomerization is critical for MAPK pathway signaling, which drives CRC pathogenesis. This study evaluated compounds that bind mutant KRAS G13D to induce non-physiological dimerization. Screening of a 4.1 billion compound DNA-encoded library led to the identification of pyridinylpiperazine/quinoline compounds. These compounds demonstrated the ability to induce RAS dimer formation, subsequently reducing MAPK signaling, exhibiting similarities to BI-2852, which is known to induce formation of non-physiologic RAS dimers. Structure-activity studies yielded indole, piperidine, and morpholine variants showing improved activity in thermal shift assays (DSF) and in cell-based assays evaluating RAS signaling (p-ERK inhibition).
Citation Format: Deekshi Angira, anbo Li, Zhiwei Zhou, Seungheon Lee, Joseph Ready, Kenneth Westover. Induction of KRAS G13D dimers as a therapeutic strategy for 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 1806.
Abstract 1842: Global proteomics reveals integrin signaling as a driver of infiltration in glioblastoma
Authors: van Winden Lennart J. , Sajid Rifat Shahriar , Borhani Okty Abbasi , Kamski-Hennekam Evelyn Rose , Gopal Nakita , Leon Alberto , Diamandis Phedias 
Published: March 2024

Abstract
Background: Glioblastoma (GBM), a notably aggressive brain cancer, presents significant treatment challenges due to its propensity for deep, diffuse infiltration into healthy brain tissue. This trait enables GBM to resist and survive following surgery and conventional adjuvant therapies. Emerging evidence suggests that signaling between GBM stem cells (GSCs) may be instrumental in this invasive behavior. Our study aimed to unravel the intricacies of these intercellular communication networks within glioblastoma by employing comprehensive proteomic profiling across a diverse array of patient-derived GSC lines.
Methods: We conducted our study using a sex-stratified cohort comprising 17 patient-derived GSC lines. Proteomic profiling encompassed analyses of both GSC lysates and conditioned media under various oxygen conditions (normoxia at 20% O2, hypoxia at 1% and 0.2% O2). Additionally, we incorporated the glioma cerebral organoid (GLICO) system, facilitating co-cultures of GSCs with human cerebral organoids. For in-depth proteomic analysis, we utilized advanced TMT-based liquid chromatography-tandem mass spectrometry (LC-MS/MS; Q-Exactive, Thermo Fisher).
Results: Our findings corroborate that GSCs adhere to the tripartite model of proliferation, invasion, and hypoxic response. A salient discovery was the consistent enrichment of integrin signaling pathways in GSCs under hypoxic conditions. Specifically, we observed a significant association between upregulation in integrin signaling (BIOCARTA_INTEGRIN_PATHWAY) and elevated KRAS activity (SWEET_KRAS_TARGETS_UP: r=0.43, p&lt;0.01), as well as hypoxic responses (WINTER_HYPOXIA_UP: r=0.76, p&lt;0.0001) in GSCs. Notably, in the GLICO model, both integrin signaling and KRAS pathways were markedly upregulated in the presence of GSCs compared to cerebral organoids alone (p&lt;0.05).
Conclusions: This research highlights the pivotal role of integrin signaling in mediating the invasive attributes of glioblastoma. The data underscore the importance of further exploring key modulators within the integrin signaling pathway, presenting a promising avenue for the discovery of novel therapeutic targets in glioblastoma treatment.
Citation Format: Lennart J. van Winden, Rifat Shahriar Sajid, Okty Abbasi Borhani, Evelyn Rose Kamski-Hennekam, Nakita Gopal, Alberto Leon, Phedias Diamandis. Global proteomics reveals integrin signaling as a driver of infiltration in glioblastoma [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 1842.
Abstract 1849: High throughput interactome profiling of small bioactive peptides
Authors: Warren Charles D. , Yardeny Noah , Geri Jacob B. 
Published: March 2024

Abstract
Interactions between individual biomolecules give rise to emergent signaling and regulatory networks that govern complex and varied biological processes. Disruption of these finely tuned interactions can result in imbalanced cellular states that drive diseases; for example, many metastatic cancers become desensitized to checkpoints encoded by molecular contacts. Still, numerous interaction networks remain unmapped within the cell, namely those between cryptic endogenous peptides and their protein targets. This is primarily due to the lack of investigation around translation events that occur from “noncoding” genetic material and limited knowledge of how translated polypeptides can mature into functional proteolytic fragments. Moreover, technologies to map protein-peptide interactions in an efficient and reliable manner are limited, leaving a gap in knowledge of how many bioactive peptides regulate cellular homeostasis. We aim to map the interactions of short (30 &gt; amino acid), bioactive peptides that are (1) translated from noncanonical open reading frames or (2) generated through proteolytic cleavage of nascent proteins. To achieve these goals, we are leveraging the recently developed MicroMap technology and label-free mass spectrometry-based proteomics. A scalable and reliable platform to discover peptide binding targets will uncover the elusive functional roles of understudied endogenous peptides in cell signaling and their part in driving cancer cell survival.
Citation Format: Charles D. Warren, Noah Yardeny, Jacob B. Geri. High throughput interactome profiling of small bioactive peptides [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 1849.
Abstract 186: Tumor exosome-macrophage interactions: The role of tumor-associated glycans and scavenger receptor class A
Authors: Jousheghany Fariba , Blitz Emily S. , Jenkins Samir V. , Post Steven R. , Raj Vinay , Kore Rajshekar A. , Jamshidi-Parsian Azemat , Griffin Robert J. , Kelly Thomas J. , Monzavi-Karbassi Behjatolah 
Published: March 2024

Abstract
Introduction: Increased macrophage infiltration and polarization towards a breast tumor-supportive phenotype have been linked to therapy resistance, immune suppression, and poor patient prognosis. Despite their importance, the specific interactions that drive tumor-associated macrophage (TAM) polarization remain poorly understood. The class A scavenger receptor (SR-A) is a pattern-recognition receptor expressed by macrophages, and the accumulation of SR-A-expressing TAMs has been correlated with poor patient outcomes. Our preliminary data show that SR-A binds to tumor-associated glycans (TAGs) on the surface of breast cancer cells. However, how macrophages bind tumor cell ligands in the tumor microenvironment (TME) is not clear. Tumor-derived exosomes (TDEs) are secreted extracellular vesicles that resemble the tumor cell membrane, carrying cargo that may mediate an immune response within the TME. In this study, we investigated whether TDE glycans represent tumor cell-surface TAGs and whether TDEs interact with macrophages through SR-A.
Methods: TDEs were isolated from the murine breast cancer cell line (E0771) by ultracentrifugation of the cell culture medium and then sized and counted using nanoparticle tracking analysis and electron microscopy. The glycans present on the tumor cell surface and TDEs were characterized using plant lectins in flow cytometry and sandwich ELISAs. The isolated TDEs were then fluorescently labeled, and their binding to the murine macrophage cell line Raw 264.7 was assayed by flow cytometry and fluorescence microscopy.
Results: SR-A binds strongly to breast cancer cell lines, and a significant portion of the binding depends on the presence of cell surface N-linked glycans. Lectins reactive with sialylated and fucosylated terminal structures showed differential binding to tumor cells and TDEs. We observed that the glycan profiles of E0771 cells and exosomes isolated from E0771 cultures were similar. Our results indicate that TDEs interact with Raw 264.7 cells, and the interaction is mediated by SR-A.
Conclusions: TDEs released in the TME can potentially interact with TAMs through SR-A. The glycan profile of TDEs is representative of host cells and may contribute to SR-A-mediated interaction with TAMs.
Citation Format: Fariba Jousheghany, Emily S. Blitz, Samir V. Jenkins, Steven R. Post, Vinay Raj, Rajshekar A. Kore, Azemat Jamshidi-Parsian, Robert J. Griffin, Thomas J. Kelly, Behjatolah Monzavi-Karbassi. Tumor exosome-macrophage interactions: The role of tumor-associated glycans and scavenger receptor class A [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 186.
Abstract 1881: Screening of Rac1 and Cdc42 inhibitors as anti-metastatic compounds
Authors: González Jessica Colón , Fuentes María C. Santa María , Vlaar Cornelis , Dharmawardhane Suranganie 
Published: March 2024

Abstract
Metastasis is responsible for &gt;90% of cancer-related deaths and is a key cause of failure of cancer therapy. The development of effective targeted therapy to prevent and treat metastasis has been challenging. Homologous Rho GTPases Rac and Cdc42 are viable metastasis targets because they have a crucial role in the signaling pathways that regulate cell survival, proliferation, and migration, so dysregulation of these proteins leads to cancer progression and metastasis of diverse cancer types. Therefore, targeting these regulatory proteins results in anticancer and antimetastatic activity, as observed with our dual Rac/Cdc42 inhibitor, MBQ-167, in triple-negative breast cancer. MBQ-167 has an IC50 of ~100nM for Rac and Cdc42 activation inhibition and a GI50 of 130nM. MBQ-167 inhibits the binding of guanine nucleotides to Rac and Cdc42 with similar efficacy. The purpose of this study was to identify MBQ-167 derivatives with similar or greater efficacy and specificity, with a range of inhibitory mechanisms, that may be specific to the different guanine nucleotide exchange factors expressed in distinct cancer cell types. Currently, over 30 different compounds with potential Rac1 and Cdc42 inhibitory activity are being evaluated. So far, some of the evaluated compounds have shown comparable GI50 values to MBQ-167 in metastatic breast cancer cell lines. From this screening, CPV-337 was selected as a compound with a GI50 of ~55nM and ~70% Rac activation inhibition at 50nM, therefore being 2X more effective than our leading compound MBQ-167. However, evaluation of CPV-337 in the viability of the MCF-10 non-tumorigenic epithelial cell line demonstrated a GI50 of ~63nM, which is similar to that of breast cancer cells. Therefore, CPV-337 may have cytotoxic effects on breast cancer. We are continuing to screen the library of MBQ-167 derivatives in breast, pancreatic, lung, and prostate cancer cell lines.
Citation Format: Jessica Colón González, María C. Santa María Fuentes, Cornelis Vlaar, Suranganie Dharmawardhane. Screening of Rac1 and Cdc42 inhibitors as anti-metastatic compounds [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 1881.