bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2611: Transcription factor-nucleosome dynamics inferred from plasma cfDNA delineates tumor and tumor-microenvironment phenotype
Authors: Rao Satyanarayan , Han Amy , Zukowski Alexis , Kopin Etana , Kabos Peter , Ramachandran Srinivas 
Published: July 2021

Abstract
Our current understanding of solid tumors and their progression primarily relies on in vitro models, cell lines, patient-derived xenografts, and scarce data from invasive tissue biopsies from patients. The ability to monitor changes in chromatin structure and transcription factor binding in tumor cells using a minimally invasive approach in humans has the potential to revolutionize our understanding of disease progression and treatment resistance. In this study, we use the example of estrogen receptor (ER) positive breast cancer, the most common disease subtype, and define the ER axis from plasma cell-free DNA (cfDNA). While lymphoid/myeloid cell turnover represents the dominant source of cfDNA in the bloodstream, a detectable fraction of DNA from tumor tissue-of-origin can be found in patients with solid cancers. cfDNA is the product of the action of endogenous nucleases on chromatin; and retains the map of epigenomes from cells of origin. Our method therefore non-invasively captures TF-nucleosome dynamics in tumor tissue-of-origin using plasma cfDNA. First, we show that we can reliably identify the active binding of hematopoietic pioneer factor PU.1 and CTCF from cfDNA of healthy humans and cancer patients. Then to define cfDNA binding of disease specific TF ER, we used ER+ patient-derived xenograft (PDX) models allowing for a clear separation of tumor signal from hematopoietic background. This allowed us to establish the sensitivity and specificity of our approach. We also identified the subset of CUT&RUN-defined ER binding sites that feature the strongest binding in vivo from both lymphocyte background as well as cancer cells. Furthermore, we can define the active binding sites of pioneer factor FOXA1, which facilitates ER binding by opening the chromatin. Based on the TF protection levels from cfDNA we were able to define tumor as well as hematopoietic-specific TF binding sites that can serve as potential hotspots to monitor ER+ disease state at around 1% tumor fraction. These data demonstrate our ability to simultaneously monitor TF and nucleosome dynamics at disease sites just from plasma that can enable real-time monitoring of disease phenotype in a minimally invasive manner.
Citation Format: Satyanarayan Rao, Amy Han, Alexis Zukowski, Etana Kopin, Peter Kabos, Srinivas Ramachandran. Transcription factor-nucleosome dynamics inferred from plasma cfDNA delineates tumor and tumor-microenvironment phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2611.
Abstract 2640: Characterization and targeted therapy using patient tumor-derived 3-D spheroids in a metastatic castrate resistant prostate cancer model
Authors: Kase Adam M. , Tan Winston , Copland John A. 
Published: July 2021

Abstract
Targeted therapy in prostate cancer is in its early stages and has a promising future since many genomic alterations in metastatic castrate resistant prostate cancer (mCRPC) do not have FDA approved agents for this indication. Three-dimensional culture has been shown to recapitulate patient response to therapy. We characterized a unique patient tumor-derived, GUR017M, 3D culture spheroid model and tested novel therapies based on its genomic profile. This tumor was obtained from a patient with mCRPC who progressed on enzalutamide, abiraterone, cabazitaxel, and had exposure to docetaxel, however discontinued due to toxicity. In order to characterize and test novel therapies for mCRPC, a 3-D spheroid drug assay was utilized and was able to recapitulate the GUR017M response to previous therapies (resistance to docetaxel and enzalutamide). Using a 3-D spheroid drug assay, single agents were investigated based on the GUR017M genomic profile which included cyclin D1, LYN, and FGF3/4/19 amplifications along with HRAS Q61R mutation, and TP53 splice site 672+2T&gt;G. Single agents (abemaciclib, bafetinib, erdafitinib, tipifarnib, MK2206, APR-246) all caused dose dependent inhibition up to 100% inhibition. This rare prostate cancer model, GUR017M allows us to test novel single agents and combination strategies in 3-D culture. This patient tumor has also proven to be a successful PDTX model which allows for confirmatory testing in animal models in order to move forward with clinical trial proposals.
Citation Format: Adam M. Kase, Winston Tan, John A. Copland. Characterization and targeted therapy using patient tumor-derived 3-D spheroids in a metastatic castrate resistant prostate cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2640.
Abstract 2642: Using 3-Dimensional in vitro models to unravel the complexity of the metastatic microenvironment in high-grade serous ovarian cancer
Authors: Malacrida Beatrice , Delaine-Smith Robin , Nichols Sam , Maniati Eleni , Jones Roanne L. , Knight Martin M. , Pearce Oliver M. , Balkwill Frances R. 
Published: July 2021

Abstract
Studying the complexity of the tumor microenvironment (TME) still represents a challenge in research. The intricate communication within the stroma - fibroblast, immune cells, endothelial cells and the extracellular matrix (ECM) - and the malignant cell compartment sustains every stage of cancer progression and resistance to cancer therapies, but it is difficult to model this using human cells. Using a multi-level deconstruction of human metastases as a template and validation, we developed multicellular models of high-grade serous ovarian cancer (HGSOC) with increased complexity. The different models - tri-, tetra- and penta-cultures - consist of different combinations of primary adipocytes, fibroblasts, mesothelial cells, HGSOC cells and myeloid cells that mimic the structure and the composition of a human omental metastatic tissue. In HGSOC biopsies, we previously identified a prognostic matrisome signature and a number of pathways correlating ECM deposition and disease progression. This knowledge combined with the versatile nature of our platforms has allowed us to identify the contributions of each cell type in supporting tumor progression and ECM remodeling. For instance, 14-day tri-culture of malignant cells, adipocytes and fibroblasts was sufficient to replicate the deposition of specific ECM proteins and the prognostic matrisome signature seen in human omental metastases. Moreover, we found that TGFβR and Hedgehog signaling pathways act together on the fibroblasts to stimulate ECM production. In addition, in the tetra-culture model, we identified platelets as promoters of early metastatic invasion by activating mesothelial cells. As the immune system plays an important role in HGSOC tumor microenvironment, we have now added myeloid cells to form a more complex penta-culture in which we can analyze the behavior and impact of myeloid cells. In conclusion, the multicellular models presented here could be a new resource to study new and established cancer therapies and provide a useful tool to better understand the molecular mechanisms that drive cancer progression.
Citation Format: Beatrice Malacrida, Robin Delaine-Smith, Sam Nichols, Eleni Maniati, Roanne L. Jones, Martin M. Knight, Oliver M. Pearce, Frances R. Balkwill. Using 3-Dimensional in vitro models to unravel the complexity of the metastatic microenvironment in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2642.
Abstract 2643: Human and mouse reconstructed plate-based 3-dimensional culture assays that mimic the tumor microenvironment
Authors: Steffey Michael E. , Qu Ying , Karalewitz Andrew , Urs Sumithra , Kirshner Julia , Wise Scott 
Published: July 2021

Abstract
In order to predict efficacy and toxicity of compounds advancing in the oncology drug discovery pipeline, and to minimize requirements for multiple animal studies, the development of in vitro assays that recapitulate in vivo conditions is increasingly important. While high throughput screening favors 2D assays, both for cost and relative speed in culturing and plating, they do not recapitulate the tumor architecture and the microenvironment that is more comparable to in vivo models. We now report this has been accomplished using zPREDICTA's organ-specific three-dimensional (3D) culture models which support long-term culture of carcinoma cells. Physiologic extracellular matrix (ECM) components are critical in maintaining the physical and spatial microenvironment as well as tumor phenotypes in reconstructed bone marrow (r-Bone) and mouse breast (r-mBreast) models. The r-Bone ECM allows for co-culture of tumor cells with mesenchymal stem cells, fibroblasts, lymphoid, myeloid, and CAR-T cells. The data here describes clear differences in the in vitro pharmacology of several standard of care agents in 2D, in adherent or suspension cultures, compared to the recapitulated 3D tumor microenvironment of the human hematopoietic compartment or the mouse breast ductal epithelium. For example, we find that cisplatin has a 10-30 fold higher IC50 in 4 different murine cell lines (MMTV-PyMT, 4T1, EMT6, and E0771) when cultured in the r-mBreast model than when those cells are adhered to the polystyrene in a 2D culture. Cytotoxicity assays such as CellTiter-Glo® can also be performed in a high throughput format in both 96 and 384-well 3D assay formats and we demonstrate equivalent bortezomib IC50 values in RPMI 8226 cell r-Bone cultures in both plate types. Additionally, cells can be isolated from the matrix after test agent exposure and analyzed by an appropriate downstream application, such as flow cytometry, where we show anti-CD19 CAR-T cell killing of CD19+ NALM6 cells in r-Bone cultures. These 3D models represent new early opportunities to screen test agents in a platform that is designed to more closely mimic in vivo tissue microenvironments and serve as a more relevant tool for multi drug screening and as a prerequisite to animal studies.
Citation Format: Michael E. Steffey, Ying Qu, Andrew Karalewitz, Sumithra Urs, Julia Kirshner, Scott Wise. Human and mouse reconstructed plate-based 3-dimensional culture assays that mimic the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2643.
Abstract 2648: A dual functional agent inhibits the angiogenesis and DNA synthesis resulting in the growth suppression of consensus molecular subtypes 1 and 4 in colorectal cancer xenografts
Authors: Rao Vaikar Navakanth , Kuppuswamy Ramajayam , Lai Kuo Chu , Su Tsann-Long , Lee Te-Chang 
Published: July 2021

Abstract
Purpose: We have synthesized a series of bifunctional molecules, which are able to induce DNA interstrand crosslinks and inhibit angiogenesis as potent anticancer agents [1] and leads to develop new hybrids molecules. To analyze one of the novel bifunctional agent BO-2762 activity in consensus molecular subtype (CMS) classified as colorectal cancer (CRC) which are classified into four subtypes [ CMS1, MSI-immune; CMS2, epithelial and canonical; CMS3, epithelial and metabolic; and CMS4, mesenchymal] in in vitro and in vivo models.
Experimental Design: We analyzed the anticancer effect of BO-2762 in CMS primary colorectal cancer cells which are reported in previous studies [2] and their respective xenografts (CMS-1: LoVo; CMS-2: LS1034; CMS-3: HT-29 and CMS-4: SW620). CMS provided a new platform to analyze BO-2762 functionalized subtype-specific sensitivity in CRC.
Results: BO-2762 has a distinct bifunctional activity by DNA crosslinking in CRC cells and inhibiting angiogenesis in endothelial cells at IC50 of nanomolar to micromolar ranges. Angiogenesis inhibition was likely due to the suppression of VEGFR-2 phosphorylation in EA.hy 926 cells. Additionally, BO-2762 could inhibit cell migration, invasion, and induce apoptotic cell death in CRC. In our observation, no subtype-sensitivity has observed in in vitro conditions as reported in previous studies [3]. Using xenograft models, 20 mg/kg BO-2762 suppressed remarkably LoVo (CMS-1), and SW620 (CMS-4) subtypes, moderately in LS1034 (CMS-2) which was administrated via i.v. injection. However, HT29 cells classified as metabolic dysregulated, which is the CMS-3 subtype, have shown resistance to BO-2762.
Conclusion: BO-2762 functions as an angiogenesis inhibitor by inhibiting the phosphorylation of VEGFR2 and inhibits the DNA synthesis by cross-linking the DNA. Consequently, BO-2762 was shown to profoundly suppress the growth of CRC xenografts of CMS-1 and 4 subtypes but not that of CMS-2 and 3. Accordingly, BO-2762 has great potential for further development as a specific anti-CRC agent against CMS-1 and 4 subtypes and lead the further investigation on how to overcome the resistance of metabolic dysregulated CMS-3 subtype as a fundamental question that warrants our investigation.
References: 1. J Med Chem, 2019. 62(5): p. 2404-2418. 2. Clin Cancer Res, 2018. 24(4): p. 794-806. 3. Neoplasia, 2020. 22(9): p. 365-375
Citation Format: Vaikar Navakanth Rao, Ramajayam Kuppuswamy, Kuo Chu Lai, Tsann-Long Su, Te-Chang Lee. A dual functional agent inhibits the angiogenesis and DNA synthesis resulting in the growth suppression of consensus molecular subtypes 1 and 4 in colorectal cancer xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2648.
Abstract 2650: Angiogenic inhibitors reduce mycosis fungoides cell survival and enhance cell death
Authors: Rendon-Serna Natalia , Dufies Maeva , Correa-Londono Luis Alfonso , Bermudez-Munoz Olga Maria , Velasquez-Lopera Margarita Maria , Pages Gilles 
Published: July 2021

Abstract
Cutaneous T-cell lymphomas (CTCL) account for approximately 80% of cases of cutaneous lymphomas. Among CTCL, mycosis fungoides (MF) is the most common and most studied type comprising up to 55% of cases. Three different MF stages are recognized in the following order of pathology evolution: patches, plaques and tumor; MF can progress to tumor stage with involvement of other organs, compromising life due to systemic malignant invasion and immunosuppression. Currently, there are not long-lasting treatment for MF. We aimed to understand if angiogenesis, involved in solid tumor progression, could be involved in MF course. For this, we studied both, MF cell lines (HH, Myla) and skin tissues from MF patients at its different stages including healthy skin, according to ethical approval statements. We evaluated the density of blood vessels in skin from MF patients using staining for CD31 by immunohistochemistry. In HH and Myla cell lines, we have studied the presence of angiogenic receptors by western blot and then we have analyzed the effect of 3 angiogenic inhibitors, axitinib, cabozantinib and sunitinib, on cell survival and cell death. We found that there is an increased number of blood vessels in tumor stage compared with patch stage and healthy skin, and in plaque stage compared with patch stage. In HH and Myla cells that express VEGR2 and c-MET, we noticed that although they are sensitive to the angiogenic inhibitors used, axitinib and specially sunitinib reduced significantly cell survival and enhanced cell death at doses between 5-10 micromolar, at 72 hours. We conclude that the density of blood vessels increases with MF progression and thus that angiogenesis takes place during MF pathophysiology. Furthermore, the fact that angiogenic inhibitors already used in tumor treatment provoke MF cell death and affect MF cell survival, suggests that the use of angiogenic inhibitors could be of great interest for controlling MF progression. Future animal model experiments and clinical trials should reveal the potential of angiogenesis inhibition as a new therapeutical option for MF treatment.
Citation Format: Natalia Rendon-Serna, Maeva Dufies, Luis Alfonso Correa-Londono, Olga Maria Bermudez-Munoz, Margarita Maria Velasquez-Lopera, Gilles Pages. Angiogenic inhibitors reduce mycosis fungoides cell survival and enhance cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2650.
Abstract 2656: Muscle wasting in head and neck carcinomas: Investigations on the underlying transcriptional reprogrammation
Authors: Hachicha Héla , Pirozhkova Iryna , Gelin Aurore , Bidault François , Rouffiac Valérie , Dayris Thibault , Ragot Thierry , Breuskin Ingrid , Even Caroline , Gorphe Philippe , Busson Pierre 
Published: July 2021

Abstract
Introduction:
Cancer cachexia is a multifactorial syndrome associated with a skeletal muscle atrophy that affects at least 55% of patients bearing Head and Neck Squamous Cell Carcinomas (HNSCCs). To our knowledge, molecular mechanisms of muscle alterations have never been investigated on clinical muscle specimens from HNSCC patients. The aim of this study was to perform transcriptome profiling by bulk RNAseq on muscle fragments from HNSCC patients with and without cachexia and from nude mice bearing human HNSCC xenografts.
Methods:
Our study was made in three parts: 1) In Vitro investigations on human myoblasts co-cultivated with HNSCC cells. 2) In Situ investigations on muscles collected from nude mice xenografted with HNSSCs cells (FADU). 3) Exploration of clinical muscle samples collected from HNSCC patients. RNA sequencing was used to assess gene expression changes and gene function enrichment related to cachexia, in myoblasts co-cultivated with malignant cells as well as skeletal muscle samples collected from mice xenografted with HNSCC cells (FADU) or HNSCC patients.
Results:
In vitro experimentations showed significant impact of malignant cells on myoblast proliferation and differentiation. In nude mice, FADU xenografts resulted in distant loss of muscle mass at various anatomic locations. RNA sequencing of muscle samples from cachectic patients showed significant differences in gene expression compared with control muscles samples from tumor-free donors. Commonly modified pathways included immune and inflammatory response, mitochondrial metabolism and striated muscle differentiation. The most remarkable finding was the up-regulation of the BIRC3 transcript which encodes the anti-apoptotic protein c-IAP2. This alteration was observed both in human cachectic muscles and murine muscle fragments from tumor-bearing mice.
Conclusions:
Although the mechanism of BIRC3 up-regulation in cachectic muscle cells is not well understood, this finding is likely to be important for patient management in a context of promising therapeutic results obtained using Smac mimetics. Because these compounds are inhibitors of the c-IAP protein family, it will be important in the future to monitor their positive or negative effects on muscle alterations in cachectic HNSCC patients.
Citation Format: Héla Hachicha, Iryna Pirozhkova, Aurore Gelin, François Bidault, Valérie Rouffiac, Thibault Dayris, Thierry Ragot, Ingrid Breuskin, Caroline Even, Philippe Gorphe, Pierre Busson. Muscle wasting in head and neck carcinomas: Investigations on the underlying transcriptional reprogrammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2656.
Abstract 2694: An anatomic proteomic atlas of human glioblastoma
Authors: Lam K.H. Brian , Djuric Ugljesa , Batruch Ihor , Richer Maxime , Diamandis Phedias 
Published: July 2021

Abstract
Glioblastoma (GBM) is an aggressive brain tumor with an expected survival of under 15 months despite spirited multimodal therapy. This grim outlook has remained virtually unchanged over the last 40 years and thus necessitates alternative research and therapeutic development strategies. Historically, traditional models of cancer biology have largely considered GBM tissue to be a homogenous mass. Emerging studies however now suggests that the interaction of tumor cells with various normal components of the brain and immune system play an important role in helping cancer grow and develop resistance to therapies. Better understanding of these hallmark features of GBM, collectively known as the “tumor microenvironment” (TME), could lead to the development of new and more effective therapies. In light of this, there is a renewed interest in revisiting our theories of cancer and preserving the microscopic anatomy of GBM in our molecular profiling efforts. Here we leverage laser capture microdissection (LCM) and mass spectrometry-based proteomics, in order to generate a detailed map of the distribution of proteins within tissues across a large number of patients. Specifically, we will isolate, and profile well-understood microscopic components of GBM: cellular tumor (CT), microvascular proliferation (MVP), infiltrating tumor (IT), palisading cells around necrosis (PAN) and normal brain tissue (LE). All of this data will be provided in an online-based GBM atlas as a publicly available resource. This atlas and the associated database for clinical and genomic data will serve as a useful platform for developing therapeutics and testing novel hypotheses related to GBM biology.
Citation Format: K.H. Brian Lam, Ugljesa Djuric, Ihor Batruch, Maxime Richer, Phedias Diamandis. An anatomic proteomic atlas of human glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2694.