bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1576: Chemotherapy induced cellular cannibalism is mediated by phosphoinositide species and clathrin
Authors: Frey Wesley D. , Anderson Ashlyn , Nguyen Julie , Cowles Emma , Jackson James 
Published: June 2022

Abstract
Cancer cells can survive chemotherapy and drive lethal relapse if they avoid cell death in conditions of 1) DNA damage and/or mitotic stress caused by treatment; 2) nutrient depletion. We and others have previously shown that the breast cancers most likely to survive chemotherapy are TP53 wild-type, and these are among the most lethal breast cancers. For instance, chemotherapy treated TNBC patients with TP53 wild-type tumors have a median overall survival of 45 months, contrasting with 263 months for TP53 mutant tumors. TP53 wild type cells survive stress by entering a state of arrest and cellular senescence. But to persist in senescence, cells must survive in limited access to vasculature and nutrient sources while also supporting a high metabolic burden that includes production of cytokines and chemokines that drive pro-tumorigenic phenotypes and relapse.
We previously showed a novel cannibalism phenotype of chemotherapy induced senescent cells. Engulfment occurred after exposure to different chemotherapy drugs in vitro, in 9 different cell lines, and in vivo in syngeneic mouse mammary tumor models. Engulfed prey cells were processed to the lysosomes of predator cells and broken down. While we showed the phenotype was unrelated to entosis, and senescent cells expressed many phagocytosis/macrophage related genes, the basic mechanisms of the engulfment are unknown.
Here, we use biosensors and live cell imaging to delineate the steps of whole cell engulfment in cells that have entered senescence to survive chemotherapy. We show predator cell filamentous actin was localized to the prey cell throughout the process of engulfment. Biosensors to various phosphoinositide (PI) species showed increased concentration and localization of predator PI(4)P and PI(4,5)P2 at the prey cell during early stages of engulfment, followed by a burst of PI(3)P before internalization. PIK3C2B, an enzyme responsible for generating PI(3)P, was required for complete engulfment. Inhibition or knockdown of Clathrin, known to associate with PIK3C2B and PI(4,5)P2, severely impaired engulfment. In sum, these data demonstrate the mechanism of cellular cannibalism used by breast cancer cells to survive chemotherapy.
Citation Format: Wesley D. Frey, Ashlyn Anderson, Julie Nguyen, Emma Cowles, James Jackson. Chemotherapy induced cellular cannibalism is mediated by phosphoinositide species and clathrin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1576.
Abstract 1593: Genetic and pharmacological modulation of DNA mismatch repair promotes immune surveillance in murine colorectal cancer
Authors: Amodio Vito , Germano Giovanni , Mussolin Benedetta , Lamba Simona , Chilà Rosaria , Rospo Giuseppe , Marchiò Caterina , Marsoni Silvia , Mauri Gianluca , Di Nicolantonio Federica , Bardelli Alberto 
Published: June 2022

Abstract
Patients affected by colorectal cancer (CRC) with microsatellite instability (MSI), which is caused by DNA mismatch repair deficiency (MMRd), are eligible for therapies based on immune checkpoint inhibitors (CPI), while microsatellite stable (MSS) tumors are not. However, a subset of MSS CRCs contains variable fractions of MMRd cells. How the presence of MMRd cells in tumors classified as MSS impacts cancer immune surveillance is largely unknown. It is also unclear whether the pharmacological modulation of MMRd cells percentage in MMR heterogeneous tumor can occur and if this might result in the improvement of tumor immune control.To shed light on these aspects we studied isogenic mismatch repair proficient and deficient mouse tumor cells, generated by genetic inactivation of MLH1, a key component of the MMR machinery. We mixed MLH1+/+and MLH1-/-cells at different ratios, injecting the resulting heterogeneous populations in mice. In the presence of a competent immune system, the tumorigenic potential and immune surveillance of MSS/MSI (MLH1+/+/MLH1-/-) heterogeneous tumors was dependent upon the MMRd fraction. Tumor rejection was observed when at least 50% of the cells were MMRd, but tumor growth delay was also evident when as low as 20% of MMRd cells were present in the mixed population and this was paralleled by immune infiltration of the tumor. Molecular profiles of samples from MSS/MSI heterogeneous tumors that evaded immune control, showed enrichment of the MSS fraction. Treatment of MSS/MSI mixed populations with the antimetabolite 6-Thioguanine (6TG) greatly enriched the MMRd fraction and improved immune response. Overall, these results suggest that genetic and/or pharmacological modulation of the DNA mismatch repair machinery can foster immune surveillance of MMR heterogeneous tumors and modulate the cancer immune environment.
Citation Format: Vito Amodio, Giovanni Germano, Benedetta Mussolin, Simona Lamba, Rosaria Chilà, Giuseppe Rospo, Caterina Marchiò, Silvia Marsoni, Gianluca Mauri, Federica Di Nicolantonio, Alberto Bardelli. Genetic and pharmacological modulation of DNA mismatch repair promotes immune surveillance in murine colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1593.
Abstract 1625: c-Myc inhibition in prostate cancer cell lines
Authors: Riveros Carlos , Chalfant Victor , Shukla Sanjeev , Osumi Teruko , Balaji KC 
Published: June 2022

Abstract
The proto-oncogene c-Myc is a transcription factor that is upregulated in several human cancers. Despite its key role, therapeutic targeting of c-Myc remains a challenge because of a disordered protein tertiary structure. The basic helical structure and zipper protein of c-Myc forms an obligate heterodimer with its partner MAX to function as a transcription factor. An attractive strategy is to inhibit MYC/MAX dimerization to decrease c-Myc transcriptional function. Several methods have been described to inhibit MYC/MAX dimerization including small molecular inhibitors and proteomimetics. We used NOD SCID gamma mice (NGS mice) that are immunodeficient, non-obese diabetic laboratory mice (Jackson Laboratories, Cat Number J000077451) carrying patient-derived xenograft (PDX) following implantation of grade IV adenocarcinoma of the prostate from a patient into the flanks of each mouse. For maximum tolerable dose studies, we used C57BL/6 wild type mice (Jackson Laboratories, Cat Number J000664). We performed a maximum dose tolerability study with the drug 3JC48-3 up to 100 mg/kg to determine limiting toxicity. We monitored the rate of growth for 2 weeks and measured the final volume of the tumors. Immunoprecipitation studies were performed using the prostate cancer cell line, PC-3, that were treated with the drug 3JC48-3 at different doses (0, 5, 10, and 20uM) for 24 hours and subsequently lysed. We found 3JC48-3 decreases prostate cancer growth and viability in a dose-dependent fashion in vitro. We confirmed the inhibition of MYC/MAX dimerization by 3JC48-3 using immunoprecipitation experiments. Normal mice and mice with patient-derived prostate cancer xenografts (PDX) tolerated intraperitoneal injections of 3JC48-3 up to 100 mg/kg body weight without dose-limiting toxicity. Preliminary results in these PDX mouse models suggest that 3JC48-3 may be effective in decreasing the rate of tumor growth. Our study demonstrates that 3JC48-3 is a potent MYC/MAX heterodimerization inhibitor that decreases prostate cancer growth and viability in association with upregulation of both PrKD1 expression and kinase activity. In addition, 3JC48-3 is well tolerated in prostate cancer PDX mice models and may be a candidate drug for further preclinical development.
Citation Format: Carlos Riveros, Victor Chalfant, Sanjeev Shukla, Teruko Osumi, KC Balaji. c-Myc inhibition in prostate cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1625.
Abstract 1646: Humanized TROP2 mice provide a preclinical tool for the evaluation of therapeutic drugs targeting TROP2
Authors: Huang Dexuan , Shen Zhiyuan , Ma Limei , Li Chong , Jin Tianquan 
Published: June 2022

Abstract
Human TROP2, also known as tumor-associated calcium signal transducer 2 (TACSTD2), is a type I cell surface glycoprotein that mediates intracellular calcium signals. It plays a crucial role in cell proliferation, survival, self-renewal, and cell adhesion. Several ligands are found to interact with TROP2, including claudin-1, claudin-7, cyclin D1, and IGF-1. TROP2 is expressed on the surface of many stem and progenitor cells as well as other tissues. Importantly, TROP2 is highly expressed in a variety of solid tumors, making it a new target for the development of antibody-conjugated drugs. To evaluate the efficacy of anti-TROP2 antibodies, we generated a humanized B-hTROP2 mouse at Biocytogen. In this mouse model, the murine TROP2 gene was replaced by the full length human TROP2 gene. Western blot analysis showed that human TROP2 protein expression was detected in skin and kidney of homozygous B-hTROP2 mice. These results suggest that B-hTROP2 mice is an ideal tool for in vivo efficacy evaluation of therapeutic drugs targeting human TROP2.
Citation Format: Dexuan Huang, Zhiyuan Shen, Limei Ma, Chong Li, Tianquan Jin. Humanized TROP2 mice provide a preclinical tool for the evaluation of therapeutic drugs targeting TROP2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1646.
Abstract 1653: Toward developing a humanized mouse model of the microenvironment associated with the malignant cells of Hodgkin lymphoma
Authors: Bilotta Maria Teresa , Antignani Antonella , Fitzgerald David J. 
Published: June 2022

Abstract
The tumor microenvironment (TME) represents a highly complex compartment that includes cancer cells, non-hematopoietic stromal cells, extracellular matrix, lymphocytes, and myeloid cells. Interactions between these populations and the factors they secrete play critical roles in determining the host response to cancer. Conventional mouse xenograft models of human cancer lack a competent immune system. Indeed, the use of xenograft models often fail to translate into effective human treatments. Classical Hodgkin Lymphoma (HL) is characterized by the presence in the lymphonodes of abnormal Reed-Sternberg cells, and many cell types beyond them, in particular Treg. To reconstitute a more complete TME, human PBMCs were injected into NSG mice bearing L540 HL cells. Then over time the presence of various human CD45+ cell populations were monitored within the tumor mass, in the spleen and in circulation. The goal of our study is to gain a better understanding of the interaction of the immune cell infiltrates into the HL microenvironment, leading ultimately to improved treatment outcomes. Lymphocyte infiltration into the tumor showed a predominance of human CD3+ cells (T lymphocytes), even if in the spleen we found both human T and B cells, indicating that this model might help us design more effective treatments. To reflect the immune reconstitution of these animals and its interaction with tumor and to better understand the capacity of T lymphocytes to kill the cancer cells, we evaluated the production of human IFN- gamma. We found an increase of IFN- gamma in L540-bearing mice reconstituted with hPBMCs compared to the mice without them, indicating a certain functionality of the T cells in these tumors. Moreover, in this model, the immune reconstitution did not decrease tumor growth, rendering this model useful for the study of biotherapeutic and immunotherapeutic studies. The model might be useful to study the anticancer therapy at a preclinical level because a remodeling of the anti-tumor immune response can be evaluated.
Citation Format: Maria Teresa Bilotta, Antonella Antignani, David J. Fitzgerald. Toward developing a humanized mouse model of the microenvironment associated with the malignant cells of Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1653.
Abstract 1674: FGF8 as a modulator of Wilms' tumor in vitro growth and longevity
Authors: Cooper Garrett , Lee Benjamin , Smyth Nate , Mittal Karuna , Lawrence Taylor , Jonus Hunter , Shim Jenny , Goldsmith Kelly , Hong Andrew 
Published: June 2022

Abstract
Wilms’ tumor is the most common pediatric renal tumor accounting for 6-7% of all childhood cancers. Development of faithful Wilms’ tumor cell lines is needed to identify novel therapeutics. Currently, established Wilms’ tumor cell lines that are suitable for high throughput studies only represent anaplastic Wilms, a rare subtype. In contrast, cell lines representing the more common favorable histology Wilms’ tumor (FHWT) often have poor proliferative capacity and are unable to passage long-term (e.g. &gt;20 passages). For this reason, there is a need to establish robust cell lines representing FHWT. We hypothesize that there are core factors missing from the cell culture medium which prevent proper growth signaling and proliferation. We first performed bulk RNA-sequencing from patients and associated cell lines at Aflac Cancer and Blood Disorders Center with an underlying diagnosis of FHWT. Transcriptomic analyses showed that the reduced growth and proliferation in these FHWT cell lines may be due to reduced presence of the mitogenic fibroblast growth factor 8 (FGF8) in the cell culture environment as compared to the tumor environment. Wilms’ tumor has notably high FGF8 expression levels compared to all other pediatric tumors, implicating FGF8 as a potential driving factor in tumor maintenance. To characterize the phenotypic effects of FGF8 reintroduction in short term FHWT cell lines, we both endogenously overexpressed FGF8 via a lentiviral vector and ectopically added recombinant FGF8 to the cell culture medium. Qualitatively, endogenous overexpression of FGF8 induced distinct morphological changes in cells, converting the enlarged and flattened cells into more focal cells resembling proliferative early passage cells. Quantitatively, overexpression of FGF8 in one favorable histology cell line led to an increased rate of cellular proliferation and extended the cellular longevity by seven passages (47% above baseline). RNA-sequencing analysis of these FGF8 overexpressing cells implicated the anti-apoptotic gene, NTSR1, and an extracellular matrix protein, SNED1, as potential downstream targets of FGF8 overexpression. However, ectopic addition of recombinant FGF8 protein to the cellular medium had less pronounced effects, with seemingly cell-line specific effects. These data demonstrate FGF8 as possibly being required for survival in certain Wilms’ tumor cell lines that can be modulated to influence in vitro proliferation and longevity.
Citation Format: Garrett Cooper, Benjamin Lee, Nate Smyth, Karuna Mittal, Taylor Lawrence, Hunter Jonus, Jenny Shim, Kelly Goldsmith, Andrew Hong. FGF8 as a modulator of Wilms' tumor in vitro growth and longevity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1674.
Abstract 1685: Deep learning approaches to deciphering intra-tumoural heterogeneity in glioblastoma
Authors: Dent Anglin J. , Faust Kevin , Lam Brian , Leon Alberto J. , Tsang Queenie , Diamandis Phedias 
Published: June 2022

Abstract
BACKGROUND: Emerging evidence strongly implicates intra-tumoral heterogeneous biology in treatment resistance and disease progression across many cancer types. Thus, there is a need for workflows capable of systematically resolving and targeting distinct tumor subpopulations1. Using glioblastoma (GBM) as a prototype, I have aimed to leverage the computational power of Artificial Intelligence (AI) and deep learning to develop an autonomous workflow for the objective definition of biologically distinct tumor subpopulations2.
OBJECTIVES: I hypothesize that AI may be leveraged as a tool to resolve spatial heterogeneity, by identifying tumoral subpopulations with unique molecular profiles and therapeutic targets. To highlight the need for routine analysis of tumor heterogeneity, I will address if:
METHODS: I apply our developed image clustering workflows to quantify AI-defined subregions within a clinical cohort of 10 GBM patient tumors2,3. Laser capture microdissection and mass spectrometry-based proteomics are leveraged to address if AI-defined subregions show intra-tumoral molecular variation. Further, existing pharmacogenomic databases are utilized to carry out drug sensitivity and transcriptional clustering to define AI-defined region-specific therapeutic sensitivities and resistances across my clinical GBM cohort4.
RESULTS: Preliminary data shows that region to region heterogeneity can be found in IDH wild-type GBM using our unbiased omics approach, in addition to predicting different pharmacogenomic sensitivities.
CONCLUSIONS: This project aims to develop the first AI-driven tool to guide the routine and systematic molecular analysis of spatial morphogenomic heterogeneity. Further, this tool may have the potential to provide novel approaches for personalized care by selecting drug combinations that target a larger fraction of a tumor’s true biology.
1. Patel, A. P. et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science (80-. ). 344, 1396-1401 (2014).
2. Faust, K. et al. Unsupervised Resolution of Histomorphologic Heterogeneity in Renal Cell Carcinoma Using a Brain Tumor-Educated Neural Network. JCO Clin. Cancer Informatics 811-821 (2020) doi:10.1200/cci.20.00035.
3. Roohi, A., Faust, K., Djuric, U. & Diamandis, P. Unsupervised Machine Learning in Pathology: The Next Frontier. Surgical Pathology Clinics vol. 13 349-358 (2020).
4. Barretina, J. et al. The Cancer Cell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity. Nat. 2012 4837391 483, 603-607 (2012).
Citation Format: Anglin J. Dent, Kevin Faust, Brian Lam, Alberto J. Leon, Queenie Tsang, Phedias Diamandis. Deep learning approaches to deciphering intra-tumoural heterogeneity in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1685.
Abstract 1718: Characterization of infiltrating immune cells after irradiation using 10x genomics single cell sequencing
Authors: Ponthan Frida , Ubertini Valentina , Beale Gary 
Published: June 2022

Abstract
Background: Radiation therapy is delivered to approximately 50% of all cancer patients. It has long been known that radiation causes not only DNA strand breaks, apoptosis, and necrosis, but also immunogenic modulation. Lately, there has been renewed interest in the potential of irradiation in colorectal cancer, not only as an adjuvant and palliative treatment, but also as an immune stimulant.
Materials and Methods: CT26 murine colorectal carcinoma cells were subcutaneously implanted on the flank of BALB/c mice. Tumors were exposed to sham, single dose or fractionated radiotherapy regimens via a 300kV, 10mA X-ray with additional filtration to give a radiation quality of 2.3mm Cu half-value layer (HVL). Mice were anaesthetized, restrained and delivered a single uniform dose of radiation at a rate of 0.696Gy/min with the whole mouse being lead shielded except for a 1cm hole in the lead above the tumor site. Tumors were harvested at different timepoints post irradiation and dissociated into single cell suspensions. The tumor microenvironment and immune response within the tumors were analyzed with flow cytometry comparing the different treatment regimens. The individual CD45+ cell profile was investigated using 10x gene expression. 10x sequencing was demultiplexed using CellRanger and data analyzed using Seurat and ACTINN.
Results: Following the initial cytotoxicity, flow cytometry showed a clear immune stimulatory effect of radiotherapy with immune cells infiltrating the irradiated tumors. The level of infiltration was dependent on the treatment scheduling. For single cell assessments, we observed approximately 8000 reads/cell and T-SNE cluster analysis using Seurat identified 16 clusters in control and treated samples. Identification of clusters by ACTINN demonstrated that CD8+ T-cells were increased 8-fold in irradiated samples whereas monocytes numbers decreased 3-fold. In irradiated tumors, the main population of CD8+ T-cells with increased numbers also expressed NKG7.
Conclusion: These data provide evidence that radiotherapy can enhance immune cell trafficking to locally treated CT26 tumors. Furthermore, 10x genomics single cell sequencing revealed increased levels of cytotoxic T-cells expressing NKG7, a protein implicated in enhanced killing of extracellular targets. This response could prime the tumors such that they may be exploited by immune modulating drugs.
Citation Format: Frida Ponthan, Valentina Ubertini, Gary Beale. Characterization of infiltrating immune cells after irradiation using 10x genomics single cell sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1718.
Abstract 1759: PRO1160, a novel CD70-directed antibody-drug conjugate, demonstrates robust anti-tumor activity in mouse models of renal cell carcinoma and non-Hodgkin lymphoma
Authors: Wang Lei , Liu Haidong , Shang Xiao , Han Tae , Zhao Baiteng 
Published: June 2022

Abstract
PRO1160 is an antibody-drug conjugate directed toward CD70, an antigen that is aberrantly overexpressed in multiple hematologic malignancies and carcinomas with limited normal tissue expression. PRO1160 is comprised of a 1) human monoclonal antibody that selectively binds to CD70, 2) a cleavable, hydrophilic linker, and 3) exatecan, a topoisomerase 1 inhibitor. Upon binding to CD70 on the surface of malignant cells, PRO1160 is internalized and exatecan released through enzymatic cleavage of the linker. Exatecan blocks the ligation step of the cell cycle and generates DNA single- and double-strand breaks, which leads to cell death. PRO1160 demonstrated robust anti-tumor activity, in vitro and in vivo. In multiple cell-derived xenograft mouse models, PRO1160 demonstrated more potent tumor growth inhibition compared to an MMAE-conjugated ADC with the same parent antibody. PRO1160 was well tolerated in mice with no to minimal impact on body weight gain. The in vivo pharmacokinetics in rats showed that PRO1160 is stable in circulation. These nonclinical data suggest the potential for a broad therapeutic window and further development of PRO1160 is warranted. PRO1160 has the potential for an expanded therapeutic index. PRO1160 is being developed for the potential treatment of patients with CD70-expressing hematologic and solid tumor cancers.
Citation Format: Lei Wang, Haidong Liu, Xiao Shang, Tae Han, Baiteng Zhao. PRO1160, a novel CD70-directed antibody-drug conjugate, demonstrates robust anti-tumor activity in mouse models of renal cell carcinoma and non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1759.