bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1149: Universal redirection of chimeric antigen receptor T cells against solid tumors via tumor cell membrane-inserting CAR ligands
Authors: Zhang Angela 
Published: June 2023

Abstract
Chimeric antigen receptor (CAR) T cell therapy is effective in treating certain hematological malignancies, but its translation to solid tumors has been challenging. Selecting an effective target antigen is hampered by heterogeneous tumor antigen expression and target antigen expression in healthy tissues. We describe a strategy to promote CAR T-mediated destruction of any tumor via intratumoral administration of a membrane-inserting fluorescein isothiocyanate lipid amphiphile molecule (“amph-FITC”) recognizable by a FITC-specific CAR. Firstly, we show labeling of tumor cells with amph-FITC in vitro, mediating cytotoxicity by FITC CAR T cells in coculture. Then, we demonstrate efficient tagging of tumor cells in vivo upon intratumoral injection with minimal labeling of non-tumor tissues, driving FITC CAR T cell proliferation and accumulation in tumors. Subsequently, we determine that this strategy stimulates an anti-tumor response that facilitates tumor regression in several syngeneic and human xenograft mouse models bearing different tissues of origin. In syngeneic models, this strategy induced the infiltration of host T cells and elicited endogenous tumor-specific T cell priming, leading to protection against tumor rechallenge. These results demonstrate the capacity to treat tumors independent of antigen expression or tissue of origin, addressing a major bottleneck in adoptive T cell therapy.
Citation Format: Angela Zhang. Universal redirection of chimeric antigen receptor T cells against solid tumors via tumor cell membrane-inserting CAR ligands [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 1149.
Abstract 124: Autocrine signaling extends PD-L1 expression in NSCLC following an active immune response
Authors: Bursell Taylor M. , Prabhakaran Sandhya , Luddy Kimberly , Pineriro Julian , Bravo Rafael , West Jeffrey , Robertson-Tessi Mark , Beg Aner , Gray Jhanelle , Antonia Scott , Gatenby Robert , Anderson Alexander 
Published: June 2023

Abstract
Checkpoint inhibitors disrupting the PD-1/PD-L1 axis are used in multiple cancer subtypes. However, not all patients respond, and predictive biomarkers are needed to better stratify patients. PD-L1, the most studied biomarker, has given mixed results. The complexity of the immune response and plastic nature of PD-L1 expression on tumor and immune cells contributes to the heterogeneity of success. Not all malignant epithelial cells express PD-L1: some express it only when the correct signal is present, while others have constitutive expression. Additionally, the PD-L1 protein has multiple functions outside immune regulation, making its dynamics difficult to predict. In this study, we investigate these complex PD-L1 dynamics through a unique combination of in vitro studies and mathematical modeling simulations. IFN-γ, a pleotropic cytokine released by activated immune cells, induces PD-L1 expression in some tumor cells. Chronic IFN-γ results in long-term PD-L1 expression. However, relaxation dynamics following removal of IFN-γ remains unexplored. We show that PD-L1 relaxation depends on autocrine signaling, demonstrated by multiple in vitro assays seeded with varying population densities. Following 48h IFN-γ treatment, sub-confluent tumor cell populations demonstrated increased duration of PD-L1 expression, linking cell density to PD-L1 expression. Conditioned-media from A549 cells previously treated with IFN-γ induced PD-L1 on IFN-γ naïve tumor cell populations, indicative of autocrine signaling not previously identified. To reinforce our in vitro findings, we develop a hybrid agent-based model (ABM) to study PD-L1 dynamics. Tumor cells have variable PD-L1 expression and IFN-γ is modeled via reaction-diffusion. IFN-γ triggers tumor cells to secrete a diffusible factor that promotes PD-L1 expression. Initial fits of the ABM capture in vitro data dynamics for different conditions. In this ongoing project, we plan to identify the underlying mechanism responsible for extended PD-L1 expression in NSCLC cells, including investigation into specific molecular pathways. Identifying the cause for this phenomenon could help clinicians improve targeted therapy and introduce a potential avenue to enhance treatment in patients responsive to checkpoint inhibitors.
Citation Format: Taylor M. Bursell, Sandhya Prabhakaran, Kimberly Luddy, Julian Pineriro, Rafael Bravo, Jeffrey West, Mark Robertson-Tessi, Aner Beg, Jhanelle Gray, Scott Antonia, Robert Gatenby, Alexander Anderson. Autocrine signaling extends PD-L1 expression in NSCLC following an active immune response [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 124.
Abstract 1304: Multiomic approaches to illuminate molecular drivers of breast cancer metastasis to the liver
Authors: Silberberg Gilad , Mosesson Yaron , Khoury Haia , Ren Xuan , Gilardi Mara , Hanson Art , Zipeto Marianna , Ritchie Michael 
Published: June 2023

Abstract
The lack of knowledge around the mechanisms underlying metastatic progression is a major hurdle in achieving a durable response in the treatment of metastatic breast cancer (BC). Accordingly, effective therapies are not yet available, and the treatment of metastatic BC remains an unmet critical medical need. Circulating BC cancer cells can colonize the lungs, bone, brain, and liver generating metastatic lesions, which lead to poor outcomes. Liver metastases account for 30% of metastatic BC cases, therefore causing the greatest therapeutic challenge. The first line of therapy for BC liver metastasis is typically an invasive surgical resection, which unfortunately does not always resolve the metastatic lesion and requires further treatment. Unfortunately, there is currently no therapeutic standard of care (SOC) for BC liver metastasis, and therapy is selected based on the molecular profiling of primary tumor and metastasis biopsies. The scarcity of reliable and biologically relevant human experimental models, to provide a deep understanding of the molecular interactions underlying metastasis, is warranted. In this study, we exploit multiomic interrogation of breast cancer PDX models established from primary lesions, and metastasis of the liver, to uncover the molecular mechanisms underlying BC cells liver colonization. The results highlight global molecular differences between models derived from primary BC tumors and BC lesions collected from the liver. The analysis also reveals several genes at the DNA, RNA, and protein expression/activity level aiding in the adaptation of BC cell colonization in the liver. These novel findings provide insight into novel mechanisms of BC liver metastasis and highlight several targets suitable for future therapeutic intervention.
Citation Format: Gilad Silberberg, Yaron Mosesson, Haia Khoury, Xuan Ren, Mara Gilardi, Art Hanson, Marianna Zipeto, Michael Ritchie. Multiomic approaches to illuminate molecular drivers of breast cancer metastasis to the liver [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 1304.
Abstract 1328: Building a 3D co-culture model for metastatic pancreatic ductal cancer using Curiochips microphysiological system
Authors: Kim Sumin , Choi Yeongmin , Baek Jihye , Garg Bharti , Pencik Jan , Lowy Andrew M. , Tiriac Herve , Yoo Sanghee 
Published: June 2023

Abstract
Despite the use of multi-agent conventional chemotherapy regimens, metastatic pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid tumors with a 5-year survival of 9%. PDAC is characterized by a complex tumor microenvironment with multilayered interplay between neoplastic and stromal cells and the natural extracellular matrix (ECM). To date, models that recapitulate the complexity of these features are only partially reproduced ex vivo and lack the capacity to recreate PDAC tumor microenvironment physiology, fluid flow and the ECM architecture. To address these issues, we developed Curiochips MPS platform for metastatic PDAC on-a-chip. To replicate an accurate PDAC complex tumor microenvironment, we investigated human pancreatic cancer cell lines with/without SMAD4 mutation as a test model. SMAD4 is among the most frequently altered genes in PDAC and its mutation accelerates pancreatic cancer cell migration. To tailor cell-ECM interactions and recreate natural biochemical environment of tumors, we examined various ECM conditions. ECM substitutes such as type I collagen and fibrin gel offer mechanical properties to closely mimic the tumor ECM. We accessed the effect of ECM condition on the pancreatic stellate cells (PSC) activation and pancreatic cancer cell migration using PANC-1 (SMAD4-WT) and BxP3 (SMAD4-null) cell lines. Notably, type I collagen induced more PSC activation than fibrin gel. Interestingly BxP3 spheroids migrated toward to the endothelial compartment compared to PANC-1. Angiogenesis of endothelial cells was more prominent in co-culture with BxP3 than PANC-1. Furthermore, we are building the metastatic model using PDAC patient derived organoids and co-culture with primary PSC in different types of ECM. Preliminary analysis showed functional responses such as 3D organoid migration and aggregation, PSC activation and migration controlled by specific properties of EMC. Our data highlight the importance of the ECM composition on PDAC migration, PSC activation and angiogenesis in the context of genetic heterogeneity and presence/absence oncogenic mutation. The 3D co-culture platform, Curiochips offers suitable and tailored solution to investigate tumor-stroma interaction and potentially can be used as a platform for drug discovery and precision oncology to target PDAC desmoplastic tumor microenvironment.
Citation Format: Sumin Kim, Yeongmin Choi, Jihye Baek, Bharti Garg, Jan Pencik, Andrew M. Lowy, Herve Tiriac, Sanghee Yoo. Building a 3D co-culture model for metastatic pancreatic ductal cancer using Curiochips microphysiological system [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 1328.
Abstract 1331: A novel approach to treating hormonal breast cancer using clinical database and 3D ex vivo model
Authors: Song Chaeun (Christine) , Lee SeungBaek 
Published: June 2023

Abstract
Type 2 diabetes (T2D) female patients have a higher risk of being diagnosed and have worse survival for breast cancer compared to non-diabetic females. Although the relationship between these two female diseases has been reported, specific functional studies on which subtypes of breast cancer are affected and which genes are regulated by T2D are little known. Here, I found that Forkhead Box A1 (FOXA1) and Metformin, anti-diabetic medication for T2D, affect hormonal positive (HR+) breast cancer tumor cell growth and metastasis. 14 diabetes-related genes highly expressed in three HR+ breast cancer cell lines but not other breast cancer subtypes using a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1, MTA3, PAK4, FGFR3, and KIF22 were highly expressed in HR+ breast cancer from 4,032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Specifically, the high expression of FOXA1 correlated to a worse ER+/PR+ breast cancer patient survival rate. Consistent with this, the loss of FOXA1 inhibited the tumor proliferation and invasion of MCF-7 and T47D HR+ breast cancer cell lines using in vitro. Metformin (1,1-dimethylbiguanide hydrochloride) conspicuously inhibits the tumor cell growth in MCF-7 human hormonal breast cancer cells. Metformin or FOXA1 deletion enhanced Tamoxifen-mediated tumor growth inhibition in HR+ breast cancer cell lines through the ex vivo three-dimensional (3D) organoid model. Therefore, HR+ breast cancer is closely related to T2D, and metformin and FOXA1 inhibition might be an optimal new treatment for patients with HR+ breast cancer when combined with tamoxifen, a hormone therapy.
Citation Format: Chaeun (Christine) Song, SeungBaek Lee. A novel approach to treating hormonal breast cancer using clinical database and 3D ex vivo model [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 1331.
Abstract 1333: A novel and highly efficient biomimetic capture approach for the isolation and characterization of circulating metastatic cancer cell clusters from lung cancer patients
Authors: Kouhmareh Kourosh , Martin Erika , Finlay Darren , Bhadada Anukriti , Downey Francisco , Allen Jeff A. , Teriete Peter 
Published: June 2023

Abstract
Capture and isolation of circulating metastatic cancer cell clusters (MCCC) is the essential first step to identify novel therapeutic targets focused on this important route of metastasis. We developed a unique biomimetic capture approach that allows selective isolation of these deadly clusters from the whole blood of lung cancer patients. Utilizing a microfluidic platform we developed a versatile smart-coating that combines biomimicry and immuno-capture for a highly efficient and selective isolation of viable MCCCs. Here we show the capture and characterization of multiple MCCCs from non-small cell lung cancer (NSCLC) patients. Table 1 shows the count of clusters detected in NSCLC patients based on a stringent criterion confirming their identification. The MCCCs were detected in every patient tested but none were detected in normal blood controls from donors of similar age. Isolated MCCC where characterized by immunofluorescence and submitted for genomic analyses.
Metastasis remains one of the leading causes of cancer related deaths worldwide. Insights into how the tumor propagates to pre-metastatic sites is necessary to develop focused therapeutic approaches. Circulating metastatic cancer cell clusters (MCCCs) have been established as a primary entity causing distal metastases. Significant advances have been made linking cluster integrity and viability to increased metastatic potential highlighting the unmet need for cluster focused therapies.
Our novel approach allows the rapid and easy capture of MCCCs paving the way for the discovery of novel or unique targets that eventually will bring new anti-metastatic therapies to the clinic.
Table 1 Patient Age/Sex Staging/Metastasis #MCCC INMC-044.1 82 M IVB/bone 2 INMC-044.2 53 F IV/bone 1 INMC-044.3 59 F IV/bone, brain 2 INMC-044.4 65 M IV/thoracic cav., lung 1 INMC-044.5 67 M IIIa/none 3 Normal Blood 54 F N/A 0 Normal Blood 68 M N/A 0
Citation Format: Kourosh Kouhmareh, Erika Martin, Darren Finlay, Anukriti Bhadada, Francisco Downey, Jeff A. Allen, Peter Teriete. A novel and highly efficient biomimetic capture approach for the isolation and characterization of circulating metastatic cancer cell clusters from lung cancer patients [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 1333.
Abstract 134: Lymph node metastases are seeded via two distinct ways in phylogenetic study of gastric cancer
Authors: Cheng Pei-Chi , Hung Wei-Ting , Jeng Yung-Ming , Lai I-Rue 
Published: June 2023

Abstract
Backgrounds: Gastric cancer (GC) ranked 5th and 8th on the list of cancer related deaths worldwide and in Taiwan, respectively. Due to its high frequency of lymph node spread, lymph node dissection has become a standard procedure in surgical treatment. A randomized trial showed that patients who underwent D2 lymphadenectomy had a better 5-year survival outcome than ones who had D1 dissection in advanced gastric cancer, implying the D2 lymph node might serve as an outpost before tumor cells spread to distant organs. This clinical observation raises a possibility that the regional lymphatic spread could be under strict selection but not a passive process.
Materials and Methods: To understand the evolutionary relationship between primary tumors, perigastric lymph nodes, and second tier of lymph nodes in the extra-perigastric area, we reconstruct their phylogeny using genetic variants in hypermutable DNA regions where the mutation rate is 102~104-fold than unique sequence. We have assembled a cohort of 10 gastric cancer patients, including intestinal-, diffuse- and mixed type GC. For each case, we collected all workable lymph node metastases and intensely sampled primary tumors. On average, we have over fifteen samples per case on the phylogenetic tree.
Results: Preliminary data of the first two patients show high heterogeneity within primary tumors as well as between different lesions of lymph nodes or peritoneal metastases in gastric cancer. Interestingly, in stark contrast to all other lymph node metastases which intermingle with primary tumors, a clade consisting of one proximal and one distal lymph node with a bootstrap value above 90% is observed in each phylogeny, and it is worth noting that samples on these clades are from intestinal type tumor.
Conclusion: Our results indicate that most tumor cells arrive both regional and distal lymph nodes passively via lymphatic drainage in GC while a selective process also exists which coincides with clinical observation. Whether the existence of tumor cells under a relatively stricter selection process would lead to different clinical outcomes is under investigation.
Citation Format: Pei-Chi Cheng, Wei-Ting Hung, Yung-Ming Jeng, I-Rue Lai. Lymph node metastases are seeded via two distinct ways in phylogenetic study of gastric 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 134.
Abstract 1378: Proguanil inhibits breast cancer in vitro and in vivo through mitochondrial dysfunction
Authors: Curcic Marina , Gupta Nehal , Srivastava Sanjay K. 
Published: June 2023

Abstract
Breast cancer remains the second leading cause of cancer-related death among women in the U.S. New treatments for this aggressive disease are thus urgently needed. Repurposing FDA-approved non-cancer drugs for cancer treatment is an alternative that saves time and lowers the costs needed for drug development. In this study, we investigated the effects of proguanil, an anti-malarial drug, in breast cancer cells. Proguanil exhibited a significant cytotoxic effect on various breast cancer cell lines including patient derived cell lines through induction of apoptosis. Our results indicated that proguanil treatment caused a 3-fold increased production of ROS compared with control and reduced the mitochondrial membrane potential, mitochondrial respiration rate, and ATP production. Our studies also revealed the phosphorylation of H2AX, a marker for DNA damage. Proguanil treatment further increased the expression of apoptotic markers Bax, cleaved PARP, cleaved-caspase 9, and down-regulated anti-apoptotic Bcl-2 and survivin in breast cancer cells. Oral administration of 20mg/kg of proguanil significantly inhibited the tumor growth by 55% in mice model. Western blot analyses of tumors from proguanil-treated group showed increased levels of p-H2AX, Bax, c-PARP, and c-caspase3 compared to control. Taken together, our results demonstrate the anti-cancer effect of proguanil by targeting mitochondria, and can be considered for clinical investigation against breast cancer.
Citation Format: Marina Curcic, Nehal Gupta, Sanjay K. Srivastava. Proguanil inhibits breast cancer in vitro and in vivo through mitochondrial dysfunction [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 1378.
Abstract 1380: Blocking autophagy ameliorates the severity of ConA induced autoimmune hepatitis in mice
Authors: Wang Juan , Qian Cheng , Yangmeng Chuanzhi , Fang Li , Yan Ruiqing 
Published: June 2023

Abstract
Autoimmune hepatitis (AIH) recognized as a typical inflammation-triggered liver disease, which usually begins as acute hepatitis and ultimately develops to fibrosis, liver damage, loss of function of liver. It largely leads to the disease-related mortality and morbidity. However, the mechanism AIH remains unclear and the novel therapeutic reagents and methodology are urgently needed. In the present study, we established the ConA induced autoimmune hepatitis model in-house and evaluate autophagy and other immune signaling pathway on the participation of AIH. Our results bring the direction for the future direction of novel therapeutic reagents discovery.
Citation Format: Juan Wang, Cheng Qian, Chuanzhi Yangmeng, Li Fang, Ruiqing Yan. Blocking autophagy ameliorates the severity of ConA induced autoimmune hepatitis in mice [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 1380.