bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1229: Deciphering molecular mechanisms of metastasis in renal cell carcinoma
Authors: Arner Emily Nicole , Wolf Melissa M. , Vlach Logan , Sih Vania J. , Greenwood Dalton L. , Haake Scott , Rathmell Jeffrey C. , Rathmell Kimryn 
Published: April 2023

Abstract
Across human cancer, tumors that are high grade, poorly differentiated, and have undergone epithelial-to-mesenchymal transition (EMT) carry a worse prognosis with a high likelihood of metastasizing to distant organs. Despite significant research efforts, metastatic cancers and relapse remain the primary cause of cancer related deaths. In renal cell carcinoma (RCC), metastasis is present in one-third of patients at the time of diagnosis, and one-third of patients who initially present with locally advanced disease eventually develop local or distant recurrence following resection of the primary tumor, highlighting the need for new RCC therapies and further insight into the metastatic process. Using patient biopsies, immunohistochemistry, sequencing, and available clinical data in a cohort of RCC patients, we found that patients with more epithelial tumors have a significantly lower risk of recurrence. Unexpectedly, patients whose tumors had a mesenchymal protein signature had significantly increased infiltration of macrophages within their tumors. Additionally, increased macrophages in the primary tumor were significantly associated with a higher tumor stage at diagnosis and worse overall survival, suggesting that macrophages may play an important role in EMT in ccRCC. Furthermore, whole exome sequencing revealed that patients with increased macrophage infiltrate had a mutational loss of SETD2, a histone methyltransferase. Additionally, macrophages and EMT are also correlated, and tumor cell adhesion is reduced when SETD2 is lost in ccRCC patients. Further studies are needed to determine if SETD2 loss plays a role in the recruitment of macrophages to the tumor and EMT. Further characterization of the gene signatures, metabolic phenotypes, and immune cell infiltrate within these patient samples will lead to a better understanding of metastasis in an oncogene- and tissue-specific manner and thus lead to more efficacious therapies for metastatic patients.
Citation Format: Emily Nicole Arner, Melissa M. Wolf, Logan Vlach, Vania J. Sih, Dalton L. Greenwood, Scott Haake, Jeffrey C. Rathmell, Kimryn Rathmell. Deciphering molecular mechanisms of metastasis in renal cell carcinoma [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 1229.
Abstract 1296: Targeting nuclear AURKA and hypoxia signaling pathway attenuates metastatic burden in triple negative breast cancer
Authors: Maskey Abha , Whately Kristina Marinak , Pugacheva Elena N. 
Published: April 2023

Abstract
Despite remarkable progress in diagnosis and treatment, metastasis from the primary tumor to distant organs is responsible for over 90% of cancer deaths. Therefore, there is a need to understand the drivers of the process to detect, target, and develop therapeutics to treat metastases better and extend their lifespan. Aurora-A Kinase (AURKA) is a serine/threonine kinase that typically localizes in the cytoplasm. However, the nuclear localization of AURKA (N-AURKA) has been reported in multiple cancers and correlates with poor survival and the advanced/metastatic stage of the disease. AURKA is often present in the nucleus of metastatic Triple Negative Breast Cancer (TNBC) cells and patient biopsies compared to non-metastatic cells. Moreover, induced translocation of AURKA to the nucleus in experimental models of TNBC results in a 5-fold increase in metastases to the bones, lungs, and liver compared to AURKA in the cytoplasm. We have previously shown that N-AURKA under normoxic conditions binds to HIF1A/1B and leads to induction of hypoxia signaling via transactivation of Hypoxia Inducible Factors (HIFs)-dependent genes, including migration/invasion, survival/death, and stemness, promoting early cancer dissemination. Transactivation of HIF1-genes requires cofactor p300/CBP. It is currently unknown if N-AURKA/HIF1 transcription is p300 dependent. In this study, we used the small molecular inhibitor Chetomin to disrupt the interaction of HIF1A and co-activator CBP/p300 in experimental TNBC and animal models combined with AURKA inhibitor Alisertib. Disruption of the hypoxia signaling pathway significantly decreases the transactivation of HIF-dependent genes, including migration/invasion, survival/death, and stemness in N-AURKA cells. Moreover, in mouse models, inhibition of HIF1 activity via treatment with Chetomin in combination with AURKA inhibitor Alisertib significantly decreased metastatic burden suggesting that p300 binding to AURKA/HIF complex is critical for gene expression and enabling metastatic dissemination/colonization. Our studies show the mechanistic relationship between N-AURKA and hypoxia signaling and lay the foundation for developing novel combination treatment strategies to improve patient outcomes.
Citation Format: Abha Maskey, Kristina Marinak Whately, Elena N. Pugacheva. Targeting nuclear AURKA and hypoxia signaling pathway attenuates metastatic burden in triple negative breast cancer [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 1296.
Abstract 1354: Proteasome activation prevents T cell exhaustion and improves antitumor activity
Authors: de Blas Ander , Andreatta Massimo , Antoñana-Vildosola Asier , Velasco Paloma , Egia-Mendikute Leire , Jimenez-Lasheras Borja , Zanetti Samanta Romina , Carmona Santiago J. , Prieto-Fernández Endika , Palazon Asis 
Published: April 2023

Abstract
Tumor infiltrating lymphocytes (TILs) exert their antitumor activity in the tumor microenvironment (TME). Chronic TCR stimulation, together with features of the tumor microenvironment such as hypoxia, result in T cell exhaustion. Exhausted T cells (TEX) are characterized by oxidative stress that leads to cellular accumulation of oxidized proteins. Because the proteasome complex clears oxidized proteins, we hypothesized that its capacity might be overloaded in TEX, limiting their fitness.
Analysis of single-cell transcriptomics data from 19 tumor types indicated an increased proteasome activity in TEX compared to non-exhausted TILs. Higher levels of ROS-induced protein oxidation, expression of proteasome genes and proteasome activity were confirmed in human TEX, suggesting that increased proteasome activity might be a compensatory mechanism to exhaustion-associated oxidative stress. We show that pharmacological activation of the proteasome prevented T cell exhaustion, and lead to superior anti-tumor control in the context of adoptive cell therapy in mouse models. Thus, modulation of the proteasome activity is an attractive strategy to prevent T cell dysfunction promoted by the TME, and to potentially overcome this major obstacle in cancer immunotherapies against solid tumors.
Citation Format: Ander de Blas, Massimo Andreatta, Asier Antoñana-Vildosola, Paloma Velasco, Leire Egia-Mendikute, Borja Jimenez-Lasheras, Samanta Romina Zanetti, Santiago J. Carmona, Endika Prieto-Fernández, Asis Palazon. Proteasome activation prevents T cell exhaustion and improves antitumor 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 1354.
Abstract 1356: The tumor immune microenvironment of recurrent nasopharyngeal carcinoma
Authors: Ma Jingyi , James Anne , Poh Jolene , Chua Magdalene Jahn May , Poh Qianhui , Alsagoff Sharifah Azzah Binte Syed Mohamad Anis , Sam Xinxiu , Tan Geksan , Lim Chekang , Selvarajan Sathiyamoorthy , Lim Tony Kiat Hon , Mong Jamie Chen Yee , Lim Chweeming 
Published: April 2023

Abstract
Nasopharyngeal carcinoma (NPC) is endemic in southern China and Southeast Asia. While primary tumors respond well to radiotherapy with or without chemotherapy, the management of recurrent/metastatic (RM) diseases is a challenge. What contributes to the refractoriness of RM NPC remains to be elucidated. In this study, we recruited patients who developed local recurrences or distal metastases. Gene expression profiles of tumor cells, tumor stroma and tumor-infiltrating immune cells in paired primary and RM NPC samples were obtained by targeted mRNA sequencing techniques. It was found that RM NPC, compared to their primary compartment, showed significant enrichment of immune cell-related gene signatures. This was associated with an altered immune cell composition, with enhanced T cell activation and exhaustion coupled with an M2-skewed macrophage population. Together, these data depict a more inflamed yet immunosuppressive microenvironment of RM NPC and highlight macrophages being a potential target to reinvigorate antitumoral immune responses.
Citation Format: Jingyi Ma, Anne James, Jolene Poh, Magdalene Jahn May Chua, Qianhui Poh, Sharifah Azzah Binte Syed Mohamad Anis Alsagoff, Xinxiu Sam, Geksan Tan, Chekang Lim, Sathiyamoorthy Selvarajan, Tony Kiat Hon Lim, Jamie Chen Yee Mong, Chweeming Lim. The tumor immune microenvironment of recurrent nasopharyngeal carcinoma [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 1356.
Abstract 1431: Sprouty 2 expression attenuates proliferation in nras-driven acute myeloid leukemia cell lines
Authors: Roberts Michael , Bahadur Sher , Albitz Coltin , Chung Jae , Garcia Samantha , Nguyen Cuong , Kovatsis Sophia 
Published: April 2023

Abstract
Oncogenic mutations in the NRAS gene are found in many cancers including a subset of acute myeloid leukemias (AML). Established AML cell lines exhibiting hyperactive signaling through the RAS-RAF-MEK-ERK pathway show constitutive ERK activation generating a transcriptome that mediates escape from programmed cell death and continuous proliferation. It has been established that exposure of many AML cell lines to phorbol esters such as phorbol-12-myristate-13-acetate (PMA) mediates cell cycle arrest, myeloid differentiation, and apoptosis. This effect seems counterintuitive given that PMA irreversibly activates protein kinase C (PKC), which enhances ERK activity leading to transcriptional upregulation of target genes controlled by ERK activated transcription factors, many of which promote proliferation. Here we define a set of PMA response genes in AML cell lines driven by oncogenic NRAS that encode negative regulators of RAS-RAF-MEK-ERK signaling, including SPRY2, RASA1, DUSP 5, and DUSP6. Additionally, we show that overexpression of SPRY2 alone attenuates proliferation by inhibiting ERK activation and altering the AML cell transcriptome through the activation of genes encoding members of the AP-1 transcription factor family, FOS, JUNB, and JUND, and the cyclin-CDK inhibitors CDKN1A and CDKN2B. We hypothesize that oncogenic NRAS signaling is overridden by PMA treatment through the activation of ERK target genes that ultimately inhibit the MAPK-ERK pathway, such as SPRY2. Finally, we show that SPRY 2 expression in AML patient samples represents a survival prognostic indicator where higher expression levels correlate with improved overall survival.
Citation Format: Michael Roberts, Sher Bahadur, Coltin Albitz, Jae Chung, Samantha Garcia, Cuong Nguyen, Sophia Kovatsis. Sprouty 2 expression attenuates proliferation in nras-driven acute myeloid leukemia cell lines [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 1431.
Abstract 1454: SMAD3 promotes expression and activity of the androgen receptor in prostate cancer
Authors: Jeon Hee-Young , Pornour Majid , Ryu Hyunju , Khadka Sudeep , Xu Rui , Jang Jihyun , Li Deqiang , Chen Hegang , Hussain Arif , Fazli Ladan , Gleave Martin , Dong Xuesen , Wang Qianben , Barbieri Christopher , Qi Jianfei 
Published: April 2023

Abstract
Overexpression of the androgen receptor (AR) is the primary cause of development of castration-resistant prostate cancer (CRPC), although mechanisms upregulating AR transcription in this context are not well understood. Our RNA-seq analysis revealed AR as the top pathway altered after SMAD3 knockdown in prostate cancer cells. SMAD3 knockdown decreased levels of AR, AR-V7 and AR target gene transcripts, whereas SMAD4 or SMAD2 knockdown had little or no effect. ChIP-seq analysis showed that SMAD3 knockdown decreased global binding of AR to chromatin. Mechanistically, we show that SMAD3 binds to intron 3 of the AR gene to promote AR expression. Targeting these binding sites by CRISPRi reduced transcript levels of AR and AR targets. In addition, ~50% of AR or SMAD3 ChIP-seq peaks overlapped, and SMAD3 may also cooperate with or co-activate AR in terms of AR target expression. Functionally, AR re-expression in SMAD3-knockdown cells partially rescued AR target expression and cell growth defects. AR and SMAD3 mRNAs were upregulated in datasets of metastatic prostate cancer and CRPC compared with primary prostate cancer. This study suggests that SMAD3 could be targeted to downregulate AR expression and activity and as potential anti-prostate cancer therapy.
Citation Format: Hee-Young Jeon, Majid Pornour, Hyunju Ryu, Sudeep Khadka, Rui Xu, Jihyun Jang, Deqiang Li, Hegang Chen, Arif Hussain, Ladan Fazli, Martin Gleave, Xuesen Dong, Qianben Wang, Christopher Barbieri, Jianfei Qi. SMAD3 promotes expression and activity of the androgen receptor in prostate cancer [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 1454.
Abstract 1458: The PAX5 transcription factor is a suppressor of NFAT-mediated breast cancer aggressivity
Authors: Després Félix , Robichaud Damien , Hannay Brandon , Robichaud Gilles A. 
Published: April 2023

Abstract
Breast cancer metastasis is responsible for 90% of deaths associated with the disease. The understanding of mechanisms driving metastasis is thus vital to mitigate mortality rates and improve patient outcome. One of these mechanisms essential for breast cancer malignancy is the activation of the Nuclear Factor of Activated T cells (NFAT) pathway. Recently, we have reported that the PAX5 transcription factor induces breast cancer cell epithelialization, which in turn extinguishes mesenchymal transitioning, malignant features, and tumor progression. Our preliminary findings also suggests that PAX5 may negatively regulate NFAT-dependant pathways to modulate breast processes and potentially disease progression. We therefore hypothesized that PAX5 suppressed breast cancer malignancy through the targeted inhibition of the pro-malignant NFAT pathway. Using breast cancer cell models, we conditionally modulated PAX5 levels by transfection and recombinant expression to characterize PAX5-induced inhibition of the NFAT activation pathway and its mechanisms of action. Technically, expression levels for NFAT members (1 to 5) and their regulators (ex: calcium mobilization, specific kinases, and phosphatases) were assessed using RT-qPCR and Western blotting. NFAT activation was also studied through the analysis of cellular compartmentalization, reporter gene assays, and microscopy. We observed that PAX5 suppressed overall NFAT-dependant transcriptional activity in breast cancer cells through various mechanisms depending on the type of breast cancer models. We also found that although elevated PAX5 expression levels do not alter total NFAT protein levels, PAX5 affects the phosphorylation status of NFAT (activation) through the regulation of NFAT-specific phosphatases and kinases controlling NFAT import and downstream transactivation pro-malignant genes. We also found that PAX5 modulates intracellular calcium mobilization, which is also essential for NFAT activation. Altogether, our findings demonstrate that PAX5 is a potent inhibitor of NFAT-dependant processes essential for in breast cancer malignancy. Interestingly, PAX5-mediated suppression of the NFAT pathway in breast cancer cells is elicited by multiple regulatory mechanisms, which also depend on breast cancer cell type. These studies provide new insight into the molecular pathways governing breast malignancy and disease progression. Further understanding of these mechanisms of action will build the future roadmaps for therapeutic and prognostic interventions.
Citation Format: Félix Després, Damien Robichaud, Brandon Hannay, Gilles A. Robichaud. The PAX5 transcription factor is a suppressor of NFAT-mediated breast cancer aggressivity [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 1458.
Abstract 1517: Genetic characterization of normal pancreas tissue using single-cell technology
Authors: Karnoub Elias-Ramzey R. , Zhang Haochen , Umeda Shigeaki , Masilionis Ignas , Chaligné Ronan , Iacobuzio-Donahue Christine 
Published: April 2023

Abstract
Mechanisms behind the evolution of normal pancreas tissue into pancreatic ductal adenocarcinoma (PDAC) are still poorly understood. More thorough characterization of mutational processes and development of clones is possible with single-cell DNA sequencing (scDNA-seq) of normal pancreas tissue. We developed a custom panel with 596 amplicons targeting over 200 genes known to be important in PDAC for use with Mission Bio’s Tapestri platform. We have recently optimized this method with nuclei which have been extracted from thirty frozen normal pancreas tissues, each from a different patient. Of these tissues, twenty-five were derived from rapid autopsies of patients with brain tumors to minimize the possibility of tumor cells being present in the pancreas. Normal pancreas tissue was verified by hematoxylin and eosin staining. Nuclei were extracted using the S2 Genomics Singulator 100 and counted with DAPI using the Countess 3 FL to ensure the concentration was adequate and that the sample was clean without excessive debris before library preparation and sequencing. Bulk whole exome sequencing (WES) and digital droplet polymerase chain reaction (ddPCR) were performed on several of these sample to validate certain mutations seen in scDNA-seq. Patients of a variety of ages ranging from five to 74 and with various risk factors including smoking and diabetes were chosen to better understand the impact on clonal expansion and genetic patterns present in normal pancreas tissue. For each of the thirty samples, an average of 2464 good quality nuclei were sequenced with over 70 reads per cell per amplicon on average. Mutations that were present in high quantities of cells were confirmed with WES and ddPCR. We found that older patients and patients that either smoke or those with diabetes had not only an increased number of mutations, but each individual cell, on average, had a significantly higher mutation count. The associated clones were also much greater in size in the higher-risk patients’ tissues. Furthermore, there was an increase in heterogeneity in the form of mutually exclusive clusters of cells. These results highlight the effects of various risk factors on normal pancreas tissue and potentially describe novel mechanisms of tumorigenesis.
Citation Format: Elias-Ramzey R. Karnoub, Haochen Zhang, Shigeaki Umeda, Ignas Masilionis, Ronan Chaligné, Christine Iacobuzio-Donahue. Genetic characterization of normal pancreas tissue using single-cell technology [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 1517.
Abstract 1531: Human anti-CD40 agonistic antibodies with enhanced FcgR engagement activate immune cell and promote anti-tumor efficacy
Authors: Wang Linya , Yuan Tom Z. , Villalta Mouna , Han Zhen , Wadhwa Hansika , Chan Kara Y. , Yang Marisa , Htoy Tammy , VanDyke Paul , Holliday Carson , Franco Hector , Giang Hoa , Axelrod Fumiko , Sato Aaron 
Published: April 2023

Abstract
Checkpoint inhibitors represent a major advance in cancer immunotherapy, and combinatorial immunotherapies with secondary drivers of anti-tumor immunity provide beneficial effects for patients that do not show a strong endogenous immune response. CD40 is a member of the TNF family of receptors that has been shown to play a crucial role in enhancing B cell and dendritic cell activity and fostering anti-tumor immune responses. Engagement of the inhibitory Fcg-receptor (FcgR) IIb is an absolute requirement for in vivo antitumor activity of agonistic anti-CD40 monoclonal antibodies, and Fc region mutant designs of anti-CD40 antibodies had been discovered to enhance FcgRIIb engagement. With Twist’s precision DNA writing technologies, we have created phage display VHH and scFv libraries with diversity greater than 1 × 1010 for optimal discovery. In this study, we performed high affinity binding of the antibodies by SPR and cell surface binding. The leads are reformatted on human IgG1, IgG4, and IgG1 mutant. The in vitro properties of the CD40 agonistic antibodies demonstrate enhanced FcgRIIb engagement by NFkB activation. B cell activation is also detected by upregulation of CD86 and IL6 secretion. In humanized hCD40 mice model, we observed the engineered anti-CD40 agonists enhance anti-tumor immune function in vivo. These studies suggest that our antibodies can be potential drug for cancer immunotherapy.
Citation Format: Linya Wang, Tom Z. Yuan, Mouna Villalta, Zhen Han, Hansika Wadhwa, Kara Y. Chan, Marisa Yang, Tammy Htoy, Paul VanDyke, Carson Holliday, Hector Franco, Hoa Giang, Fumiko Axelrod, Aaron Sato. Human anti-CD40 agonistic antibodies with enhanced FcgR engagement activate immune cell and promote anti-tumor efficacy [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 1531.