bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4202: A novel 3D model investigating the pathophysiology of prostate cancer bone marrow metastasis
Authors: Yang Jianhui 
Published: March 2024

Abstract
Our study is aimed to apply a 3-dimensional (3-D) in vitro model emulating the extracellular matrix (ECM) of the bone marrow microenvironment (BMM) to explore the interaction of disseminated Prostate Cancer (PC) cells and ECM. Wharton's Jelly (WJ), which histologically and biochemically resembles the ECM part of the hematopoietic stem cell (HSC) niche, was decellularized as a novel 3-D culture platform, named as decellularized WJ matrix (DWJM). CD133, a critical marker of PC stem cells (PCSC), was chosen to initially evaluate the PCSC phenotype of DU-145 cells cultured using DWJM by flow cytometry and Image-Stream. DWJM was used to culture PC Cell line DU-145 cells. Enriched CD133(+) cells by Fluorescence-Activated Cell Sorting (FACS) were further analyzed for functional phenotypes of PCSC, and the mechanism of reactivated expression of CD133 was also investigated. A small percentage (about 2-5%) of CD133(+) DU-145 cells were detected after DU-145 cell culturing using DWJM for 3-7 days. Sorted CD133+ cells formed more colonies in vitro and manifested some characteristics of Epithelial-to-Mesenchymal Transition (EMT), including increased nuclear to cytoplasmic ratio and spindle-cell morphology. The undetectable expression of CD133 mRNA and protein in parental DU-145 cells was at least partly caused by promotor methylation, while culturing using DWJM reactivated the expression of CD133 by demethylating the CD133 DNA promotor. Taken together, our in vitro findings provide preliminary findings to support the possible conversion of disseminated PC cells to PCSC by epigenetic modulation in the BMM, and these early findings warrant further validation using an in vivo mouse model.
Citation Format: Jianhui Yang. A novel 3D model investigating the pathophysiology of prostate cancer bone marrow metastasis [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 4202.
Abstract 4216: Indication agnostic evaluation of CAR T cell function using patient-derived immunocompetent tumoroid modelling platform
Authors: Ochola Damieanus O. , Mundo Huckie Dell , Samuel Preethi , Korkorina Natalia , Dave Bhuvanesh 
Published: March 2024

Abstract
Introduction: Engineered T cells redirected towards tumor-specific cytotoxicity is a promising immunotherapeutic modality that has been well characterized for efficacy against B cell malignancies and evaluated in multiple tumor types. However, the development and optimization of CAR T cell therapies requires a rigorous preclinical model for the evaluation of CAR T cell function, tumor killing, cytokine production, and memory responses.
Experimental Procedure: We are evaluating our model platform Custom Organoid Modelling Platform for Accurate and Speedy SolutionS (COMPASS 2) as a comprehensive platform for testing developmental and functional stages of CAR T cells including activation, memory, and exhaustion. We are performing qualitative and quantitative analyses of surface markers to recapitulate the complexity of human cancer. Additionally, since CAR T cells mediate crosstalk with other immune components in the TME, we also evaluate and monitor the presence of B cells, NK cells, macrophages, and endogenous T cells. Triple Negative Breast Cancer (TNBC); Immunophenotyping (IP); Immunofluorescence (IF); Fluorescence Activated Cell Sorting (FACS); T regulatory (Treg).
Summary of Results: Our evaluation of COMPASS 2 for functional testing of CAR T cells demonstrates the feasibility of the platform in preclinical CAR T cell evaluation. We showed T cell infiltration and analyzed cytokine production that may alter tumor cells and TME. Crosstalk with other immune cells will be evaluated. We are currently evaluating the tumor volume changes using an EGFRvIII-targeted CART cell therapy on TNBC model systems, followed by apoptosis and EGFR analysis using FACS.
Conclusion: Our COMPASS 2 model platform enables studies that require recapitulating hurdles to CAR therapy, including antigen escape, T cell dysfunction and trafficking; to reveal an essential role of the endogenous immune response mediating the antitumor effect following CAR therapy.
Citation Format: Damieanus O. Ochola, Huckie Dell Mundo, Preethi Samuel, Natalia Korkorina, Bhuvanesh Dave. Indication agnostic evaluation of CAR T cell function using patient-derived immunocompetent tumoroid modelling platform [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 4216.
Abstract 4244: Clinical response assessment of immune checkpoint inhibitors in mismatch repair-deficient endometrial cancer using a T cell organoid coculture system
Authors: Oh Ju Hee , Choi Eun Hye , Lee Ji Eun , Nam Eun Ji 
Published: March 2024

Abstract
Endometrial cancers with the mismatch repair deficiency (MMR-D) phenotype exhibit characteristics such as an increased burden of tumor mutations and the presence of tumor-infiltrating lymphocytes (TILs) involved in tumor invasion. While monotherapy using immune checkpoint inhibitors (ICIs) has shown clinical improvement in MMR-D endometrial cancer (EC), observed response rates ranging from 30% to 50% suggest the existence of inherent resistance mechanisms. One notable feature of MMR-D tumors is the high proportion of tumor-infiltrating lymphocytes (TILs) encompassing various lymphocytes with diverse effects on immune interactions. Therefore, we aim to assess the feasibility of a self T-cell-tumor organoid co-culture platform for individual MMR-D endometrial cancer patients. We provide evidence that co-culturing self-tumor organoids with peripheral blood lymphocytes can be utilized to evaluate ICI responsiveness in MMR-D endometrial cancer patients. The application of a specific T-cell organoid co-culture platform to a cohort of patient resistant to monotherapy ICIs offers a means to anticipate the timing for minimal immunotherapeutic intervention and the appropriate timing for combination therapy.
Citation Format: Ju Hee Oh, Eun Hye Choi, Ji Eun Lee, Eun Ji Nam. Clinical response assessment of immune checkpoint inhibitors in mismatch repair-deficient endometrial cancer using a T cell organoid coculture system [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 4244.
Abstract 4302: ONECUT2 activates diverse resistance drivers of androgen receptor-independent heterogeneity in prostate cancer
Authors: Qian Chen , Yang Qian , Rotinen Mirja , Huang Rongrong , Kim Hyoyoung , Gallent Brad , Yan Yiwu , Cadaneanu Radu M. , Zhang Baohui , Kaochar Salma , Freedland Stephen J. , Posadas Edwin M. , Ellis Leigh , Vizio Dolores Di , Morrissey Colm , Nelson Peter S. , Brady Lauren , Murali Ramachandran , Campbell Moray J. , Yang Wei , Knudsen Beatrice S. , Mostaghel Elahe A. , Ye Huihui , Garraway Isla P. , You Sungyong , Freeman Michael R. 
Published: March 2024

Abstract
Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 targets include the glucocorticoid receptor (GR) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease.
Citation Format: Chen Qian, Qian Yang, Mirja Rotinen, Rongrong Huang, Hyoyoung Kim, Brad Gallent, Yiwu Yan, Radu M. Cadaneanu, Baohui Zhang, Salma Kaochar, Stephen J. Freedland, Edwin M. Posadas, Leigh Ellis, Dolores Di Vizio, Colm Morrissey, Peter S. Nelson, Lauren Brady, Ramachandran Murali, Moray J. Campbell, Wei Yang, Beatrice S. Knudsen, Elahe A. Mostaghel, Huihui Ye, Isla P. Garraway, Sungyong You, Michael R. Freeman. ONECUT2 activates diverse resistance drivers of androgen receptor-independent heterogeneity in prostate 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 4302.
Abstract 4342: Breast cancer multi-omic single cell profiling identifies key progressive disease markers
Authors: Russell Hugh , Rao Manisha , Duclos Grant , Aguilar Rogelio , Barkas Nick , Callahan Megan , Chaudhary Ojasvi , Gathungu Peter , Rands Chris , Shankarappa Varsha , Stetson Daniel , Rotem Asaf , Scaltriti Maurizio , Dougherty Brian 
Published: March 2024

Abstract
Breast cancer is one of the most diagnosed cancers and has a complex tumor microenvironment (TME). Breast tumors are subtyped by receptor expression, and all have a high degree of cellular heterogeneity. We analyzed tumors from 8 individuals with early-stage breast cancer. The patients had either triple negative breast (TNBC) or an estrogen receptor (ER) positive cancer. The tumors and normal adjacent tissue were profiled by single-nuclei gene expression (GEX) and ATAC data using the 10X multi-ome methodology. Gene set analysis identified specific epithelial clusters associated with the estrogen early/late response, epithelial mesenchymal transition, and several key cytokine pathways. From those epithelial cells, a subset highly proliferative in nature emerged. It consists of both ER positive and TNBC tumor types enriched for specific DNA transcriptional motifs including those for stem cell (Yamanaka) factors and other cellular proliferation motifs. GEX proliferation markers such as MKi-67 were also highly expressed. Overlaying GEX and ATAC data, it was possible to filter the numerous differentially expressed genes and peaks into a subset of genes specific to progressive breast cancer within the proliferative cluster. Those genes included ESRP1, POP4, CCNE1, and AAMDC all of which are associated with progressive breast cancer. To further elucidate the complexity of the TME, we examined clusters of fibroblasts from our dataset. A difference in cancer associated fibroblast marker gene expression was related to the level of ER expression expressed in the tumor epithelium. In general, ER-low tumor fibroblasts had higher expression of immune cancer associated fibroblasts (iCAFs) markers while ER-positive and TNBC tumors had greater expression of extracellular matrix associated markers (emCAFs). Specific clusters were enriched for emCAFs and iCAFs representing another critical part of the TME. In conclusion, using a multi-modal single-cell approach to the TME allowed the identification of an aggressive cluster of epithelial cells marked by genes for cellular proliferation and noted therapeutic targets while also characterizing other critical TME components especially, CAFs.
Citation Format: Hugh Russell, Manisha Rao, Grant Duclos, Rogelio Aguilar, Nick Barkas, Megan Callahan, Ojasvi Chaudhary, Peter Gathungu, Chris Rands, Varsha Shankarappa, Daniel Stetson, Asaf Rotem, Maurizio Scaltriti, Brian Dougherty. Breast cancer multi-omic single cell profiling identifies key progressive disease markers [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 4342.
Abstract 4423: Cholesterol and arachidonic acid promote the tumor growth of epithelial ovarian cancer via MAPK signaling pathway
Authors: Sakaguchi-Mukaida Hitomi , Hiramatsu Kosuke , Kakuda Mamoru , Nakagawa Satoshi , Kimura Toshihiro , Ueda Yutaka , Kimura Tadashi 
Published: March 2024

Abstract
Introduction: Previously, we reported that VLDL promoted cell proliferation of epithelial ovarian cancer (EOC) cells in vitro. In vivo, we also confirmed that High-Fat Diet (HFD) strongly promoted the tumor growth of EOC. These results suggest that lipid molecules in HFD might contribute to cell proliferation of EOC cell. In this study, we performed metabolome analysis and analyzed the metabolomic profile of lipid molecules of HFD fed mouse serum. Finally, we demonstrated that some lipid molecules promoted the cell proliferation of EOC cells in vitro and vivo.
Methods: We obtained the serum of HFD and normal diet (ND) fed mouse (non-tumor bearing) and performed metabolome analysis to identify the lipid molecules which associate with cell proliferation. In addition, we demonstrated that the lipid molecules promoted cell proliferation and activated signaling pathway of EOC cells in vitro. Moreover, we evaluated that the lipid molecules-rich diet promoted the tumor growth of EOC in vivo.
Results: The tumor growth of EOC (EOC cell line; KURAMOCHI and RMG-I) was significantly promoted by HFD compared to ND in vivo (p &lt; 0.05, respectively). Metabolome analysis using the serum of HFD and ND fed mouse (non-tumor bearing) detected 210 metabolites, and principal component analysis showed obvious different metabolic profiles of HFD fed mouse serum compared to ND. Partial least squares-discriminant analysis revealed cholesterol and arachidonic acid (AA) as the lipid molecules with high VIP score in the serum of HFD fed mouse. In vitro, cholesterol and AA significantly promoted cell proliferation, respectively (p &lt; 0.05) through the activation of MAPK signaling pathway. In vivo, we also confirmed that cholesterol and AA-rich feed promoted the tumor growth of EOC, respectively (p &lt; 0.05).
Conclusions: Cholesterol and AA significantly promoted the tumor growth of epithelial ovarian cancer through the activation of MAPK signaling pathway.
Citation Format: Hitomi Sakaguchi-Mukaida, Kosuke Hiramatsu, Mamoru Kakuda, Satoshi Nakagawa, Toshihiro Kimura, Yutaka Ueda, Tadashi Kimura. Cholesterol and arachidonic acid promote the tumor growth of epithelial ovarian cancer via MAPK signaling pathway [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 4423.
Abstract 4466: Omega-3 fatty acid-induced ferroptosis in 4T1 breast cancer through CD36/FABP5 axis
Authors: Avellino Anthony , Hao Jiaqing , Yorek Matthew , yu Jian , Li Bing 
Published: March 2024

Abstract
Mammalian cells utilize energy from many different sources, and fatty acids are one of these sources. Dietary fats contain various structures of fatty acids, each impacting cell lipid metabolism in unique ways. Omega-3 fatty acids are known to induce breast cancer cell death through ferroptosis. However, the specific molecular mechanisms by which omega-3 fatty acids trigger ferroptosis have yet to be fully elucidated. Fatty acid binding proteins (FABPs) constitute a family of evolutionarily conserved lipid chaperones, facilitating the transport and utilization of fatty acids within cells. Notably, FABP5 is highly expressed in breast cancer, especially in the most aggressive form, triple-negative breast cancer. We hypothesized that FABP5 acts as a lipid sensor, mediating the ferroptosis induced by omega-3 fatty acids in triple-negative breast cancer cells. To test this, we created Fabp5 stable knockout cell lines in 4T1 and MDA-MB-231, two commonly used triple-negative breast cancer cell lines, using CRISPR/Cas9 technology. When treated with docosapentaenoic acid (DPA), these Fabp5-knockout cells exhibited reduced ferroptosis compared to their wild-type counterparts. Interestingly, blocking the surface protein CD36, either with inhibitors or antibodies, also reduced DPA-induced ferroptosis. Furthermore, mutations in Fabp5 decreased maximal mitochondrial respiration in both 4T1 and MDA-MB-231 cells, suggesting a crucial role for FABP5 in mediating oxygen consumption and reactive oxygen species (ROS) production during DPA-induced ferroptosis. Additionally, mice fed a high-fat diet rich in omega-3 fatty acids showed reduced tumor size and lung metastasis. Collectively, our data indicate that FABP5 is a key molecular sensor mediating oxygen consumption and ROS production, thus contributing to ferroptosis induced by omega-3 fatty acids in triple-negative breast cancer.
Citation Format: Anthony Avellino, Jiaqing Hao, Matthew Yorek, Jian yu, Bing Li. Omega-3 fatty acid-induced ferroptosis in 4T1 breast cancer through CD36/FABP5 axis [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 4466.
Abstract 4513: Exploration degradation of intrinsically disordered protein YAP induced by PROTACs
Authors: Zhou Chen , Sun Chunbao , Pi Liya , Li Chenglong 
Published: March 2024

Abstract
Yes-associated protein (YAP), a potent oncogene and a key player in the Hippo tumor suppression pathway, has long been considered challenging to target due to its partially intrinsically disordered nature. However, recent advancements in High-throughput Screening (HTS) have yielded a breakthrough, as several YAP binders have been identified, igniting new possibilities in the quest to combat YAP-driven malignancies. Building upon this progress, a novel approach utilizing Proteolysis-Targeting Chimera (PROTAC) technology was employed to design and synthesize a series of YAP degraders. Here, our degraders were created by linking NSC682769, a previously reported YAP binder, with either VHL ligand 2 or pomalidomide using various linkers of different lengths and types. Among these degraders, YZ-6 emerges as the most promising, inducing rapid and sustained YAP degradation via promoting its ubiquitination-proteasome-dependent proteolysis. This process effectively suppressed YAP/TEAD-led transcription in both YAP-dependent NCI-H226 and Huh7 cancer cell lines. In addition to its degradation capabilities, YZ-6 also exhibited antiproliferative activity in both cell lines. Importantly, YZ-6 efficiently suppressed tumor development in the Huh7 xenograft mouse model, accompanied by a remarkable decrease in YAP levels, without adverse effects on the mice. These findings highlight the potential of PROTAC-mediated degradation as a viable strategy for reducing oncogenic YAP levels and attenuating downstream signaling in cancer cells. Moreover, the development of PROTACs based on NSC672869 holds promise for treating YAP-driven malignancies, opening new avenues for cancer therapy.
Citation Format: Chen Zhou, Chunbao Sun, Liya Pi, Chenglong Li. Exploration degradation of intrinsically disordered protein YAP induced by PROTACs [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 4513.
Abstract 4516: Inhibiting YAP activity in cancers by targeted degradation of TEAD
Authors: Chen Hui , Gridnev Artem , Schlamowitz Netanya , Zheng Guangrong , Misra Jyoti R. 
Published: March 2024

Abstract
The oncogenic transcriptional coactivators YAP/TAZ function as the terminal effectors of the Hippo signaling pathway and are dysregulated in many human cancers, where they promote cancer cell proliferation, survival, stemness, and resistance to targeted therapies, and thus provide a critical point for therapeutic targeting. YAP/TAZ activity is regulated by phosphorylation mediated by the kinase cascade of the Hippo signaling pathway, where phosphorylation causes cytoplasmic retention. Aberrantly activated Hypo/unphosphorylated YAP/TAZ translocates into the nucleus, where it exerts its oncogenic activity by associating with the TEAD1-4 transcription factors and inducing expression of genes encoding pro-proliferative and antiapoptotic factors. Since YAP/TAZ cannot be directly therapeutically targeted, its oncogenic transcriptional activity can be controlled indirectly by targeted degradation of TEAD. Here we report on the development of Proteolysis Targeting Chimeras that potently induces degradation of TEAD and inhibits YAP transcriptional activity and cell proliferation in YAP-dependent cancers.
Citation Format: Hui Chen, Artem Gridnev, Netanya Schlamowitz, Guangrong Zheng, Jyoti R. Misra. Inhibiting YAP activity in cancers by targeted degradation of TEAD [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 4516.