bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3367: Tumor-derived Extracellular Vesicles as a potential PD biomarker for TEAD central pocket binder activity in liquid biopsy
Authors: Nunes Manoel , Spanakis Emmanuel , Dos-Santos-Bele Wilson , Rabia Emilia , Soubigou Stephane , Muzard Gaelle , Dos-Santos Odette , Pollard Jack , Hadjipanayis Angela , Delahaye Fabien , Venier Olivier , Debussche Laurent , Jackson Don , Dib Colette , Valtingojer Iris , Cesaroni Matteo 
Published: April 2023

Abstract
We assessed the utility of mRNAs in extracellular vesicles as biomarkers for inhibition of YAP1/TEAD signaling by the TEAD central pocket inhibitor. The field of liquid biopsies is of enormous interest for noninvasive monitoring of cancer progression and response to treatment. Extracellular Vesicles (EVs) such as exosomes, microvesicles, and apoptotic bodies, are nanoparticles found in all biological fluids. These cell-derived, small secreted vesicles convey biological information, either by surface-to-surface interaction or by shuttling bioactive molecules to a recipient cell’s cytoplasm. Because EVs harbor the cargos of their original cells, their contents may be useful as biomarkers to follow drug activity. (F. Urabi et al., 2020). We compared the effects of YAP1/TEAD inhibitor treatment on intracellular and EV-encapsulated mRNAs in three compound-sensitive tumor cell lines (and one insensitive cell line) based on TEAD inhibitor IC50 assay profiles. Cell lines were treated at four doses of YAP1/TEAD inhibitor (0.0 µM, 0.3 µM, 1.0 µM & 3.0 µM) for 24h. EVs and intracellular RNAs were isolated and profiled by RNAseq. To estimate YAP1/TEAD pathway activity, we used a transcriptomic signature identified previously by our group (L. Calvet et al., 2022) and we showed that the effects of YAP1/TEAD inhibitor treatment on the YAP1/TEAD score in intracellular mRNAs corresponded to a decrease of the score in EV-secreted RNAs. In addition, we ran an unbiased analysis to identify single transcripts in the EVs that were modulated by YAP1/TEAD inhibitor. One of the best markers identified by regression analysis was CYR61, that is part of the signature and is a well-established downstream target of YAP/TEAD pathway. In conclusion, these results suggest that the YAP1/TEAD signature in EV mRNAs represents a relevant PD biomarker to monitor YAP1/TEAD inhibitor activity and could potentially serve as a noninvasive liquid biopsy-based biomarker detection in the clinic.
Citation Format: Manoel Nunes, Emmanuel Spanakis, Wilson Dos-Santos-Bele, Emilia Rabia, Stephane Soubigou, Gaelle Muzard, Odette Dos-Santos, Jack Pollard, Angela Hadjipanayis, Fabien Delahaye, Olivier Venier, Laurent Debussche, Don Jackson, Colette Dib, Iris Valtingojer, Matteo Cesaroni. Tumor-derived Extracellular Vesicles as a potential PD biomarker for TEAD central pocket binder activity in liquid biopsy [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 3367.
Abstract 3416: Suppression of AXL inhibits tumor growth through promotion of dendritic cell migration in lung cancer
Authors: Kim Da-Som , Lee Cha Won , Im Kyungtaek , Choi Yun Jung , Kim Dong Ha , Choi Chang-Min , Ji Wonjun , Lee Jae Cheol , Rho Jin Kyung 
Published: April 2023

Abstract
AXL is a receptor tyrosine kinase (RTK) that has a various role in tumor progression such as proliferation, metastasis, angiogenesis, drug resistance and immune tolerance. Although targeting AXL exhibits an anti-cancer effects partially depending on the immune system, their molecular mechanisms have not been fully elucidated. To search the roles of AXL in immune tolerance of tumor, we generated AXL knockout (KO) mice. These AXL KO mice showed the reduced tumor growth in syngeneic LLC-1 model compared to wild type mice. To validate the mechanisms underlying the inhibition of AXL KO-derived tumor growth, we examined tumor-infiltrating lymphocytes (TIL). Compared with tumor-bearing wild type mouse, CD45-positive cells were significantly enhanced in tumor-bearing AXL KO mouse. Especially, these results were dominant in CD8-positive cells and dendritic cells (DCs). Tumor-infiltrating DCs showed the reduction of PD-L1 and Tim3 expression. In addition, the inhibition of AXL led to induce the DCs migration. In conclusion, our data demonstrated that targeting AXL may inhibit tumor growth through the activation of DCs including the enhancement of migration and reduced expression of immune check point proteins.
Citation Format: Da-Som Kim, Cha Won Lee, Kyungtaek Im, Yun Jung Choi, Dong Ha Kim, Chang-Min Choi, Wonjun Ji, Jae Cheol Lee, Jin Kyung Rho. Suppression of AXL inhibits tumor growth through promotion of dendritic cell migration in lung 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 3416.
Abstract 3429: Beyond cereblon IMIDs - biophysics-based discovery of novel molecular glue chemotypes
Authors: Zhang Yujia , Bates Jessica , Gourdet Benoit , Birch Louise , Addis Philip , Hjerpe Roland , Jordan Allan M. 
Published: April 2023

Abstract
Molecular glue degraders are compact, low molecular weight molecules that can efficiently induce specific and potent degradation of a target protein. This class of degraders function by inducing interactions between a target of interest and a ubiquitin-ligase, either by stabilization of weak pre-existing interactions, or by generation of entirely novel interactions. These molecules offer significant opportunity beyond heterobifunctional degraders such as PROTACs, not least in terms of improved molecular properties.
However, beyond the IMID molecular glues, typified by thalidomide, pomalidomide and lenalidomide, novel molecular glue chemotypes remain scarce.
To address this need, we have developed biophysics-based molecular glue screening platform, exploiting our internal, high quality fragment library and proximity-based screening platforms to rapidly identify promising new molecular glues for further optimization. A potential advantage of utilizing cell-free biophysical systems is the opportunity to select both the target and the desired ligase, opening up for development of degraders that capitalize upon differential expression of ligases in different tissues.
As proof of concept, we have applied this platform to find new molecular glues to degrade CK1α. This Ser/Thr kinase has been found to be over-expressed in metastatic colorectal cancer, and this over-expression correlates with poor overall survival. The kinase has also been implicated as an oncogenic driver in tumors such as B-Cell lymphomas and non-Hodgkin lymphomas, suggesting a potential therapeutic application for novel CK1α molecular glues.
Utilizing known IMID-derived molecular glues between CK1α and CRBN as benchmark controls, we identified several non-IMID derived chemotypes as tentative stabilizers of the CRBN/CK1α interaction. Further studies on these novel candidate degrader templates are now underway.
Citation Format: Yujia Zhang, Jessica Bates, Benoit Gourdet, Louise Birch, Philip Addis, Roland Hjerpe, Allan M. Jordan. Beyond cereblon IMIDs - biophysics-based discovery of novel molecular glue chemotypes [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 3429.
Abstract 3527: WNT5B drives osteosarcoma stemness, metastasis and chemoresistance
Authors: Perkins Rachel S. , Suthon Sarocha , Miranda-Carboni Gustavo A. , Krum Susan A. 
Published: April 2023

Abstract
Osteosarcoma is a pediatric bone cancer that has no targeted therapy and has had no treatment advances for the last three decades. Osteosarcoma frequently metastasizes to the lungs, reducing patient survival with metastatic disease to 20% after 5 years. The goal of this study is to describe the function of WNT5B and its signaling pathway in osteosarcoma stem cells, metastasis and chemoresistance and its potential as a therapeutic target. Using RNA sequencing from publicly available datasets and immunohistochemistry on tumor microarrays, we reveal that WNT5B is the most expressed WNT in osteosarcoma patients and correlates with both metastasis and survival. Osteosarcoma is thought to result from a block in differentiation, and based on WNT5B’s role in inhibiting osteoblast differentiation of mesenchymal stem cells from normal bone, we hypothesized a role for WNT5B in osteosarcoma stem cells. In spheroids, we show that both protein and mRNA levels of WNT5B are enhanced in the stem cell population compared to adherent cells. We found that WNT5B upregulates the expression of the stemness gene SOX2 and directs stemness phenotypes, such as sphere forming efficiency, proliferation and migration. We show a reduction in sphere forming efficiency with 143B-WNT5B-knockdown cells compared to parental control cells which can be rescued with re-introduction of WNT5B. Additionally, we show that WNT5B drives proliferation and migration of osteosarcoma stem cells through increasing sphere size and capability to migrate on collagen matrix. Further, WNT5B enhances osteosarcoma chemoresistance to methotrexate. Through revealing a novel role for WNT5B in osteosarcoma cancer stem cells and therapy resistance, we present the WNT5B pathway as a candidate for therapeutically targeting osteosarcoma stem cells in patients.
Citation Format: Rachel S. Perkins, Sarocha Suthon, Gustavo A. Miranda-Carboni, Susan A. Krum. WNT5B drives osteosarcoma stemness, metastasis and chemoresistance. [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 3527.
Abstract 3534: Interrogating the immune microenvironment of a novel mouse model of fusion positive rhabdomyosarcoma
Authors: Resch Erin E. , Oristian Kristianne M. , Mendes Elizabeth , Linardic Corinne M. , Ladle Brian H. 
Published: April 2023

Abstract
Immunotherapies have been largely ineffective for pediatric soft tissue sarcomas, in particular for fusion-positive rhabdomyosarcoma (FP-RMS), characterized by the PAX-FOXO1 gene fusion. We are hampered by a paucity of predictive, immune-competent mouse models of this cancer with which to develop novel and effective immune-based therapies. To overcome this barrier, we analyzed the immune microenvironment of one of the few genetically-engineered mouse models (GEMM) of FP-RMS. Briefly, this model is driven by conditional knock-in expression of Pax3:Foxo1 at the endogenous Pax3 locus, with or without conditional loss of MST1/2 (gene name Stk4/3), a Hippo pathway mediator that is modulated by PAX3-FOXO1. These two genotypes demonstrate different disease penetrance and tumor location, with mice bearing loss of MST1/2 exhibiting higher tumor penetrance and favoring head and neck disease sites. We hypothesize that these models exhibit differences in tumor-immune interactions in the microenvironment that correlate with these phenotypic differences. We aim to characterize the immune microenvironment differences between these tumors and to establish this GEMM as a predictive, syngeneic model of FP-RMS. Tumors were generated spontaneously from a GEMM of FP-RMS. Tumors expressed PAX3-FOXO1 and either carried a conditional loss of MST1/2 (MSTnull) or native MST1/2 (MSTwt). We analyzed 8 formalin-fixed, paraffin-embedded (FFPE) tumors and 2 tumor-derived cell lines from these novel models. FFPE tumor samples were analyzed via immunohistochemistry (IHC) for CD3 (T cell marker) and CD11b (myeloid cell marker) and were scored for immune cell infiltration. Overall, tumors demonstrate poor CD3+ T cell infiltration with significantly higher infiltration of CD11b+ myeloid cells (p=0.0002); this trend is also seen within the individual MSTwt (p=0.0286) and MSTnull cohorts (p=0.0286). There was no significant difference in CD3+ T cell or CD11b+ myeloid cell density between the two genotypes. The drivers of this immune phenotype and the role of Hippo pathway signaling in mediating RMS tumor immune cell infiltration warrants further investigation. Additional ongoing studies are utilizing a spatial gene expression platform to visualize the spatially-preserved transcriptome of intact tumors to reveal potential pathways mediating the immune microenvironment.
Citation Format: Erin E. Resch, Kristianne M. Oristian, Elizabeth Mendes, Corinne M. Linardic, Brian H. Ladle. Interrogating the immune microenvironment of a novel mouse model of fusion positive rhabdomyosarcoma. [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 3534.
Abstract 3610: Prenylated PALM2 promotes the migration of esophageal squamous cancer cells through activating ezrin
Authors: Deng Danxia , Li Chengyu , Zheng Zhenyuan , Wen Bing , Liao Liandi , Li Enmin , Xu Liyan 
Published: April 2023

Abstract
Proteins containing a CAAX motif at the C-terminus can occur prenylation modification and regulate the localization and activity of a series of key regulatory proteins, including RAS superfamily members, heterotrimeric G proteins, nuclear lamina protein, and several protein kinases and phosphatases. However, studies of prenylated proteins in esophageal cancer are limited. Here, we found that paralemmin-2 (PALM2), a potential prenylated protein, was up-regulated and associated with a poor prognosis of patients, through research on large-scale proteomic data of esophageal cancer in our laboratory. The low throughput verification also showed that the expression of PALM2 in esophageal cancer tissues was higher than that in their paired normal esophageal epithelial tissues, and it was generally expressed in the membrane and cytoplasm of esophageal squamous cancer cells (ESCC). PALM2 interacted with the two subunits of farnesyl transferase (FTase), FNTA and FNTB. The FTase inhibitor weakened the membranous location of PALM2 and mutation in the CAAX motif of PALM2 (PALM2C408S) impaired its membranous localization, indicating PALM was prenylated by FTase. Overexpressed PALM2 promoted the migration of cancer cells, whereas PALM2C408S lost this ability. Mechanistically, PALM2 interacted with the N-terminal FERM domain of ezrin of Ezrin/Radixin/Moesin (ERM) family dependent on its prenylation. The mutagenesis indicated that lysine residues K253/K254/K262/K263 in ezrin’s FERM domain and cysteine residue C408 in PALM2’s CAAX motif were important for their interaction and ezrin activation. The knockout of ezrin prevented enhanced cancer cell migration by PALM2 overexpression. PALM2, depending on its prenylation, made ezrin get more membranous distribution and increased the phosphorylation of ezrin Y146 site. In summary, prenylated PALM2 promoted the migration of cancer cells through activating ezrin. (This work was supported by the National Natural Science Foundation of China (82173034, 81172264), and Innovative Team Grant of Guangdong Department of Education (2021KCXTD005)).
Citation Format: Danxia Deng, Chengyu Li, Zhenyuan Zheng, Bing Wen, Liandi Liao, Enmin Li, Liyan Xu. Prenylated PALM2 promotes the migration of esophageal squamous cancer cells through activating ezrin. [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 3610.
Abstract 3631: Infiltrating Bruton’s tyrosine kinase expressed B cells effects on prostate cancer metastasis
Authors: Byrd Crystal , Liou Geou- Yarh 
Published: April 2023

Abstract
Prostate cancer is the most common type of cancer found in senior males and is the 2nd leading cause of cancer death in American males. Although prostate cancer grows slowly within the prostate glands, because of a lack of efficient treatments at the appropriate timing, cancer cells eventually become aggressive and metastatic. The progression of cancer is supported by many factors, such as signals received from surrounding cells, like B cells and other effector cells. B cells play a role as a part of the adaptive immune system to produce antibodies. To become mature B cells, they rely on activation of a non-receptor kinase, Bruton’s Tyrosine Kinase (BTK). Preliminary data from our lab showed that in the prostate cancer tissues, more infiltrated B cells expressing BTK were present nearby the prostate cancer cells. Upon this finding, we hypothesize that BTK expressed B cells will support the survival of prostate cancer cells through BTK signaling. In this study, we will overexpress BTK in B cells to study the proliferation and migration of prostate cancer cells through a co-culture system. Our findings will show an increase in migration of prostate cancer cells when cultured with BTK expressed B cells. In the future, we will validate the importance of BTK in regulating prostate cancer migration and invasion; and identify their mechanisms. Our overall findings from this project would reveal key elements of the signaling pathways of BTK expressed B cells to promote prostate cancer migration.
Citation Format: Crystal Byrd, Geou- Yarh Liou. Infiltrating Bruton’s tyrosine kinase expressed B cells effects on prostate cancer metastasis. [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 3631.
Abstract 3666: A human skeletal muscle stem/myotube model reveals multiple signaling targets of cancer secretome in skeletal muscle
Authors: Wang Ruizhong , Kumar Brijesh , Bhat-Nakshatri Poornima , Khatpe Aditi Sanjay , Murphy Michael P. , Wanczyk Kristen E. , Doud Emma H. , Mosley Amber L. , Liu Yunlong , Chen Duojiao , Simpson Ed , Gao Hongyu , Nakshatri Harikrishna 
Published: April 2023

Abstract
Skeletal muscle dysfunction due to the effects of cancer secretome is observed in multiple cancer types and extreme dysfunction is manifested as cachexia. Major preclinical studies on cancer-associated muscle defects utilized mouse models or mouse C2C12 mouse myoblast cell line for in vitro studies. Because of species specificity of certain cytokines/chemokines in the secretome, a human model system is required to fully comprehend the effects of cancer secretome on skeletal muscle. Here, we report a simple method to establish skeletal muscle stem cell line (hMuSC), which can be differentiated into myotubes. Using single nuclei ATAC-seq (snATAC-seq) and RNA-seq (snRNA-seq), we document chromatin accessibility and transcriptomic changes associated with hMuSCs to myotube transition. Cancer cell line derived factors accelerated stem to myotube differentiation with accompanying changes including an increase in PAX7+/MyoD+ myogenic progenitor cells. Among the pathways activated by cancer-derived factors include inflammatory pathway involving CXCL8 (also called IL-8), glucocorticoid receptor (GR) pathway, and wound healing pathway. Furthermore, cancer-derived factors significantly altered splicing machinery in hMuSCs. Additionally, AKT and p53 pathways that function in metabolic/survival pathways of the skeletal muscle were adversely affected when hMuSCs were exposed to cancer cell-derived factors. Cancer-derived factors increased the expression levels of previously known cachexia-associated genes such as MT-2, ZIP14, and PDK4. Thus, the model system not only recapitulates results of previous mouse studies but also provides much needed human model system that can easily be adapted for large scale studies to explore the epigenomic changes during hMuSC differentiation and to screen for drugs that restore skeletal muscle function in various diseases.
Citation Format: Ruizhong Wang, Brijesh Kumar, Poornima Bhat-Nakshatri, Aditi Sanjay Khatpe, Michael P. Murphy, Kristen E. Wanczyk, Emma H. Doud, Amber L. Mosley, Yunlong Liu, Duojiao Chen, Ed Simpson, Hongyu Gao, Harikrishna Nakshatri. A human skeletal muscle stem/myotube model reveals multiple signaling targets of cancer secretome in skeletal muscle. [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 3666.
Abstract 3700: Isocitrate dehydrogenase 1 sustains a hybrid cytoplasmic-mitochondrial tricarboxylic acid cycle in prostate cancer
Authors: Gonthier Kevin , Weidmann Cindy , Berthiaume Line , Jobin Cynthia , Lacouture Aurélie , Lafront Camille , Harvey Mario , Neveu Bertrand , Loehr Jérémy , Bergeron Alain , Fradet Yves , Lacombe Louis , Riopel Julie , Latulippe Éva , Atallah Chantal , Shum Michael , Lambert Jean-Philippe , Pouliot Frédéric , Pelletier Martin , Audet-Walsh Étienne 
Published: April 2023

Abstract
Background: The androgen receptor (AR) is an established orchestrator of cell metabolism in prostate cancer (PCa), notably by inducing an oxidative mitochondrial program. Intriguingly, AR regulates cytoplasmic isocitrate dehydrogenase 1 (IDH1) but not its mitochondrial counterparts IDH2 and IDH3. Here, we aimed to understand the functional role of IDH1 in PCa.
Methods: Mouse models, in vitro human PCa cell lines, and human prostate organoids were used to study the expression and activity of IDH enzymes in the normal prostate and PCa. Genetic and pharmacological inhibition of IDH1 was then combined with extracellular flux analysis and gas chromatography-mass spectrometry for metabolomic analyses and cancer cell proliferation in vitro and in vivo.
Results: In PCa cells, more than 90% of the total IDH activity is mediated through IDH1 rather than its mitochondrial counterparts. This profile seems to originate from the specialized prostate metabolic program, as observed using mouse prostate and human patient-derived organoids. Pharmacological and genetic inhibition of IDH1 impaired mitochondrial respiration, suggesting that this cytoplasmic enzyme contributes to the mitochondrial tricarboxylic acid cycle (TCA) in PCa. Mass spectrometry-based metabolomics confirmed this hypothesis, showing that inhibition of IDH1 impairs carbon flux into the TCA cycle. Consequently, inhibition of IDH1 decreased PCa cell proliferation in vitro and in vivo.
Conclusions: These results demonstrate that PCa cells have a hybrid cytoplasmic-mitochondrial TCA cycle that depends on IDH1. This metabolic enzyme represents a metabolic vulnerability of PCa cells and a potential new therapeutic target.
Citation Format: Kevin Gonthier, Cindy Weidmann, Line Berthiaume, Cynthia Jobin, Aurélie Lacouture, Camille Lafront, Mario Harvey, Bertrand Neveu, Jérémy Loehr, Alain Bergeron, Yves Fradet, Louis Lacombe, Julie Riopel, Éva Latulippe, Chantal Atallah, Michael Shum, Jean-Philippe Lambert, Frédéric Pouliot, Martin Pelletier, Étienne Audet-Walsh. Isocitrate dehydrogenase 1 sustains a hybrid cytoplasmic-mitochondrial tricarboxylic acid cycle 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 3700.