bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4145: Frizzled-4 expression enhances hepatocellular carcinoma progression, sorafenib resistance and suppresses anti-tumor CD8 T cell immunity
Authors: Luo Jie , Gong Lanqi , Yang Yuma , Liu Qin , Huang Jiao , Fang Xiaona , Guan Xin-Yuan 
Published: April 2023

Abstract
Background: Hepatocellular carcinoma (HCC) is one of the most common and deadliest cancers. Sorafenib remains the globally accepted systemic first-line treatment for advanced HCC although acquired drug-resistance is becoming increasingly common. Hopefully, immune-checkpoint inhibitor therapy has recently revolutionized the treatment for advanced HCC that have poor response to sorafenib, but the durable response rate remains low in most patients for unknown reasons. This fuels a wave of research into the molecular mechanisms of tumor-intrinsic resistance to both chemotherapy and immune checkpoint blockade (ICB), which may provide potential systemic treatment options for advanced HCC patients.
Methods and Results: RNA sequencing of sorafenib-resistant HCC cell lines was performed to identify Frizzled-4 (FZD4) as a critical gene for drug resistance that was further validated in animal models. Clinical implication of FZD4 overexpression was studied in HCC patients. Using genetic and pharmacological approaches, we found that FZD4 was sufficient to increase clonogenicity, migration and invasion, and prevent sorafenib-induced apoptosis. In addition, FZD4 could reduce secretion of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), as well as intracellular levels of cytotoxic granzyme A and perforin in CD8+ T cells, indicating significant suppression of CD8+ T cell-mediated antitumor immunity in HCC tumors. In vivo studies also revealed that FZD4 expression promoted tumorigenesis and accelerated HCC cell metastatic lung colonization. Combination therapy of FZD4 inhibitor FzM1 with sorafenib in HCC of MYC/sgp53-induced model showed a tendency to significantly impede tumor growth and improve mice survival. Moreover, gene set enrichment analysis (GSEA) identified the cholesterol homeostasis and fatty acid metabolism signaling signatures as the top activated pathways in FZD4-high HCC cells. This evidence suggests a crucial role of FZD4-involved lipid metabolism linked to the development of therapeutic resistance.
Conclusion: Our study demonstrates that FZD4 expression plays a pivotal role in HCC progression and holds the potential for expanding the scope of targeted/ICB therapies to tumors that are currently unresponsive, especially in advanced HCC. The resistance mechanisms will be addressed in further work.
Citation Format: Jie Luo, Lanqi Gong, Yuma Yang, Qin Liu, Jiao Huang, Xiaona Fang, Xin-Yuan Guan. Frizzled-4 expression enhances hepatocellular carcinoma progression, sorafenib resistance and suppresses anti-tumor CD8 T cell immunity. [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 4145.
Abstract 4149: Anti-CTLA-4 generates memory T-cells with greater expansion and functionality than anti-PD-1
Authors: Mok Stephen , Anang Nana-Ama A.S. , Mancuso James J. , Allison James P. 
Published: April 2023

Abstract
Blocking either cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed cell death-1 (PD-1) pathway relieves the negative regulation of T-cells resulting in durable tumor rejection in patients with cancer and improved survival rate. However, it remains unclear how these immunotherapies affect memory T-cell response. Here we address whether anti-CTLA-4 and anti-PD-1 have different effects on memory T-cells. We used anti-CTLA-4 or anti-PD-1 therapy in combination with irradiated cancer vaccine in mice. After re-challenge, we observed that in murine tumor models, anti-CTLA-4 generates a more robust memory antitumor response than anti-PD-1 as demonstrated by smaller tumor volumes at all time points. We have traced and profiled antigen-specific CD8 T-cells throughout priming, memory phase, and re-challenge. We observed the memory responses generated by anti-CTLA-4 and anti-PD-1 diverge at priming; where anti-CTLA-4 generates more TCF-1+ memory-like T-cells than anti-PD-1, and remains apparent throughout activation and expansion as anti-PD-1 results in a higher percentage of TOX1+ terminally-differentiated T cells. During re-challenge, the memory T-cells generated by anti-CTLA-4 1) expand in greater frequency, 2) have greater cytokine production and antitumor activity, and 3) more frequently differentiate into the population of KLRG1+ effector CD8 T-cells than those generated with anti-PD-1. We found each of these traits correlated with a more effective memory response.
Citation Format: Stephen Mok, Nana-Ama A.S. Anang, James J. Mancuso, James P. Allison. Anti-CTLA-4 generates memory T-cells with greater expansion and functionality than anti-PD-1. [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 4149.
Abstract 4274: Functional dissection of complex tissue microenvironment using spatial transcriptomics data
Authors: Zhou Xinyu , White Alexander , Guo Tingbo , Dang Pengtao , Wei Yuhui , Wang Xiao , So Kaman , Zhang Chi , Cao Sha 
Published: April 2023

Abstract
Spatial transcriptomics (ST) data holds enormous potential to provide new perspectives for biologists seeking to understand the tumor tissue microenvironments. Cells in the same microenvironment are always exposed to biochemical conditions displacing specific spatial patterns. To truly dismantle the tissue microenvironment heterogeneity as well as cells’ diverse responses to the variable microenvironment, we rely on spatial information to dissect the tissue into different functional regions, which are spatially dependent and biologically meaningful.
We have developed a statistical method, smooth Low Rank approximation and Clustering (smoothLRC) to model the spatial transcriptomic data as its low-rank approximation with spatial smoothness. smoothLRC accomplishes this by extracting the latent low-rank structure of the expression profiles. We present a regularized maximum likelihood estimator approximating the noisy observed expression matrix. This estimator incorporates spatial information and addresses expression dropout. It uses a low-rank Poisson distribution to account for the noise that plagues ST-based gene expression data with severe dropout events and a spatial smoothness penalty to encourage neighboring cells to fall into the same functional region. A dropout is an event where genes expressed in a given cell or region are incorrectly measured as unexpressed.
SmoothLRC has the following key features: 1) it is a statistically rigorous method; 2) the spatially smooth low-rank subspace could enable meaningful functional dissection, which is an unprecedented capability; 3) the low-rank structures could be used to recover the original expression, saving many expression values that are not captured.
Citation Format: Xinyu Zhou, Alexander White, Tingbo Guo, Pengtao Dang, Yuhui Wei, Xiao Wang, Kaman So, Chi Zhang, Sha Cao. Functional dissection of complex tissue microenvironment using spatial transcriptomics data. [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 4274.
Abstract 4492: A novel and potent FLT3 and IRAK4 dual inhibitor for the treatment of acute myeloid leukemia
Authors: Yang Rui , Wu Lei , Zhang Bing , Xiang Michael , Wang Suyue , Xiang Camille , Lu Zhijian , Xiang Jason 
Published: April 2023

Abstract
Several potent FMS-like tyrosine kinase 3 (FLT3) inhibitors have been developed and approved for the treatment of FLT3-mutant acute myeloid leukemia (AML) recently. These inhibitors block the signaling pathways involved in proliferation of leukemic cells, and have shown favorable initial results in early-stage AML patients. However, a significant percentage of patients relapsed with poor prognoses. The relapse is generally caused by a compensatory innate immune stress response, such as Toll-like receptor activation, which induces adaptive resistance to the FLT3 inhibition. Interleukin-1 receptor associated kinase 4 (IRAK4) functions as a mediator of Toll-like receptor and interleukin-1 receptor signaling pathways. Patients harboring a U2AF1 or SF3B1 spliceosome mutation were found to express a longer and more active isoform of IRAK4 kinase, which could result in lasting activation of NF-κB and MAPK in oncogenic and innate immune signaling. Emavusertib (CA-4948), an IRAK4/FLT3 inhibitor, is currently in phase I clinical trials. To address the critically unmet medical needs of myeloid leukemia patients, we have developed a novel and potent FLT3 and IRAK4 dual inhibitor HPB-092 with excellent selectivity to provide durable efficacy in myeloid malignancies by eliminating adaptive resistance.
HPB-092 significantly inhibited MV4-11 tumor cell proliferation at low nanomole concentration. HPB-092 demonstrated good oral bioavailability in several animal species. In a disseminated MV4-11 xenograft mouse model, HPB-092 displayed strong anti-tumor activity at 5mg/kg. HPB-092 was well-tolerated with no obvious adverse events at a dose of 40 mg/kg in two-weeks safety study in SD rats. In addition, no rhabdomyolysis side-effect was observed upon histological analysis. These results underscore the potential therapeutic benefit and safety profile of HPB-092 for the treatment of AML, especially in patients with mutations in U2AF1 or SFF3B1 spliceosome.
Citation Format: Rui Yang, Lei Wu, Bing Zhang, Michael Xiang, Suyue Wang, Camille Xiang, Zhijian Lu, Jason Xiang. A novel and potent FLT3 and IRAK4 dual inhibitor for the treatment of acute myeloid leukemia. [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 4492.
Abstract 4504: Targeting cMYC in metastatic castration resistant and neuroendocrine prostate cancer
Authors: Awah Chidiebere U. , Ogunwobi Olorunseun O. 
Published: April 2023

Abstract
Prostate cancer is the most common cancer in men and the second leading cause of cancer death among men in the United States according to the National Cancer Institute. Current treatment modalities involve prostatectomy, androgen receptor blockade and supportive/palliative care. Despite these treatment options, metastatic castration resistant prostate cancer and neuroendocrine prostate cancer still have very dismal clinical outcomes. Therefore, there is a need to understand the biology of the aggressive prostate cancer subtypes to identify novel targetable molecules. The castration resistant prostate cancer, neuroendocrine prostate cancer and the metastatic prostate cancers that recur have c-MYC amplification. These cancers are not responsive to androgen blockade or deprivation therapy. Attempts to target c-MYC have been difficult due to the intrinsic disordered nature of c-MYC. Various approaches have been attempted to control c-MYC; namely RNAi which has high off target effects, anti-sense oligonucleotides (ASO) which have low cellular penetrance and needs phosphorothioate modification, G-quadruplex inhibitors which are unspecific as they block POLII, the BRD4 and CDK inhibitors which are indirect inhibitors of c-MYC. Only OmoMyc a bHLH domain mutant with enhanced leucine zipper dimerization is in phase 1 trials with limited bioavailability. To explore the possibility of targeting c-MYC in these difficult-to-treat prostate cancers, we transfected C4-2B, a cellular model of metastatic castration resistant prostate cancer, with engineered destabilized 3‘UTR AU rich element of c-MYC. We found that we degraded c-MYC transcript and protein and killed the cancer cells. Taken together, we offer preliminary evidence that we can directly target c-MYC and inhibit these difficult-to-treat cancers. In vivo studies to validate these findings are ongoing.
Citation Format: Chidiebere U. Awah, Olorunseun O. Ogunwobi. Targeting cMYC in metastatic castration resistant and neuroendocrine 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 4504.
Abstract 4564: Liquid-phase-based cell culture platform that enables polymer surface stimuli-induced generation of patient-specific glioma stem cell-like tumor spheroids
Authors: Song Junhyuk , Choi Yoonjung , Lee Yumi , Moon Hyo E. , Seo Changjin , Park Hyung W. , Kim Dohyeon , Song Chang W. , Lee Daeyoup , Paek Sun H. , Jon Sangyong 
Published: April 2023

Abstract
Despite the rapidly growing interest on cancer stem cells (CSCs) from cancer biologists, oncologists and the clinic because of their crucial role in recurrence and metastasis due to resistance in solid cancers, including GBM, there is still a lack of robust, effective in vivo-like 3D CSC models from cancer cells or patient-derived tumor tissues. In this sense, we developed a novel functional polymer thin film (Poly-X-PTF) via a streamlined liquid-phase synthesis, a more facile and advanced version than previous lab-made vapor-deposited poly(2,4,6,8-tetravinyl-2,4,6,8-tetramethyl cyclotetrasiloxane) called pV4D4-PTF. Emerging from a previous success with pV4D4, the new platform, Poly-X, could also simply stimulate surface stimuli-guided, rapid transformation of differentiated cancer cells to a number of ECM-enriched, similar-sized 3D CSC-like tumor spheroids from both commercialized cancer cell lines and patient-derived primary GBM cells. Varied GBM patient-derived cancer spheroids demonstrated a variety of phenotypes and transcriptomic profiles known about glioma stem cells (GSCs) in common. Notably, respective sensitivities of different patient-based 3D GSC spheroids to irradiation with or without temozolomide were retrospectively associated with the individual therapeutic outcome and overall survival, as a result of clinically relevant concurrent chemoradiation treatment (CCRT) regimens proposed in a fast Poly-X-spheroids-based 3D viability assay format. Ultimately, this versatile platform may serve to study fundamental CSC biology. Furthermore, it may translate into a powerful preclinical ex vivo tool in glioma medical settings both to aid in on-site prospective prediction of the patient-specific prognosis via CCRT viability responses within around 10 days and assess a patient-tailored, promising drug candidate or combination treatment.
Citation Format: Junhyuk Song, Yoonjung Choi, Yumi Lee, Hyo E. Moon, Changjin Seo, Hyung W. Park, Dohyeon Kim, Chang W. Song, Daeyoup Lee, Sun H. Paek, Sangyong Jon. Liquid-phase-based cell culture platform that enables polymer surface stimuli-induced generation of patient-specific glioma stem cell-like tumor spheroids. [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 4564.
Abstract 4574: Long-term drug efficacy evaluation using stiffness-tunable scaffolds colonized by a three-dimensional tumor microenvironment
Authors: De Vlieghere Elly , De Wever Olivier 
Published: April 2023

Abstract
Long-term drug evaluation heavily relies upon rodent models. Methods to reduce animal models in oncology may include three-dimensional cellular systems that take into account tumor microenvironment (TME) cell types and biomechanical properties. Innovative translational research is needed in low-grade serous ovarian cancer (LGSOC) in which the presence of oncogenic mutations in the RAS pathway likely suggest the opportunity to test targeted treatments. To address all these needs this study reports on an elastic polymer, to print a scaffold that mimics tissue relevant stiffness. Introduction of single cell suspensions from LGSOC patient-derived early passage cultures of cancer cells and cancer-associated fibroblast form heterocellular spheroids mimicking the growth ratio and spatial organization of the LGSOC TME. The resulting scaffold allows long-term (&gt;40 days) follow-up and targeted compound evaluation confirmed the durable response to a drug combination. The drug-response results from this long-term in vitro model are compared with drug responses in an orthotopic LGSOC xenograft mouse model. In conclusion, the stiffness-tunable scaffolds colonized by a three-dimensional LGSOC TME allow long-term drug evaluation and can be considered as a valid alternative to reduce, replace and refine animal models in drug discovery.
Citation Format: Elly De Vlieghere, Olivier De Wever. Long-term drug efficacy evaluation using stiffness-tunable scaffolds colonized by a three-dimensional tumor microenvironment. [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 4574.
Abstract 4653: Spatial architecture of tumor-infiltrating macrophagesorchestrates tumor immunity and therapeutic response
Authors: Zhang Yuanyuan , Peng Fuduan , Pei Guangsheng , Liu Yunhe , Han Guangchun , Wang Linghua 
Published: April 2023

Abstract
Tumor-infiltrating macrophages, a major cellular component in the tumor microenvironment (TME), have been proven to be linked with tumor progression and immunotherapy resistance. Tremendous heterogeneity has been revealed for tumor-associated macrophages (TAMs) in different cancer types, however, how these TAM subtypes are localized and interact with tissue ecosystems remains poorly understood. Here, we perform an integrative analysis of TAMs, malignant and non-malignant cells from 10 cancer types, based on single-cell RNA-seq and spatial transcriptomic data. By interrogating the spatial distributions of different TAM subtypes in situ, we reveal spatially restricted developmental, regulation, and functional heterogeneity of TAMs in TME. Different cancer types show distinct TAM subtype enrichments with specific interface architectures, which is potentially shaped by the cellular compositions and spatial niches of tumor cells. Furthermore, the compartmentalized TAM subpopulations can reflect the spatial architecture of surrounding stromal and immune cells, and thus orchestrate tumor immunity and therapeutic response. Our study demonstrates the cellular and molecular underpinnings of TAM heterogeneity and stochastic regulations of TAMs for TME architecture, tumor progression and immunotherapy responses, which will assist in the identification of possible therapeutic targets.
Citation Format: Yuanyuan Zhang, Fuduan Peng, Guangsheng Pei, Yunhe Liu, Guangchun Han, Linghua Wang. Spatial architecture of tumor-infiltrating macrophagesorchestrates tumor immunity and therapeutic 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 4653.
Abstract 4824: Intracellular ferritin expression levels regulate growth and resistance to ferroptosis in pancreatic cancer cell lines
Authors: Maruno Masataka , Kanamori Yo-hei , Matsumoto Takashi , Shiraishi Yuta , Takematsu Toru , Miyata Tatsunori , Mima Kosuke , Nakagawa Shigeki , Nitta Hidetoshi , Hayashi Hiromitsu , Moroishi Toshiro , Baba Hideo 
Published: April 2023

Abstract
Background: Pancreatic cancer is one of the cancers with the highest mortality rate, and it is important to develop effective treatments and elucidate prognostic factors. It has been reported that elevated serum ferritin is associated with the prognosis of pancreatic cancer. However, there are few reports on how ferritin in pancreatic cancer tissue acts in pancreatic cancer. Ferritin heavy chain (FTH) is a major component of ferritin, which stores iron and plays a role in suppressing iron-induced generation of reactive oxygen species. In this study, we aimed to examine the expression level of FTH in pancreatic cancer cells and its prognostic and cell biological roles.
Methods: We performed immunostaining of FTH in pancreatic cancer tissue specimens operated on at our hospital and classified the expression level of FTH by scoring the immunostaining intensity and staining rate. The expression levels and prognosis were then evaluated. The overexpression and knockout strains of FTH were generated using a human pancreatic cancer cell line (MIAPaCa-2), and their proliferative and stress tolerance abilities were compared with those of the control group.
Results: Immunostaining of 149 pancreatic cancer surgical specimens showed that the group with high FTH had a significantly shorter overall survival rate than the group with low FTH (5-year survival rate; 16.8% vs. 36.9%, p = 0.018). In multivariate analysis, high FTH expression was also a prognostic factor: in vitro, cell lines overexpressing FTH had enhanced proliferative potential compared to controls, while knockout lines were suppressed. In addition, the knockout lines showed decreased resistance to RSL-3, an inducer of ferroptosis. Additional studies are currently underway to examine resistance to other drugs and the production of reactive oxygen species in the cells.
Conclusion: In pancreatic cancer, high ferritin expression is associated with worse prognosis and may enhance cell proliferation and stress tolerance, and might be a new treatment or biomarker.
Citation Format: Masataka Maruno, Yo-hei Kanamori, Takashi Matsumoto, Yuta Shiraishi, Toru Takematsu, Tatsunori Miyata, Kosuke Mima, Shigeki Nakagawa, Hidetoshi Nitta, Hiromitsu Hayashi, Toshiro Moroishi, Hideo Baba. Intracellular ferritin expression levels regulate growth and resistance to ferroptosis in pancreatic cancer cell lines. [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 4824.