bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4132: Low-dose carbon monoxide therapies suppress cancer metastasis
Authors: Zhang Tiantian , Zhang Cheryl , Chen Xiang , Yang Xiaoxiao , Mao Qiyue , Zhang George , Chen Zhengming , Tan Adrian , Xiang Jenny Zhaoying , Hissong Erika , Chen Yao-Tseng , Wang Binghe , Du Nancy 
Published: March 2024

Abstract
Metastasis is the primary cause of cancer-related deaths. Novel systemic therapies for metastatic cancer are urgently needed. Carbon monoxide (CO) is an endogenously produced signaling molecule in the human body with demonstrated pharmacological activities, including organ protection and anti-inflammation. We determined the therapeutic effect of low-dose CO and CO prodrugs on cancer progression in this study. We found that low-dose CO inhibits the migration of cancer cell lines including breast, pancreatic, colon, prostate, liver, and lung cancer. We showed that low-dose CO inhibits lung metastasis of breast cancer and liver metastasis of pancreatic cancer in preclinical mouse models. Further, to provide safer and more reliable CO delivery, we developed metal-free, organic CO prodrugs and showed that CO prodrugs inhibit tumor growth and metastasis. We demonstrated that low-dose CO blocks the transcription of heme importers, leading to diminished intracellular heme levels. Altogether, our work lays a strong foundation for the development of CO-based systemic cancer therapies.
Citation Format: Tiantian Zhang, Cheryl Zhang, Xiang Chen, Xiaoxiao Yang, Qiyue Mao, George Zhang, Zhengming Chen, Adrian Tan, Jenny Zhaoying Xiang, Erika Hissong, Yao-Tseng Chen, Binghe Wang, Nancy Du. Low-dose carbon monoxide therapies suppress cancer 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 4132.
Abstract 4190: Patient-derived xenograft (PDX) models with differential HER2 expression for preclinical evaluation of HER2-targeted therapies
Authors: Yang Xiaoliu , Guo Shiying , Wang Huiyi , Su Xu , Zhao Jing , Gao Xiang , Ju Cunxiang 
Published: March 2024

Abstract
Human epidermal growth factor receptor 2 (HER2) is a critical therapeutic target in gastric cancer. However, the varying expression levels of HER2 in patients present a significant challenge in selecting the appropriate HER2-targeted therapies. Patient-derived xenograft (PDX) models offer a valuable tool to address this clinical concern.
We established a panel of PDX models derived from gastric cancer patients, each representing a distinct range of HER2 expression levels. These models were subsequently treated with HER2-targeted drugs, including Trastuzumab (Herceptin), Margetuximab, and Enhertu.
Our results demonstrated differential drug responses corresponding to the varying HER2 expression levels in the PDX samples. Trastuzumab, Margetuximab, and Enhertu exhibited distinct efficacies across the HER2 expression spectrum. This underscores the significance of selecting the right therapeutic approach based on the HER2 status of individual patient.
Our collection of PDX models with differential HER2 expression levels provides a robust platform for preclinical evaluation of HER2-targeted therapies. This approach not only addresses the clinical challenge of HER2 heterogeneity but also facilitates a more personalized and effective treatment strategy for gastric cancer patients.
Citation Format: Xiaoliu Yang, Shiying Guo, Huiyi Wang, Xu Su, Jing Zhao, Xiang Gao, Cunxiang Ju. Patient-derived xenograft (PDX) models with differential HER2 expression for preclinical evaluation of HER2-targeted therapies [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 4190.
Abstract 4191: Delayed onset of GvHD in PBMC humanized NCG-B2m KO mice provides an enhanced model for oncology studies
Authors: Bronson Steven , Harris David , Avrutskaya Anya , Eberle Christoph , Rowe Jenny 
Published: March 2024

Abstract
Humanized mice are specialized animal models incorporating components of the human immune system. These models are valuable tools for assessing the efficacy of human immunotherapies on tumors. Humanized mice are created by injecting human CD34+ hematopoietic stem cells (HSCs) or human peripheral blood mononuclear cells (PBMCs) into an immunodeficient mouse. PBMC humanized (HuPBMC) mice engraft within a few weeks and can recapitulate a robust human T cell population. One challenge when using HuPBMC mice is the onset of graft versus host disease (GvHD), limiting their lifespan compared to hCD34+ HSC humanized mice. The onset of GvHD varies in the HuPBMC model depending on the donor cells. The development of xenogeneic GvHD is dependent on the expression of major histocompatibility complex (MHC) on host cells and lowering MHC expression can delay the onset of GvHD.NCG-B2m KO mice lack beta-2 microglobulin, a component of MHC I, and have lower cell surface expression of MHC I molecules. This leads to a decrease in recognition of host cells by human immune cells. Here we compared the onset of GvHD between HuPBMC NCG-B2m KO mice and HuPBMC NCG mice. PBMC donor variability was also compared between the two PBMC humanized models by evaluating multiple donors and assessing additional collections from the same donor. After the PBMC engraftment was characterized, HuPBMC NCG mice and HuPBMC NCG-B2m KO mice were enrolled in tumor studies comparing outcomes and tumor growth kinetics in mice treated with human immune checkpoint blockade therapy.NCG and NCG-B2m KO mice were injected with 1x107 PBMCs from individual donors. Animals were weighed three times a week to monitor for changes in body weight and general health status. Peripheral blood was collected at day 10, 20, 30, 40, 60 and 90 post injection for flow cytometry screening of human immune cell engraftment (hCD45+, hCD3+, hCD4+ and hCD8+). Human PBMCs isolated from additional collections from the same donors were also injected into both NCG-B2m KO mice and NCG mice and flow cytometry was performed. HuPBMC NCG-B2m KO mice survived longer than HuPBMC NCG mice allowing for the potential use in longer term tumor studies before the results are confounded by GvHD. PBMC humanized mice are an important model for translational research using immunotherapies and the PBMC humanized NCG-B2m KO model provides an expanded study window ideal for oncology studies.
Citation Format: Steven Bronson, David Harris, Anya Avrutskaya, Christoph Eberle, Jenny Rowe. Delayed onset of GvHD in PBMC humanized NCG-B2m KO mice provides an enhanced model for oncology studies [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 4191.
Abstract 42: Tunneling CARs: Gene modifications to enhance CAR-T infiltration into solid tumors
Authors: Van Pelt Stacey N. , Omer Bilal , Talbot Lindsay , Rooney Cliona , Fernandes Rohan , Tat Candise , White Mark 
Published: March 2024

Abstract
Background: CAR-T therapy has been largely ineffective in solid tumors because the dense, rigid, extracellular matrices (ECMs) and basement membranes (BMs) that encapsulate these tumors exclude T cells. Tumor-specific ECMs and BMs, made of type I and type IV collagen respectively, are heavily cross-linked and characterized by small pores. T cell infiltration into tumors relies upon the enzymatic degradation of these matrix fibers, and adhesion molecule-mediated movement. Gene expression analysis of tumor infiltrating leukocytes from patient samples showed that MMP-7, an enzyme that degrades type IV collagen, and osteopontin (OPN), a molecule that interacts with adhesion molecules to mediate movement, were highly upregulated in infiltrating cells compared to those that were tumor adjacent, suggesting they may be important in navigating tumor-specific environments. We hypothesized that overexpressing MMP-7 and/or OPN in CAR-T cells will enhance their infiltration into solid tumors.
Methods: We overexpressed MMP-7 and OPN in second-generation CAR-Ts (GD2-28Z and HER2-28Z) and evaluated their infiltration in vitro using Halo invasion assays. T cell movement out of type IV collagen and into tumor droplets, composed of tumor targets polymerized in type I collagen, was visualized over time to characterize T cell movement through the tumor-specific BM and ECM, respectively. The expansion, phenotype, and cytotoxicity of OPN and MMP-7-modified GD2-28Z CAR-Ts was compared to unmodified GD2 CAR-Ts by counting, flow cytometry and chromium release, respectively. We then used a xenograft model of neuroblastoma to determine if increases in GD2 CAR-T infiltration led to reduced tumor burden.
Results: In vitro, MMP-7 overexpression increased GD2-28Z (2.05-fold, p&lt;0.0001) and HER2-28Z (3.16-fold, p&lt;0.0001) CAR-T infiltration, and OPN overexpression increased GD2-28Z (1.20-fold, p=0.0496) and HER2-28Z (1.49-fold, p=0.002) CAR-T infiltration. In vivo, 52 days after CAR-T infusions, mice treated with OPN-modified GD2-28Z CAR-Ts had reduced tumor burden (0.206 cm, ±0.21) compared to GD2-28Z CAR-Ts (0.903 cm, ±0.33, p=0.0449).
Conclusions: The overexpression of MMP-7 or OPN in second-generation CAR-Ts enhances CAR-T infiltration in vitro, and the expression of these genes does not impair CAR-T expansion, phenotype or cytotoxicity. The overexpression of OPN in GD2-28Z CAR-T enhances tumor clearance in a xenograft model of neuroblastoma, and may increase overall survival.
Citation Format: Stacey N. Van Pelt, Bilal Omer, Lindsay Talbot, Cliona Rooney, Rohan Fernandes, Candise Tat, Mark White. Tunneling CARs: Gene modifications to enhance CAR-T infiltration into solid 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 42.
Abstract 423: Cell state-specific genomics to define plasticity along the epithelial-mesenchymal transitioncontinuum
Authors: Williams Destinee K. , Hou Nicholas 
Published: March 2024

Abstract
The epithelial-to-mesenchymal transition (EMT) is a biological process that allows epithelial cells to convert into a mesenchymal phenotype, acquiring increased mobility and the capacity to migrate. EMT has historically been represented as binary states; however, a growing consensus supports an EMT continuum involving multiple intermediate stable states. While we lack a comprehensive understanding of the EMT continuum, several reports indicate that the late stable states lead to optimal stem cell traits for cancer. In addition, it has been suggested that EMT heterogeneity within tumor cell populations is associated with poor patient prognosis. Hence, there is a clear need to define the genetic drivers of EM plasticity in heterogeneous cell populations along the EMT continuum. To fulfill this need, we will collect and analyze single cell RNA sequencing (scRNA-seq) data from EMT-cell-state specific genetic CRISPR screens on EMT-heterogeneous cell populations. Here, we apply a series of cloning techniques including polymerase chain reaction and Gibson ligation to engineer an adeno-associated virus (AAV) plasmid containing the avian TVA receptor gene under control of the N-cadherin promoter. Since N-cadherin is predominantly expressed in mesenchymal cells, this AAV enables us to generate cell lines that will exclusively express the TVA receptor when in a mesenchymal state. Consequently, we will be able to deliver mesenchymal-specific CRISPR gene edits via an avian retrovirus-derived RCAS system.
Citation Format: Destinee K. Williams, Nicholas Hou. Cell state-specific genomics to define plasticity along the epithelial-mesenchymal transitioncontinuum [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 423.
Abstract 4242: Preserving lung cancer patient mutations in 3D organoid models: Advancing cancer research through innovative culture systems
Authors: Park Ji-yeon , Gu Seo Rin , Lee Jiyeon , Lee Na-Gyeong , Choi Dojin , Park Sang Eun , Kim Ji Min , Rheey Jinguen 
Published: March 2024

Abstract
Lung cancer is one of the most prevalent cancers worldwide. There are currently many anticancer drugs available, but they have numerous issues in terms of treatment, such as drug resistance and recurrence. Culturing systems that can replace a patient's cancer tissue are crucial, and the existing 2D culturing systems have many limitations. Patient-derived cancer organoid culture is the most advanced culture system for understanding mechanism of cancers. Using a 3D organoid culture system, we have successfully established a culture system for lung cancer using biopsy/surgical specimens and malignant effusions, including a long-term culture system. There are two critical indicators to determine the success of 3D organoid culture. One is whether the organoids retain their cancer-specific mutations from patient’s lung cancer tissue, and the second is whether the organoids grow well and can be maintained in long-term culture for more than 20-30 passages. We typically assess gene mutations in EGFR, ALK, ROS, and P53 when evaluating lung cancer organoids. We confirm these mutations when we establish organoids. and currently we have established a total of 127 patient-derived lung cancer organoids. Among the 127 organoids, we completed NGS analysis on 108 of them and validated that 86.5% exhibit similarity when compared to lung cancer tissues. Additionally, we achieved a 100% retention of mutations in the long-term culturing of these organoids. Our studies indicate that patient-derived lung cancer organoids represent a meaningful organoid system for cancer tissue replacement and treatment response in the context of precision cancer medicine.
Citation Format: Ji-yeon Park, Seo Rin Gu, Jiyeon Lee, Na-Gyeong Lee, Dojin Choi, Sang Eun Park, Ji Min Kim, Jinguen Rheey. Preserving lung cancer patient mutations in 3D organoid models: Advancing cancer research through innovative culture systems [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 4242.
Abstract 4280: Regulatory T cells contribute to tumor cell dissemination by extracellular matrix remodeling
Authors: Garcia-Santillan Ailen , Lichtenberg Jessanne Y. , Shen He , Dozmorov Mikhail G. , Olex Amy L. , Hwang Priscilla Y. , Bos Paula D. 
Published: March 2024

Abstract
Regulatory T (Treg) cells function to enforce peripheral tolerance and are potent suppressors of tumor immunity. In breast cancer, we have shown that Treg cells promote tumor growth by favoring alternative activation of macrophages via suppression of IFN-γ. The tumor-associated extracellular matrix (ECM) is a key regulator of metastatic dissemination and is emerging as a critical regulator of tumor immunity. However, the reciprocal effects of the immune system on the ECM remain elusive. Using murine in vivo, ex vivo and bioengineering models we describe Treg cell-dependent changes in the tumor ECM that facilitate tumor cell movement and metastatic dissemination. Further, Treg cell-dependent matrisome signatures correlate with survival in human breast cancer samples. This work underscores a previously unrecognized role of Treg cells on the ECM that facilitates metastasis and is consistent with tissue Treg cell emergent function as critical regulators of tissue repair and cancer.
Citation Format: Ailen Garcia-Santillan, Jessanne Y. Lichtenberg, He Shen, Mikhail G. Dozmorov, Amy L. Olex, Priscilla Y. Hwang, Paula D. Bos. Regulatory T cells contribute to tumor cell dissemination by extracellular matrix remodeling [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 4280.
Abstract 4307: Quantifying the cell-intrinsic and cell-extrinsic growth effects of cancer-causing mutations in vivo
Authors: McFarland Christopher Dennis , Maltas Jeff 
Published: March 2024

Abstract
Adaptive driver phenotypes in cancer must confer either a cell-intrinsic (birth minus death) or cell-extrinsic (field) effect on growth. These effects can be summarized by an r/K logistic growth curve, whereby cell-intrinsic effects manifest as a change in the early, exponential growth constant (r) of a tumor population while cell-extrinsic effects alter the long-term ‘carrying capacity’ (K). Previously, we developed a novel genetically-engineered mouse model that tracks tumor growth dynamics with unprecedented precision via Tumor Barcoding, termed TuBa-seq1. Here, we quantify the growth trajectories of thousands of Kras-driven lung tumors over eight months. Median tumor size is best-described by a Gomp-Ex growth law (i.e. Nν/K where ν → +0), which also characterizes advanced-stage human tumors2. Carrying capacities of individual isogenic tumors varied by over four orders of magnitude, suggesting that microenvironmental heterogeneity profoundly impacts growth dynamics. Our approach further allowed us to track the growth effects of eleven canonical tumor suppressor gene knockouts introduced via multiplexed CRISPR/Cas genome-engineering. All but one of these secondary mutations augmented either the exponential growth rate or the carrying capacity of the tumor. However, only three tumor suppressor losses increased both growth parameters (Rb1, Setd2, and Stk11). Hence, the growth benefits of most cancer-causing mutations are missed when growth is measured only at a single time point. Clinically, we find that r-promoting and K-promoting mutations interact synergistically to create the most aggressive tumors in human patients (HR = 1.71, P-value &lt; 10-10). Collectively, these results support a universal r/K framework for tumor growth and progression.
References1.Rogers, Z. N. et al. A quantitative and multiplexed approach to uncover the fitness landscape of tumor suppression in vivo. Nat. Methods 14, 737-742 (2017).2.Benzekry, S. et al. Classical mathematical models for description and prediction of experimental tumor growth. PLoS Comput. Biol. 10, e1003800 (2014).
Citation Format: Christopher Dennis McFarland, Jeff Maltas. Quantifying the cell-intrinsic and cell-extrinsic growth effects of cancer-causing mutations in vivo [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 4307.
Abstract 4311: The interplay of SYNCRIP deficiency, APOBEC activity, and extrachromosomal DNA in castration-resistant prostate cancer drug resistance
Authors: Li Xiaoling , Deng Su , Wang Choushi , Wang Yunguan , Mu Ping 
Published: March 2024

Abstract
Background: Prostate cancer, particularly in its castration-resistant form (CRPC), frequently develops resistance to androgen receptor (AR)-targeted therapies. This resistance involves complex factors, including tumor mutational burden and heterogeneity. APOBEC proteins, associated with mutagenesis and DNA damage, are implicated in this process. Our study centers on SYNCRIP, a key regulator of APOBEC activity, and investigates its influence on extrachromosomal DNA (ecDNA) in CRPC. Objective: This research aims to explore how SYNCRIP deficiency leads to increased APOBEC activity, and to examine its possible implications for ecDNA formation and its contribution to drug resistance and tumor heterogeneity in CRPC.
Methods: Genomic and transcriptomic analyses, such as whole exome sequencing and single-cell RNA-seq, were performed on CRPC cell lines and patient-derived samples, with an emphasis on SYNCRIP-deficient models. The study focused on understanding the relationship between elevated APOBEC activity due to SYNCRIP deficiency and potential ecDNA changes, evaluating their effect on AR-targeted drug sensitivity and overall tumor behavior.
Results: SYNCRIP was identified as a critical factor in resistance to AR therapy in both in vitro and in vivo models. Its deficiency resulted in increased therapy resistance and amplified APOBEC-mediated mutagenesis. Functional CRISPR screening identified eight key drivers of resistance in SYNCRIP-deficient tumors. Single-cell RNA sequencing revealed APOBEC-driven mutagenesis as a key factor in promoting intratumoral heterogeneity and resistance. Notably, in SYNCRIP-deficient CRPC samples, increased APOBEC activity and significant DNA damage were observed, prompting an investigation into a possible correlation between resistance and ecDNA presence.
Conclusion: The study uncovers a significant link between SYNCRIP deficiency and increased APOBEC activity in CRPC. While it also hints at a potential connection with ecDNA alterations, further research is necessary to establish this relationship firmly. This interplay contributes to the complexity of drug resistance in CRPC, highlighting the need for novel therapeutic targets. The dynamics among SYNCRIP, APOBEC activity, and ecDNA offer valuable insights into the molecular underpinnings of therapy resistance in prostate cancer, suggesting new directions for treatment strategies.
Citation Format: Xiaoling Li, Su Deng, Choushi Wang, Yunguan Wang, Ping Mu. The interplay of SYNCRIP deficiency, APOBEC activity, and extrachromosomal DNA in castration-resistant prostate cancer drug resistance [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 4311.