bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2578: Phosphorylation of AHR by PLK1 promotes metastasis of LUAD via upregulation of DIO2
Authors: Li Chaohao , He Daheng , Mao Fengyi , Wang Xinyi , Hao Yanning , Kong Yifan , Brainson Christine F. , Liu Jinghui , Zhang Yanquan , Wang Ruixin , Zhang Qiongsi , Li Zhiguo , Rao Xiongjian , Wu Sai , Wang Chi , Wei Qiou , Wang Jianlin , Liu Xiaoqi 
Published: April 2023

Abstract
Non-small cell lung cancer (NSCLC) is one of the most aggressive cancer types, and metastasis of cancer cells is the major reason leading to death of patients. Aryl hydrocarbon receptor (AHR) is an important transcription factor involved in the initiation and progression of lung cancer. Polo-like kinase 1 (PLK1), a serine/threonine kinase, is another oncogene that promotes the malignancy of multiple cancer types. Preliminary examination indicates that AHR is a potential substrate of PLK1. Nonetheless, the phosphorylation and interaction of these two factors, as well as the subsequent biological significance in lung cancer remain to be determined. Here we prove that PLK1 phosphorylates AHR at serine 489 (S489) in lung adenocarcinoma (LUAD), a subtype of NSCLC. Overexpressing of exogenous AHR with mutation of phosphomemetic amino acid (S489D), enhances migration and invasion in transwell assays compared to cells harboring AHR that is unable to be phosphorylated (S489A), indicating that phosphorylation of AHR by PLK1 induces the metastatic potential of lung cancer. This is further confirmed in mouse studies using intravenous or subcutaneous inoculation of cancer cells. RNA-seq analyses of cells with S489D or S489A show that type 2 deiodinase (DIO2) is underrepresented in S489A but overexpressed in S489D. DIO2 converts thyroxine (T4) to triiodothyronine (T3), which is the more active form of thyroid hormone and activates downstream effect. Treatment with T3 or T4 promotes the metastasis of LUAD, whereas depletion of DIO2 or treatment with deiodinase inhibitor iopanoic acid disrupts this property. Furthermore, this phenomenon is verified by in vivo mouse experiment using intravenous injection of DIO2-depleted cancer cells. Taken together, these results identify phosphorylation of AHR by PLK1 as a mechanism that leads to progression of LUAD.
Citation Format: Chaohao Li, Daheng He, Fengyi Mao, Xinyi Wang, Yanning Hao, Yifan Kong, Christine F. Brainson, Jinghui Liu, Yanquan Zhang, Ruixin Wang, Qiongsi Zhang, Zhiguo Li, Xiongjian Rao, Sai Wu, Chi Wang, Qiou Wei, Jianlin Wang, Xiaoqi Liu. Phosphorylation of AHR by PLK1 promotes metastasis of LUAD via upregulation of DIO2 [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 2578.
Abstract 287: Novel p62 interaction suggests novel role in glutamate metabolism
Authors: Dahl Haley Christine , Konakalla Anisha R. , Kanumuri Preethi , Mansoor Basir , Kelley Anastasia , Shipurkar Riya , Delk Nikki A. 
Published: April 2023

Abstract
Prostate cancer (PCa) is the second most common cause of cancer-related death among American men. Androgen Receptor (AR) transcriptional activity is required for PCa tumor growth. Thus, androgen deprivation therapy (ADT) is a first line PCa therapy. However, 10-20% of patients will inevitably develop lethal castration-resistant PCa (CRPC). Thus, we must uncover the mechanisms that drive CPRC. Chronic inflammation is a known hallmark of cancer initiation and progression. Using the LNCaP human PCa cell line, we have shown that chronic exposure to the inflammatory cytokine, interleukin-1 (IL-1) can transform castration-sensitive PCa cells into castration-resistant PCa cells. IL-1 is elevated in PCa patient tissue and serum and is associated with disease progression and metastasis. IL-1 is clinically relevant, but the role of IL-1 in CRPC development is not fully elucidated. To mimic ADT, we serum-starved LNCaP and the chronic IL-1 sublines, LNas1 and LNbs1, and performed mass spectrometry to identify chronic IL-1-induced changes in protein-protein interactions. Specifically, we looked at p62 protein interactors. p62 is a multi-domain, multifunctional pro-survival protein that mediates autophagic flux in response to cellular stress and serum starvation, promotes NF-κB inflammatory signaling and induces NRF2 antioxidant signaling. We discovered that p62 forms a constitutive interaction with KEAP1 under serum starved and normal growth conditions in the chronic IL-1 sublines. KEAP1 inhibits NRF2 nuclear translocation. In response to antioxidant stress, p62 binds and sequesters KEAP1 from NRF2 to activate NFR2 signaling. Surprisingly, we do not observe constitutive canonical NRF2 signaling in the chronic IL-1 sublines. However, in response to serum starvation, we do see both high basal levels and upregulation, specifically, of the NRF2-induced gene, GCLC. GCLC is a glutamate-cysteine ligase that synthesizes the antioxidant, glutathione. Therefore, using mass spectrometry and immunoprecipitation western blotting, we looked at p62 interactions under serum starvation conditions. While we did not find p62 interaction with GCLC in the chronic IL-1 sublines, we do find that p62 interacts with GLUL. GLUL is a glutamate-ammonia ligase that plays a role in cellular detoxification. These data suggests that chronic IL-1 exposure induces novel p62 interactions that have a role in glutamate metabolism.
Citation Format: Haley Christine Dahl, Anisha R. Konakalla, Preethi Kanumuri, Basir Mansoor, Anastasia Kelley, Riya Shipurkar, Nikki A. Delk. Novel p62 interaction suggests novel role in glutamate metabolism [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 287.
Abstract 2945: Depleting hCCR8 mAb Therapy #2: Selection of candidates for the development of innovative depleting anti CCR8 therapeutic antibodies to control the immunosuppressive tumor microenvironment
Authors: Maurin Alice Gentil Dit , Richert Iseulys , Fernandez Maria Dolores Garcia , Janvier Aurélie , Rose Solene , Jeannelle Megane , Chraa Dounia , Dietsch Camille , Urquia Pauline , Ruet Quentin , Schappler Malaury , Baron Luc , Ayachi Safia , Blanchard Orphée , Franchet Christel , Fontayne Alexandre , Vermot-Desroches Claudine , Schann Stephan , Lenne Nathalie 
Published: April 2023

Abstract
Tumor-infiltrating Tregs (TITR) constitute a sub-family of immuno-suppressive cells abundantly found in multiple solid cancers. They play a critical role in tumor progression and their specific depletion has been recently propose as a novel therapeutic strategy to fight cancers. Based on the transcriptional analysis of tumor infiltrating immune cells, the G-protein coupled receptor CCR8 was found to be expressed on murine and human TITR, but not on proinflammatory effector T cells. The CCR8 receptor therefore represents a unique TITR target for the development of novel depletive antibody-based therapeutics. At Domain Therapeutics, a diverse library of several dozens of mouse mAbs directed against the hCCR8 was discovered and characterized, providing a unique source for the development of a best-in-class and well differentiated anti-hCCR8 depleting antibody for the treatment of cancers.Special attention was paid on two important characteristics for the selection of our depleting mAb candidates: (1) their ability to detect all CCR8 positive immunosuppressive cells and (2) the combination of different killing modes of action (ADCC, ADCP, CDC) to trigger an optimal depletion.Our selected mAb candidates were nominated based on their capacity to bind to immunosuppressive cells present in different tumor tissues and optimal depleting activity. The impact of our mAbs on tumor growth and on the immune tumor microenvironment (TME) were also studied in mouse hCCR8-KI mice. Finally, following a comprehensive in vitro benchmarking mAb analysis, we identified key differentiating points versus competitor’s mAbs. Nominated candidates wil be ready to enter cell line generation efforts in early 2023.
Citation Format: Alice Gentil Dit Maurin, Iseulys Richert, Maria Dolores Garcia Fernandez, Aurélie Janvier, Solene Rose, Megane Jeannelle, Dounia Chraa, Camille Dietsch, Pauline Urquia, Quentin Ruet, Malaury Schappler, Luc Baron, Safia Ayachi, Orphée Blanchard, Christel Franchet, Alexandre Fontayne, Claudine Vermot-Desroches, Stephan Schann, Nathalie Lenne. Depleting hCCR8 mAb Therapy #2: Selection of candidates for the development of innovative depleting anti CCR8 therapeutic antibodies to control the immunosuppressive tumor microenvironment [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 2945.
Abstract 3442: FXR mediates macrophage intrinsic responses to suppress colon cancer progression
Authors: Fu Ting , Dong Xingchen 
Published: April 2023

Abstract
Bile acids (BAs) affect the intestinal environment by ensuring barrier integrity, regulating epithelium turnover, maintaining microbiota balance, and modulating the immune system. As a master regulator of BAs homeostasis and innate immunity, Farnesoid X Receptor (FXR), is severely compromised in inflammatory bowel disease (IBD) and colitis-associated colorectal carcinoma (CAC) patients. At the front line, gut macrophages react to the microbiota and metabolites that breach the epithelium. We aim to study the role of the BAs-FXR axis in macrophages. To dissect how inflammation drives tumorigenesis, we employed a classic mouse model of CAC, profiled BAs and cytokines, monitored tumorigenesis, and examined the function of macrophages and Th17 cells. Moreover, we investigated the potential of FexD, an FXR agonist, in ameliorating intestinal inflammation, thus inhibiting tumorigenesis. Further, we identified how macrophage intrinsic FXR senses the BAs abnormality and reshapes the gut macrophages in vivo and ex vivo. We also investigated the potential role of pro-inflammatory cytokines in stimulating intestinal stem cells (ISCs)’ stemness using mouse organoids. This study demonstrates that inflammation-induced epithelial abnormalities compromised FXR signaling and altered BAs profile in CAC. Gut macrophage intrinsic FXR senses the aberrant BAs, leading to the secretion of pro-inflammatory cytokines, which promotes ISCs’ proliferation. Notably, FexD reduced intestinal inflammation and tumorigenesis by suppressing pro-inflammatory responses in gut macrophages and Th17 cells. Mechanistically, FXR regulates gut macrophages' recruitment, polarization, maturation, and crosstalk with Th17 cells. In summary, we uncovered a novel role of FXR modulation of gut macrophages, highlighting the potential of FXR as a therapeutic target over biologicals for treating colon cancer.
Citation Format: Ting Fu, Xingchen Dong. FXR mediates macrophage intrinsic responses to suppress colon cancer progression [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 3442.
Abstract 3497: The polyclonal path to malignant transformation in familial adenomatous polyposis
Authors: Schenck Ryan O. , Khan Aziz , Horning Aaron , Esplin Edward D. , Monte Emma , Wu Si , Hanson Casey , Bararpour Nasim , Neves Stephanie , Jiang Lihua , Contrepois Kévin , Lee Hayan , Guha Tuhin K. , Hu Zheng , Laquindanum Rozelle , Mills Meredith A. , Chaib Hassan , Chiu Roxanne , Jian Ruiqi , Chan Jeannie , Ellenberger Mathew , Becker Winston R. , Bahmani Bahareh , Michael Basil , Shen Jeanne , Lancaster Samuel , Ladabaum Uri , Kundaje Anshul , Longacre Teri A. , Greenleaf William J. , Ford James M. , Snyder Michael P. , Curtis Christina 
Published: April 2023

Abstract
Familial adenomatous polyposis (FAP) patients develop hundreds of premalignant polyps that progress to colorectal cancer due to a germline mutation in the APC tumor suppressor. Polyps from FAP patients uniquely facilitate interrogation of the continuum of malignant transformation from histologically normal mucosa to benign and dysplastic polyps and eventual adenocarcinomas. As part of the Human Tumor Atlas Network (HTAN), we performed multi-omic profiling, including whole genome sequencing, on 135 samples from six FAP patients across the pre-malignant continuum spanning all physical regions of the large intestine, and serving as the most comprehensive FAP dataset available. Through a comparative analysis with a published FAP cohort (58 multi-region samples across 5 patients) and sporadic colorectal cancer cohort (n=57), each including benign and malignant samples, we evaluate the timing of driver acquisitions at each stage of malignant progression. Despite being separated by vast regions of histologically normal mucosa, independently evolving polyps show extensive mutation sharing, suggesting FAP polyps are polyclonal in origin. Finally, we leverage a simplified mechanistic model of embryonic colonic development demonstrating that the path to malignant transformation in FAP is consistent with polyclonal origins attributable to early mixing, perhaps as early as in-utero. Taken together, the HTAN FAP Atlas provides a novel window into the earliest stages of cancer formation and may illuminate barriers to malignant transformation and opportunities for earlier intervention.
Citation Format: Ryan O. Schenck, Aziz Khan, Aaron Horning, Edward D. Esplin, Emma Monte, Si Wu, Casey Hanson, Nasim Bararpour, Stephanie Neves, Lihua Jiang, Kévin Contrepois, Hayan Lee, Tuhin K. Guha, Zheng Hu, Rozelle Laquindanum, Meredith A. Mills, Hassan Chaib, Roxanne Chiu, Ruiqi Jian, Jeannie Chan, Mathew Ellenberger, Winston R. Becker, Bahareh Bahmani, Basil Michael, Jeanne Shen, Samuel Lancaster, Uri Ladabaum, Anshul Kundaje, Teri A. Longacre, William J. Greenleaf, James M. Ford, Michael P. Snyder, Christina Curtis. The polyclonal path to malignant transformation in familial adenomatous polyposis [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 3497.
Abstract 3737: A novel mechanism of NF-κB activation by genotoxic chemotherapy
Authors: Venkatesh Jaganathan , Muthu Magesh , Rishi Arun K. 
Published: April 2023

Abstract
CARP-1, a perinuclear phospho-protein, is a biphasic regulator of cell survival and apoptosis signaling. Genotoxic drugs induce apoptosis in part by elevating CARP-1 levels while also promote cell survival in part by activating NF-κB that involves CARP-1 interaction with NF-κB kinase subunit γ (aka, NEMO). We previously noted interaction of CARP-1 with RIPK1, and since RIPK1 is known to regulate NF-κB signaling, we investigated whether RIPK1-CARP-1 interaction is involved in genotoxic chemotherapy-dependent apoptosis or NF-κB-activated survival signaling. Mutagenesis and co-IP-WB analyses revealed that a 40-amino acid epitope within the amino-terminal catalytic domain of RIPK1 interacted with CARP-1 (611-640) peptide. Overexpression of this CARP-1/CCAR1-binding (CB) epitope peptide or RIPK1 mutant that has in-frame deletion of CB-epitope resulted in moderate but significant reduction in viabilities of cells treated with Adriamycin or Cisplatin relative to the viability loss noted in cells expressing RIPK1 (WT). However, no significant differences in loss of cell viabilities were noted in cells expressing various substitution mutants of RIPK1 (aspartate (D) 138 to asparagine (N), serine (S) 109 and threonine (T) 110 to alanines (A), lysine (K) 87 to arginine (R), K97 to R, K105 to R, or K115 to R) relative to their RIPK1 (WT) expressing counterparts when treated with genotoxic drugs. Interestingly, CB-epitope mutant, but not RIPK1 (WT), failed to translocate to cytoplasm in Adriamycin-treated cells. Genotoxic drugs activated p65/RelA in cells expressing RIPK1 (WT), while expression of RIPK1 CB-epitope mutant resulted in abrogation of p65/RelA activation by Adriamycin or Cisplatin but not by TNFα. Collectively our data demonstrate that CARP-1 interaction with RIPK1 promotes nuclear export of RIPK1 and consequent NF-κB activation in cells exposed to genotoxic drugs.
Citation Format: Jaganathan Venkatesh, Magesh Muthu, Arun K. Rishi. A novel mechanism of NF-κB activation by genotoxic chemotherapy. [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 3737.
Abstract 3739: MAFG promotes melanomagenesis through the transcriptional regulation of hypoxic and immune responses
Authors: Vera Olga , Martinez Michael , Karreth Florian A. 
Published: April 2023

Abstract
The small MAF family of transcription factors, consisting of MAFG, MAFF, and MAFK, dimerize with CNC/BACH proteins to regulate diverse transcriptional programs. Previously, we have shown that miRNA-29 suppresses melanoma development, at least in part, by repressing MAFG expression. Moreover, analysis of the TCGA revealed frequent copy number gains and/or overexpression of MAFG in melanoma. However, whether MAFG has oncogenic effects in and is critical for melanoma is unknown. We found that silencing of MAFG, but not MAFF or MAFK, abrogates growth of melanoma cells in vitro, while melanocyte cell lines are less reliant on MAFG. Conversely, MAFG overexpression promoted proliferation and focus formation of human melanocyte and melanoma cell lines. Using a high-throughput melanoma mouse modeling (ESC-GEMM) platform, we found that in vivo overexpression of MAFG in BRAFV600E; PTEN+/- mice potently accelerated melanoma development. RNA-sequencing revealed that MAFG regulates transcriptional programs associated with hypoxic and immune responses. Accordingly, MAFG overexpressing cells exhibited better ability to survive under hypoxic conditions, probably through the regulation of HIF1A. Moreover, MAFG overexpressing cells showed increased expression of cytokines of the of the C-C chemokine family, CCL3 and CCL5. MAFG overexpressing tumors from ESC-GEMM mice and MAFG-High melanomas from TCGA had features of immune-cold milieus, characterized by reduced infiltration of CD45+ immune cells and CD8+ T cells. Altogether, we demonstrate that MAFG promotes melanomagenesis, in part, by regulating the response to hypoxic conditions and chemokine expression, which may rewire the tumor immune microenvironment.
Citation Format: Olga Vera, Michael Martinez, Florian A. Karreth. MAFG promotes melanomagenesis through the transcriptional regulation of hypoxic and immune responses. [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 3739.
Abstract 387: Enolase-1 as a candidate theranostics target for neuroendocrine prostate cancer
Authors: Torres Krystal Rubi Santiago , Duran Alfonso 
Published: April 2023

Abstract
Prostate cancer (PCa) is the second most common cancer in American men, with men of African ancestry (AA) having twice the mortality of men of European ancestry (EA). Although taxane-based chemotherapy is the last line of defense in men with advanced PCa, it ultimately fails due to chemoresistance. The protein-specific membrane antigen (PSMA) has been an effective target for the imaging and therapy of advanced PCa. Specifically, PSMA radioligand therapy (PSMA-RLT) is a theranostics (therapy + diagnostics) option for men with advanced PCa. However, about 30% of men with advanced PCa have limited response to PSMA-RLT due to the presence of neuroendocrine-differentiated PCa (NEPC), which lacks PSMA expression. A promising alternative to PSMA targeting is the glycolytic enzyme enolase (ENO), which localizes to the cell surface in advanced tumors. There are three enolases with similar functions, with ENO-1 and ENO-2 implicated in PCa. Here, we demonstrate, using immunoblotting, confocal microscopy, and cell fractionation studies with specific monoclonal antibodies, that chemosensitive NEPC cells express both ENO-1 and ENO-2; however, docetaxel (DTX)-resistant PC3-DR and DU145-DR cells only express ENO-1 with clear loss of ENO-2. Loss of ENO-2 in chemoresistant PCa cells generates a metabolic vulnerability due to loss of ENO redundancy. We also initiated the testing of small molecule inhibitors (SMIs) targeting ENO-1 in chemoresistant and chemosensitive NEPC cells, showing that these inhibitors have cytotoxic activity against these cells, with IC50 values in the low micromolar range. These results support the hypothesis that ENO-1 is expressed in the surface of NEPC cell lines and can be targeted with SMIs that could be modified as potential theranostics agents. Our long-term goal is to identify an alternative treatment for patients with NEPC by establishing ENO-1 as a novel cell surface theranostics target.
Citation Format: Krystal Rubi Santiago Torres, Alfonso Duran. Enolase-1 as a candidate theranostics target for neuroendocrine 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 387.