bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5364: Progesterone receptor modulates the antigen processing and presentation machinery decreasing MHC class I expression on tumors
Authors: Tinoco Julio , Werner Lauryn , Chowanec Eilidh , Saunders Harmony , Xiaopeng Sun , Gertz Jay , Balko Justin , Hartman Zachary C. , Hagan Christy 
Published: March 2024

Abstract
Hormone receptor (HR) positive breast cancers, which account for approximately 75% of all breast cancers and express both estrogen receptor (ER) and progesterone receptor (PR), have been the subject of much research. As such, successful anti-estrogen/ER-based therapies have been very successful in the treatment of HR+ breast cancer. Despite this success, over 1/3 of patients will eventually progress on current ER/estrogen-targeted therapies, underscoring the need for new targeted therapies in HR+ breast cancer. Unlike ER, the role of PR in breast cancer progression has received far less attention. In a previous study, we found that a mouse mammary tumor cell line E0771, modified to express the mouse progesterone receptor (mPR) and the OVA peptide, demonstrated decreased T cell-mediated cell death when treated with progesterone compared to the control group. Progesterone-mediated protection from T-cell death was only observed in mPR+ cell lines. Flow analysis of the E0771-Ova-mPR cells also revealed a decrease in MHC Class I presentation in progesterone-treated cells compared to a vehicle control. To further explore the role of the machinery required for antigen processing and presentation of MHC Class I molecules, we conducted additional experiments using the E0771 cell line. Our results showed that treatment with progesterone led to a reduction in RNA levels of all the machinery required for antigen processing and presentation (APP). Based on these findings, we hypothesize that activation of the progesterone receptor by progesterone may decrease MHC Class I expression by regulating APP. Our results showed that treatment with progesterone resulted in a reduction in RNA levels of Tap1, Tap2, Tapbp, Nlrc5, B2m, and Psmb8, which are essential for APP. We therefore propose that activation of the progesterone receptor by progesterone may decrease MHC Class I expression by directly modulating the APP pathway. The findings of this study may have significant implications for our understanding of how breast cancer cells evade T-cell mediated cytotoxicity.
Citation Format: Julio Tinoco, Lauryn Werner, Eilidh Chowanec, Harmony Saunders, Sun Xiaopeng, Jay Gertz, Justin Balko, Zachary C. Hartman, Christy Hagan. Progesterone receptor modulates the antigen processing and presentation machinery decreasing MHC class I expression on tumors [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 5364.
Abstract 5366: ATR promotes extracellular matrix stiffness mediated cytoskeleton remodeling and immunosuppression
Authors: Tu Xinyi , Lou Zhenkun , Mutter Robert 
Published: March 2024

Abstract
The stiffening of the extracellular matrix (ECM), a phenomenon that often promotes metastasis and immunosuppression in many cancers, is a process that is not yet fully understood. Our study reveals that ATR, a molecule primarily recognized for its role in maintaining the genome, plays a crucial role in ECM stiffness-induced immune evasion and metastasis in triple negative breast cancer (TNBC) through DNA repair independent manner. In response to ECM stiffness, ATR activates SUN2, a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex. This activation enhances the interaction of SUN2 with outer nuclear membrane proteins KASH1 and KASH2. The interaction between SUN2 and KASH1/2 facilitates the nuclear localization of β-catenin, which in turn promotes epithelial mesenchymal transition (EMT) and reduces the expression of E-cadherin. E-cadherin is essential for attracting CD103+ immune cells that perform anti-tumor immunity. Interestingly, inhibiting ATR reduces EMT in tumor cells, leading to an increase in CD103+ dendritic cell infiltration while decreasing neutrophil and polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) infiltration. Further, we found that ATR levels are inversely correlated with immunotherapy response rates in patients. The alteration in immune cell composition sensitizes tumors to immunotherapy, thereby suppressing tumor growth and metastasis. In conclusion, the role of ATR in remodeling the immune environment could be crucial for optimizing the clinical use of ATR inhibitors. This makes ATR a promising target for overcoming immunotherapy resistance. We suggest early or prolonged treatment with an ATR inhibitor to potentially reduce metastasis rates and improve the prognosis of TNBC patients. Furthermore, we suggest using ATR levels as a marker to predict response rates and prognosis in TNBC patients. For patients with higher ATR expression levels, combination treatment with ATR inhibitors and immunotherapy may yield better outcomes. Enhanced anti-tumor immunity could increase the chances for patients to eliminate cancer cells and help end breast cancer. Finally, our research suggests the combined treatment of ATR inhibition and immunotherapy for patients without necessarily applying DNA damage stimulation. This approach could potentially reduce toxicity while still benefiting patients.
Citation Format: Xinyi Tu, Zhenkun Lou, Robert Mutter. ATR promotes extracellular matrix stiffness mediated cytoskeleton remodeling and immunosuppression [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 5366.
Abstract 5393: Characterization of small ubiquitin-like modifier (SUMO) protein complex expression in human cancer cells to identify novel therapeutic targets
Authors: Salih Mohammed Abdullah Mohammed , Williamson Ritchie , Kantamneni Sriharsha 
Published: March 2024

Abstract
SUMOylation is a post-translational modification where a number of small ubiquitin-like modifier proteins (SUMO) are conjugated to lysine residues of the target proteins and contribute to various cellular functions essential for cancer cell survival and proliferation. The unique behaviors, phenotypic and molecular adaptations found in the naked-mole rat (NMR) suggest a high stability and effective functioning of the molecular machinery that counteracts damage accumulation in its genome. NMR can reach 32 years, shows no signs of ageing, and possesses a very efficient mechanism of resistance to cancer. This study aims to investigate the regulation of SUMOylation machinery between NMR tissues in comparison to human cancer cells, to find novel targets for cancer therapy. Gene expression of SUMO isoforms between NMR and humans, were investigated through qRT-PCR. The data suggests a significant low expression level for most SUMO machinery (except PIAS4) in NMR brain and intestine tissues compared to MCF-7, DLD-1, SH-SY5Y, and MCF-10A cells. Western blotting analysis also revealed high protein expression of PIAS4 in NMR compared to SENP1 and Ubc9. Also, SUMO machinery expression levels from NMR are recapitulated in cancer cells either silencing (hUBE2I: shRNA, hSENP1: shRNA) or overexpression (Myc/hPIAS4: Exp). Further, cytotoxicity assay was analyzed in relevance to Doxorubicin in MCF-7, 5-Fluorouracil in DLD-1 and Methotrexate in SH-SY5. The functional assays such as clonogenic and invasion assays were performed including apoptotic mechanisms (Bcl-2, and BID). In conclusion, the data revealed important differences in SUMOylation machinery between NMR and human cancer cells, which provides a future therapeutic path for cancer treatment.
Citation Format: Mohammed Abdullah Mohammed Salih, Ritchie Williamson, Sriharsha Kantamneni. Characterization of small ubiquitin-like modifier (SUMO) protein complex expression in human cancer cells to identify novel therapeutic targets [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 5393.
Abstract 5395: The influence of hyperthermia on epigenetic signaling in dysbiotic tumor vasculature
Authors: Kristian Hailey , Jenkins Samir , Griffin Robert , Dings Ruud Petrus 
Published: March 2024

Abstract
The overall use of antibiotics has increased significantly in recent years. Although they resolve infections, oral antibiotics (ABX) severely alter the gut microbiota, disrupting commensal bacteria crucial for maintenance of various homeostatic processes. ABX-induced microbial imbalance, or dysbiosis, has systemic and long-lasting deleterious effects on the host. For example, we and others have shown that distal, non-GI tract solid tumors show accelerated progression during dysbiosis due to vascular immune suppression. Localized hyperthermia has been increasingly recognized to elicit various cellular responses, yet the epigenetic effects of hyperthermia on the tumor vasculature during ABX-induced dysbiosis are unknown. The balance of histone acetylation and deacetylation plays a critical role in the regulation of gene expression and thereby cellular processes. Therefore, we assessed which histone deacetylases (HDACs) are expressed and their abundance in endothelial cells of various sources with or without dysbiotic stress and/or hyperthermia to understand the utility of thermal medicine to promote normal functioning of the vasculature in dysbiotic patients. We found that HDAC expression levels differed among endothelial origins and that hyperthermia (60 min of either 41.5 °C or 43 °C) influenced the HDAC levels differentially. Especially HDAC 2, 3 and 8 were inhibited by hyperthermia. Additionally, we found that the vasculature receptors for endogenous HDAC inhibitors, GPR41, GPR43, and GPR109a are less abundant intrinsically on dysbiotic than orthobiotic tumor endothelial cells and that hyperthermia increased this expression. Although further studies are warranted, these results demonstrate that hyperthermia exerts epigenetic effects and is capable of overcoming the dysbiosis-induced phenotype. Since anti-cancer treatment with HDAC inhibitors has shown promise in the clinic but is hindered by systemic toxicities, localized hyperthermia may become a viable alternative in the future.
Citation Format: Hailey Kristian, Samir Jenkins, Robert Griffin, Ruud Petrus Dings. The influence of hyperthermia on epigenetic signaling in dysbiotic tumor vasculature [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 5395.
Abstract 5400: CD160 regulates angiogenesis in activated human endothelial cells
Authors: Aziz Abdel-ilah , Mocquery-Corre Maxence , Jean Chloé , Oumeslakht Loubna , Chazée Lise , Thevenard-Devy Jessica , Fatimy Rachid El , Bensussan Armand , Mkaddem Sanae Ben , Devy Jérôme 
Published: March 2024

Abstract
Angiogenesis, the process of forming new blood vessels from pre-existing ones, plays a pivotal role in various physiological and pathological conditions. CD160, a cell surface receptor known for its modulatory function in the immune response, has recently garnered attention as a surface marker for activated endothelial cells. In this study, we investigate the anti-angiogenic effects of a novel anti-CD160 antibody. Using the tube formation assay, we evaluated the novel anti-CD160 antibody's ability to inhibit neovascularization potential in activated Human umbilical vein endothelial cells (HUVEC) in vitro. Our results revealed a significant reduction in total tube length, the number of branches, and closed networks, indicating the antibody's efficacy in impeding neovascularization. In addition, we explored the molecular mechanisms underlying CD160's anti-angiogenic properties, showing its ability to selectively decrease fibroblast growth factor-2-induced angiogenesis. Furthermore, we assessed the safety profile of our new anti-CD160 antibody by examining its impact on endothelial cell apoptosis. Encouragingly, our findings demonstrated no induction of apoptosis, suggesting the antibody's selective targeting of angiogenic processes without compromising endothelial cell viability, thus supporting CD160's vascular normalization properties. In conclusion, our research provides compelling evidence for the anti-angiogenic effects of the CD160 antibody, as evidenced by its inhibition of tube formation without inducing apoptosis in activated endothelial cells. These findings hold promising therapeutic implications for targeting angiogenesis in various pathological conditions, warranting further exploration for potential clinical applications.
Keywords: CD160, Angiogenesis, Endothelial cells. HUVECs.
Citation Format: Abdel-ilah Aziz, Maxence Mocquery-Corre, Chloé Jean, Loubna Oumeslakht, Lise Chazée, Jessica Thevenard-Devy, Rachid El Fatimy, Armand Bensussan, Sanae Ben Mkaddem, Jérôme Devy. CD160 regulates angiogenesis in activated human endothelial cells [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 5400.
Abstract 542: Development of novel syngeneic tumor models with intrinsic or extrinsic resistance mechanisms to PD-1 blockade
Authors: Wang Xiaomin , Zhang Ziwei , Liu Longzhou , Zhang Xue , Wang Dong , Xu Nengwei , Qiang Xiangnan , Gu Qingyang , Xiang Jian , Zhang Zhixiang 
Published: March 2024

Abstract
Programmed cell death-1 (PD-1) blockade has demonstrated remarkable clinical efficacy across various tumor types. However, the current PD-1 blockade monotherapy benefits only a small proportion of patients, and primary or acquired resistance can ultimately lead to cancer progression in clinical settings. Understanding the underlying mechanisms of resistance is both necessary and urgent to enhance clinical outcomes. Increasing evidence suggests that resistance to PD-1 therapy can arise from both tumor-cell-intrinsic and tumor-cell-extrinsic factors. Loss-of-function mutations in the antigen presentation pathway and downstream elements represent intrinsic mechanisms, while tumor-infiltrating immunosuppressive cells such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) contribute to immune tolerance as extrinsic factors. Currently, the rational design of combination therapies based on these resistance mechanisms remains to be achieved.
In this study, we developed two types of anti-PD-1 antibody-resistant models based on the intrinsic anti-PD-1 treatment-sensitive MC38 models. These models include genetically engineered resistant models with B2M or STK11 knockout (KO) and induced resistant models through in vivo progressive drug selection. STK11 KO mutations resulted in reduced expression of PD-L1 on tumor cells and a lower infiltration of CD8+ cytotoxic T lymphocytes in the tumor microenvironment, while B2M KO led to a lack of antigen presentation on the tumor cell surface, blocking the binding of the anti-PD-1 antibody. In terms of the induced anti-PD-1 resistant models, a higher proportion of immunosuppressive cells, including Tregs, MDSCs, and TAMs, were observed in the tumor microenvironment compared to the parental counterparts, contributing to immune escape from PD-1 blockade. These models simulate extrinsic and intrinsic mechanism-based anti-PD-1 resistance, allowing for the identification of combination therapies to overcome resistance to anti-PD-1.
Our study enhances our understanding of the biological basis of anti-PD-1 resistance and supports the discovery of mechanistically-designed combination therapies to overcome resistance to anti-PD-1 therapy, potentially broadening its clinical applicability.
Citation Format: Xiaomin Wang, Ziwei Zhang, Longzhou Liu, Xue Zhang, Dong Wang, Nengwei Xu, Xiangnan Qiang, Qingyang Gu, Jian Xiang, Zhixiang Zhang. Development of novel syngeneic tumor models with intrinsic or extrinsic resistance mechanisms to PD-1 blockade [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 542.
Abstract 5433: Functional involvement of ribosomal protein L9 to colorectal cancer stemness
Authors: Jeon Eun-Hye , Park Keun Uk , Ryoo Hun-Mo , Hwang Ilseon , Lee Yun-Han 
Published: March 2024

Abstract
We have previously demonstrated that targeting of ribosomal protein L9 (RPL9) suppresses the growth of colorectal cancer (CRC) via the inactivation of Id-1/NF-κB signaling axis which is known to augment tumor stemness. Thus we aimed in this study to investigate whether the function of RPL9 was associated with CRC stemness properties. It was initially evidenced that inhibition of RPL9 expression reduces the migration and invasion abilities of HT29 parental cell population. We have then sorted out CD133+ cancer stem cells (CSCs) from HT-29 parental cell culture and treated RPL9-specific siRNAs to the isolated CSCs to observe the effect of RPL9 targeting on stemness. As results, knockdown of RPL9 significantly suppressed the proliferation potential and sphere forming capacity of CD133+ HT29 CSCs accompanying with the reduction in CD133 and Id-1 levels. Reflecting these molecular alterations, targeting RPL9 also inhibited the abilities of migration and invasion in CD133+ HT29 CSCs population. Taken together, these findings suggest that RPL9 could be a therapeutic target for both primary CRC treatment and the prevention of metastasis and/or recurrence.
Citation Format: Eun-Hye Jeon, Keun Uk Park, Hun-Mo Ryoo, Ilseon Hwang, Yun-Han Lee. Functional involvement of ribosomal protein L9 to colorectal cancer stemness [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 5433.
Abstract 5489: The spatial landscape of early-stage lung adenocarcinoma
Authors: Kim Junbum , Ravichandran Hiranmayi , Yoffe Liron , Binder Bhavneet , McGraw Timothy , Altorki Nasser K. , Mittel Vivek , Elemento Olivier 
Published: March 2024

Abstract
Cellular and molecular basis of ground-glass opacities (GGO), which has been used as a screening indicator for lung cancer, remains a gray area. Our aim was to investigate the tumor-immune microenvironment (TIME) in a cohort of early-stage lung adenocarcinomas (LUAD) through imaging mass cytometry, enabling us to examine the TME spatial composition of nodules at single-cell resolution. We collected 354 imaging mass cytometry (IMC) regions of interest (ROI) from 135 early-stage lung adenocarcinoma patients to investigate the spatial and molecular profiles of early stage LUAD. Specifically, we gathered 27 solid (S), 39 part-solid (PS), 74 pure non-solid (PNS) patients and 89 matched adjacent-normal cases to profile the phenotype of 2.24 million cells across the two IMC panels to characterize the cellular and molecular composition of GGO nodules. Comparing progression from adjacent normal, pure non-solid, part-solid, to solid, we observed consistent reduction in RAGE+ AT1 cells (p*&lt;1.6E-7) and a reciprocal increase in SFTPC+ AT2 cells (p*&lt;1.3E-8) and PanCK+Ki67+ proliferative epithelial cells (p*&lt;2.8E-7). We also report fibrogenesis and an increase in immune cell populations such as regulatory (p*&lt;1.4E-5), CD4 (p*&lt;0.0024), CD8 T (p*&lt;0.017) cells, B (p*&lt;5.5E-9) cells, and macrophages. Spatially, we quantify an upregulation of tumor-tumor and tumor-fibroblast interaction, and a downregulation of tumor-immune interaction. We believe this evidence suggests the role of fibroblasts as liner for tumors, barricading immune infiltration and harvesting uninterrupted tumorigenesis. In summary, we performed a highly multiplexed IMC data to analyze the TIME spatial profiles of GGO nodules in early-stage LUAD at a single-cell level. Spatial analysis of this integrated multidimensional omics dataset provides insight into the pivotal role of fibroblasts in early-stage LUAD in immune suppression, evasion, tumorigenesis, and potentially metastasis.
Citation Format: Junbum Kim, Hiranmayi Ravichandran, Liron Yoffe, Bhavneet Binder, Timothy McGraw, Nasser K. Altorki, Vivek Mittel, Olivier Elemento. The spatial landscape of early-stage lung adenocarcinoma [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 5489.
Abstract 5490: Spatial profiling of inflamed tumor microenvironment of clear cell renal cell carcinoma
Authors: Pellinen Teijo , Luomala Lassi , Mattila Kalle , Säilä Jenni , Hemmes Annabrita , Valimaki Katja , Bruck Oscar , Paavolainen Lassi , Nisen Harry , Järvinen Petrus , Kallioniemi Olli , Vainio Paula , Jaakkola Panu , Mirtti Tuomas 
Published: March 2024

Abstract
Clear cell renal cell carcinoma (ccRCC) presents a distinctive tumor microenvironment (TME) characterized by extensive vascularization and immune infiltration. This unique TME makes ccRCC an attractive target for anti-angiogenesis and immune checkpoint blockade (ICB). To better understand the complexity of ccRCC and the associated cell types and states involved in disease progression, we conducted high-throughput single-cell immunofluorescence imaging on tissue sections from 437 localized tumors that were surgically resected. These samples included regions from the tumor center, tumor edge, and adjacent benign areas (TMA cores, n=1859). Our primary focus was on tumors with elevated immune cell enrichment (CD45high), as these tumors are known to be aggressive and may respond well to immunotherapy. Our study reveals the intricate interactions between tumor, vascular, stromal, and immune cells within ccRCC. We find that CD45high tumors, upon losing epithelial marker expression, acquire tumor cell PD-L1 and mesenchymal markers such as Fibroblast activation protein (FAP). This shift is indicative of the epithelial-mesenchymal transition (EMT) process. These CD45high and EMThigh tumors are enriched with changes in TME, including elevated FAP+ cancer-associated fibroblasts (CAFs) and subsets of immune suppressive T cells and macrophages. We report that ccRCC patients with high tumor PD-L1 expression or abundant FAP+ CAFs are associated with earlier metastasis and, in sunitinib-treated patients, shorter progression-free survival. This study illuminates the intricate connection between immune cell infiltration, stromal biology, and EMT in ccRCC, offering a deeper understanding of the disease's complex biology and potentially guiding future therapeutic approaches and strategies.
Citation Format: Teijo Pellinen, Lassi Luomala, Kalle Mattila, Jenni Säilä, Annabrita Hemmes, Katja Valimaki, Oscar Bruck, Lassi Paavolainen, Harry Nisen, Petrus Järvinen, Olli Kallioniemi, Paula Vainio, Panu Jaakkola, Tuomas Mirtti. Spatial profiling of inflamed tumor microenvironment of clear cell renal cell carcinoma [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 5490.