bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5515: Low body mass index (BMI) induces neuronal NPY and promotes brain metastasis of lung cancer
Authors: Tyagi Abhishek , Wu Shih-Ying , Deshpande Ravindra , Wu Kerui , Liu Liang , Watabe Kounosuke 
Published: March 2024

Abstract
Brain metastases (BrMs) are a common occurrence in lung cancer with a dismal outcome. To develop a more effective therapeutic strategy, it is crucial to understand the underlying pathological mechanism of brain metastasis. Recent clinical data has unveiled a significant association between low body mass index (BMI) and an increased risk of brain metastasis in lung cancer patients, leading to reduced survival rates compared to other primary tumors. However, the molecular mechanism underlying this paradoxical relationship, often referred to as the "obesity paradox," in the context of lung cancer mortality presents a complex and intriguing puzzle and warrants in-depth investigation. Here, we examined biological mechanism of how low BMI promotes lung cancer brain metastasis. In this study, we conducted a retrospective pan-analysis of 5,516 patient cohorts with brain metastasis originating from lung, breast, melanoma, and renal cancers with their BMI status. We found that lung cancer patients with low BMI have significantly higher brain metastatic incidence compared to the high BMI patients, in contrast to breast, melanoma, and renal cancers. Furthermore, we found that low BMI plays a pivotal role in mediating neuron activation within the brain and that the secretion of neuronal neuropeptide Y (NPY), a protein involved in appetite and energy homeostasis via GHSR-receptor manner, promotes metabolic switching through NPY/NPY5R axis in the tumor cells in the brain thereby enabling metastasis. Elevated levels of neuronal NPY in the brains of cancer-free subjects with low BMI suggest its potential utility as a promising prognostic biomarker for identifying the increased risk of metastatic disease in lung cancer patients with low BMI. We also demonstrated that reversing low BMI or blocking the NPY/Y5R interactions effectively abrogated brain metastasis in our animal model. Our findings suggest a novel pro-metastatic role of low BMI-induced NPY in the progression of brain metastasis. We emphasize the importance of elucidating the clinical implications of this relationship to develop an updated intervention strategy for the clinical care of patients with lung cancer and low BMI.
Citation Format: Abhishek Tyagi, Shih-Ying Wu, Ravindra Deshpande, Kerui Wu, Liang Liu, Kounosuke Watabe. Low body mass index (BMI) induces neuronal NPY and promotes brain metastasis of lung 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 5515.
Abstract 5524: Identification of PAEP as an immune activity modulator to mediate the immune resistance in tumor metastasis
Authors: Buenaventura Rand Gabriel M. , Chen Weiping , Zhang Shuling , Mock Beverly , Merlino Glenn , Yu Yanlin 
Published: March 2024

Abstract
Most cancer-related deaths are associated with the complex phenotypic behavior of metastasis, a process in which tumor cells spread from their initial site to distant sites. To successfully metastasize, the tumor cell will be required to make numerous adjustments and survive a series of stages involving intravasation, circulation in the blood or lymph system, extravasation, and growth at distant organs, and overcome the challenges of immunosurveillance. The tumor microenvironment is the ecosystem that surrounds and feeds the tumor. The molecular mechanism by which the metastatic tumors survive and escape from immune attack in the tumor microenvironment remains unclear. To study the molecular mechanism of interaction between metastatic tumors and the immune system in metastasis, we established immune-resistant metastatic models. We identified that PAEP, a progestogen-associated endometrial protein, is significantly upregulated in immune-resistant metastatic tumors compared with non-immune-resistant tumors. PAEP is a glycoprotein that inhibits cell immune function and plays an essential role in the pregnancy process. To examine the function of PAEP in tumor metastasis, we first introduced PAEP into non-immune resistant and poorly metastatic melanoma and rhabdomyosarcoma (RMS) cells. We found that overexpression of PAEP significantly promotes tumor metastatic potential of both melanoma and RMS cells in immunocompetent mice. Interestingly, there was no difference in metastasis between the control and overexpression groups in immunodeficient mice. These data suggest that PAEP may mediate tumor metastasis relating to host immunity. To further confirm the function of PAEP in tumor metastasis, we use CRISPR/Cas9 technology to knockout endogenous PAEP and will test the metastatic potential in different hosts. We will also investigate the molecular mechanisms using RNA sequencing and Digital Spatial Profiling (DSP) to analyze the metastatic samples. Our study will uncover a new mechanism for how tumors survive in the microenvironment and identify a novel target for the treatment of metastatic diseases.
Citation Format: Rand Gabriel M. Buenaventura, Weiping Chen, Shuling Zhang, Beverly Mock, Glenn Merlino, Yanlin Yu. Identification of PAEP as an immune activity modulator to mediate the immune resistance in tumor 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 5524.
Abstract 5527: Spatiotemporal analysis of growth factor regulation of osteosarcoma AKT and ERK signaling dynamics in an ex vivo lung metastasis model
Authors: Makkawi Rawan , Roberts Ryan D. , Copperman Jeremy , Davies Alexander E. 
Published: March 2024

Abstract
In the present study, we investigated the relationships between spatiotemporal distribution of growth factors in the lung microenvironment, metastatic osteosarcoma cell signaling, and intratumoral gene expression heterogeneity. Osteosarcoma is an aggressive bone malignancy that commonly metastasizes to the lungs, resulting in significant patient mortality. During metastasis, disseminated cancer cells are exposed to microenvironment-derived growth factors that result in signaling pathway activation. Two such pathways are MAPK/ERK and PI3K/AKT, which regulate complex transcriptional programs underlying cell proliferation and survival decisions. In this study, we utilized precision cut lung slices (PCLS) obtained from mice with established osteosarcoma metastases to ex vivo model associations between the spatiotemporal distributions of growth factors in the lung, osteosarcoma signaling dynamics, and intratumoral gene expression heterogeneity, with single cell precision. To accomplish this, we engineered osteosarcoma cells that co-expressed genetically-encoded ERK and AKT sensors, engrafted them into PCLS tissues, then recorded sensor dynamics via live-cell microscopy. These tissues were subsequently fixed and immuno-stained for measurement of growth factor expression in resident lung cells and spatial correlation with observed tumor cell ERK-AKT signaling dynamics. Using this approach, we found that growth factor expression was diffusely increased within areas bordering osteosarcoma metastases. FGF2 and IGF1, which we have previously demonstrated to potently induce ERK signaling in osteosarcoma cells, were both significantly upregulated in these regions. However, despite relatively uniform overexpression of growth factors adjacent to tumors, individual osteosarcoma cells displayed stochastics patterns of ERK and AKT signaling, and downstream gene targets. These findings revealed that upregulation of lung growth factors, and the inherent systems-level properties of osteosarcoma signaling networks, can converge to promote intratumoral signaling and gene expression heterogeneity. Together, our results, using a novel PCLS and live-cell biosensor imaging approach, provide new insight into how spatial and temporal changes in microenvironmental signaling composition are integrated by metastatic osteosarcoma cells to promote heterogeneity.
Citation Format: Rawan Makkawi, Ryan D. Roberts, Jeremy Copperman, Alexander E. Davies. Spatiotemporal analysis of growth factor regulation of osteosarcoma AKT and ERK signaling dynamics in an ex vivo lung metastasis model [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 5527.
Abstract 553: Assessment of CNTN4 expression and its association with PD-L1 across 18 various cancers using an artificial intelligence-powered immunohistochemistry analyzer
Authors: Shin Seunghwan , Moon Jimin , Cho Soo Ick , Ock Chan-Young , Jeon Bu-Nam , Kim Gyeongyeon , Yu Hyunkyung , Cha Miyoung 
Published: March 2024

Abstract
Background: Contactin-4 (CNTN4) has been identified as an inhibitory immune checkpoint protein and mainly expressed on tumor cells. It interacts with APP present in T cells, leading to a reduction in T cell proliferation, activation, and responsiveness to tumors. In this study, we applied artificial intelligence (AI)-powered analyzers to examine the expression of CNTN4 and its association with PD-L1 in various solid tumors.
Methods: The AI-powered immunohistochemistry (IHC) analyzers were developed using pan-cancer whole slide images (WSIs) stained with 18 different IHC types. Pathologists annotated cells and tissues on the WSIs. The universal model was trained by annotations from IHC WSI, which could detect tumor cells with four grade intensities (strong, moderate, weak, and negative) and segment invasive cancer area. Finally, the AI analyzer can count the tumor cells in an invasive cancer area and calculate the ratio based on intensity. The AI analyzer was applied to the pan-cancer tissue microarray dataset (n=795) consisting of 18 cancers to validate the analyzer. The dataset was stained with rabbit monoclonal antibody (clone EPR 8735) and PD-L1 22C3 antibody, respectively. The expression levels of CNTN4 and PD-L1 were calculated with H-score (range 0 to 300) or tumor proportion score (TPS).
Results: When positivity was defined as moderate-to-strong staining intensity in ≥ 30%, 50%, 75%, and 90%, 42.4% (337/795), 25.5% (203/795), 11.4% (91/795), and 5.2% (41/795) of samples were CNTN4 positive, respectively. In case of moderate-to-strong staining in ≥ 50% tumor cells, CNTN4 expression were most frequently observed in hepatocellular carcinoma (63.9%), endometrial carcinoma (50.0%), stomach cancer (43.9%), pancreatic cancer (40.0%), and prostate cancer (35.4%). Notably, 10% of cases with an H-score &lt; 200 (75/757) showed a range of PD-L1 expression (PD-L1 TPS ≥ 1%), while all of the samples with an H-score ≥ 200 (n=38) were PD-L1 TPS &lt;1%.
Conclusions: This study describes the CNTN4 expression levels in various tumors using an AI-powered IHC analyzer. CNTN4 tends to be expressed in opposition to PD-L1, making it a viable immune therapeutic target in cancers that do not conventionally express PD-L1.
Citation Format: Seunghwan Shin, Jimin Moon, Soo Ick Cho, Chan-Young Ock, Bu-Nam Jeon, Gyeongyeon Kim, Hyunkyung Yu, Miyoung Cha. Assessment of CNTN4 expression and its association with PD-L1 across 18 various cancers using an artificial intelligence-powered immunohistochemistry analyzer [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 553.
Abstract 5541: The unique metabolite landscape of the aged microenvironment dictates melanoma migratory and invasive capacity
Authors: Alicea Gretchen Marie , Patel Payal , Wei Meihan , Rebecca Vito , Wirtz Denis 
Published: March 2024

Abstract
Metastatic burden and organ failure are the root causes of mortality in patients with advanced melanoma; however, little is known of the metabolic drivers that enable organ colonization and the formation of overt metastases. Recent studies have drawn attention to the importance of metabolism in the survival and colonization of cancer cells. In melanoma, there have been studies focusing on the invasive capabilities of cells; however, not much is known regarding metabolic plasticity in melanoma migratory, invasive and ultimately metastatic capabilities.We have previously shown changes in the lipid landscape of the aged microenvironment promotes melanoma resistance to targeted therapy. Here, we find a distinct metabolite landscape in the aged microenvironment elevates melanoma metastatic capacity. We utilized a panel of well characterized melanoma models and tested their invasiveness and motility under different metabolite levels modeled after the aged microenvironment. Transcriptomic and proteomic analysis identifies distinct signatures that explain the migratory and invasive differences in cells cultured in varying metabolic environments. We hypothesize that different nutrient availabilities melanoma cells are exposed to during the metastatic phase affect the migratory and invasive capacity of the cell. We tested this by performing 3D migration assays, organoids and transwell assays of cells grown in media with varying nutrient levels. Further analysis is currently underway to better understand the mechanisms in which these metabolic differences facilitate cell migration, invasion and eventually colonization. This work has important implications for our understanding of the metabolic determinants of melanoma migration and metastatic colonization, and we hypothesize restraining tumor metabolic plasticity is vital to prevent and treat metastases in melanoma.
Citation Format: Gretchen Marie Alicea, Payal Patel, Meihan Wei, Vito Rebecca, Denis Wirtz. The unique metabolite landscape of the aged microenvironment dictates melanoma migratory and invasive capacity [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 5541.
Abstract 5545: FADD activation renders hepatocellular carcinoma sensitive to immune checkpoint blockade by turning cold tumors hot
Authors: Zhou Jingying , Lu Jiahuan 
Published: March 2024

Abstract
The heterogenicity of hepatocellular carcinoma (HCC) remains a key obstacle in turning the majority of ‘immune-cold’ tumors ‘hot’ for effective immune checkpoint blockade (ICB) therapy. Through studying the naturally-existed ‘hot’ HCC variant lymphoepithelioma-like (LEL)-HCC by RNA and whole exome sequencing analysis, we identified fas-associated death domain (FADD) as one of the top differentially expressed genes that associated with high tumoral CD8+T cell abundance. Of note, FADD upregulation was also observed in HCC patients with better ICB responsiveness. As FADD was mainly expressed in tumor cells from HCC by scRNAseq analysis, we constructed Fadd knockout stable cells using murine HCC cell lines. Interestingly, CRISPR knockout of tumoral Fadd led to increased tumor weights in immunocompetent but not immunodeficient mice, accompanied with decreased tumoral CD8+T cells. Mechanistically, FADD phosphorylation promoted NF-κB transcriptional activity to increase CCL5 secretion from HCC cells via interacting with its nuclear binding partners Src-associated-substrate-during-mitosis-of-68kDa/KH domain containing, RNA binding, signal transduction associated 1 (Sam68/KHDRBS1) and lysine (K)-specific methyltransferase 2D (KMT2D), thus directing CD8+T cell tumor infiltration. In addition, anti-PD1 triggered FADD phosphorylation via IFN-γ and TNF-ɑ release from CD8+T cells in ICB-sensitive but not resistant tumors. Most importantly, sequential FADD activation via genetic and pharmacologic approaches could re-sensitize the therapeutic efficacy of anti-programmed death 1 (PD1) antibody in ICB-resistant orthotopic and spontaneous HCC models by turning cold tumors hot. Taken together, our findings reveal a key molecular feature of ICB-responsive hot tumors that may guide the development of sequential combinatory immunotherapies for the majority of HCC patients with low responsiveness to ICB monotherapy. This project is supported by the University Grants Committee through General Research Fund (24110323, 14107622, 14104820) and the Health and Medical Research Fund (07180556).
Citation Format: Jingying Zhou, Jiahuan Lu. FADD activation renders hepatocellular carcinoma sensitive to immune checkpoint blockade by turning cold tumors hot [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 5545.
Abstract 5560: Role of SPARC and collagen in immunogenicity of cancer: A theoretical approach
Authors: Are Ramakrishna Prasad , Babu Anju R 
Published: March 2024

Abstract
Secreted protein acidic and rich in cysteine (SPARC), is a multifunction protein that interacts with extracellular matrix (ECM), cell surface receptors, and signaling molecules. These interactions in cancer cells result in less susceptible of cells to the immune system, leading to poor prognosis. SPARC plays a crucial role in transporting collagen, a significant component of the ECM, from the site of synthesis to the basement membrane of the cells. Collagen mediated rigidity enhancement of cell microenvironment promotes cancer cell growth, proliferation, and angiogenesis. Collagen remodeling plays a complex and multifaceted role in cancer immunomodulation. Our current research focuses on exploring the cancer treatment mechanism by immunomodulation based on SPARC and collagen through theoretical and computational approaches. Our previous investigations identified SPARC and collagen as potential biomarkers for targeting cancer cells. Our current theoretical research identifies the role of SPARC and collagen in tuning the tumor microenvironment and altering the immune system cell surface receptors. This theoretical investigation is followed by computational study to formulate the pathway from secretions of both SPARC and collagen to reprogramming of tumor microenvironment. SPARC and collagen’s effects on the cell immune system are analyzed by performing molecular interaction and molecular dynamics studies for SPARC and collagen with the cell surface receptors. From our study, we identify the cellular mechanisms involved either actively or passively in the progression and prognosis of the cancer. Our study will provide insight into a novel pathway for targeting the cancer microenvironment, which will be helpful in the formation of low-dosage cancer drugs, resulting in the decreased adverse effects of drugs and increased patient quality of life.
Citation Format: Ramakrishna Prasad Are, Anju R Babu. Role of SPARC and collagen in immunogenicity of cancer: A theoretical approach [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 5560.
Abstract 5564: The regulation of PD-L1 in glioblastoma cells involves Pyk2 signaling
Authors: Porter Tyrel , Kucheryavykh Lilia 
Published: March 2024

Abstract
Glioblastoma (GBM), the most aggressive brain cancer which is usually fatal within a year after diagnosis, poses a significant therapeutic challenge with conventional treatments providing limited success. Despite advancements in immune checkpoint blockade, PD-L1 inhibitors exhibit suboptimal efficacy in recurrent GBMs with recent clinical trials demonstrating only 8% objective responses in patients. Utilizing the R2 Genomic Analysis Visualization Platform, we identified a positive 8-18% correlation between Pyk2 and PD-L1 gene expression in human GBM specimens. We hypothesize that Pyk2 signaling is involved in the regulation of PD-L1 expression in GBM cells. In this study, primary human glioblastoma cell lines and GL261 mouse glioma cells were assessed employing CRISPR/Cas9 Pyk2 knockout (Pyk2KO) combined with pharmacological Pyk2 inhibition. Flow cytometric analysis revealed a 35% decrease in PD-L1 expression in Pyk2KO GL261 cells compared to wild-type cells. SiRNA knockdown against Pyk2 in primary human GBM cells demonstrated a similar response, with a 50% decrease in PD-L1 expression compared to MOCK control cells. Additionally, the application of the Pyk2/FAK inhibitor defactinib at a concentration of 0.2 μM reduced PD-L1 expression by 32% in both GL261 and primary human GBM cells. These findings highlight Pyk2 as a potential therapeutic target for modulating the immunosuppressive microenvironment in GBM and enhancing the effectiveness of immune checkpoint blockade therapies.
This study was supported by: NIH Grant 1SC1GM122691 and PRSTRT2022.
Citation Format: Tyrel Porter, Lilia Kucheryavykh. The regulation of PD-L1 in glioblastoma cells involves Pyk2 signaling [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 5564.