bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B50: HnRNP A3 regulates the nuclear EGFR localization and cancer progression
Authors: Chen Chi-Yuan , Lin Yu-Han , Wang Tong-Hong , Wu Chih-Ching 
Published: June 2020

Abstract
Aberrant subcellular translocation and distribution of epidermal growth factor receptor (EGFR) represents a major yet underappreciated cancer development mechanism in non-small cell lung cancer (NSCLC). In this study, we investigated the subcellular interactome of EGFR by free labeling approaches combined with LC-MS/MS, aiming to understand the associated protein networks involved in the tumorigenesis of NSCLC. A total of 54, 77, and 63 EGFR-interacting proteins were identified specifically in the cytosol, mitochondria, and nucleus fractions, respectively. Pathway-wise analyses of these proteins using the KEGG database revealed that the proteins interacting with cytosolic and nuclear EGFR proteins are involved in pathways of ribosome and spliceosome, respectively. The EGFR-interacting proteins in mitochondria are involved in the metabolism of propanoate, fatty acid, valine, leucine, and isoleucine. One of the nuclear EGFR-interacting proteins, hnRNP A3, was shown in this work to modulate the accumulation of nuclear EGFR. Downregulation of hnRNP A3 reduced the nuclear EGFR accumulation and was accompanied with reduced tumor growth ability both in vitro and in vivo. These results suggest that variations in the subcellular translocation and distribution of EGFR within NSCLC cells could affect tumor progression.
Citation Format: Chi-Yuan Chen, Yu-Han Lin, Tong-Hong Wang, Chih-Ching Wu. HnRNP A3 regulates the nuclear EGFR localization and cancer progression [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B50.
Abstract IA04: Stem cells: Coping with stress and cancer
Authors: Fuchs Elaine 
Published: June 2020

Abstract
Adult tissue stem cells have the ability to self-renew long term and differentiate into one or more tissues. Many stem cells are used sparingly to replenish cells during normal homeostasis. However, even stem cells that are quiescent must be able to respond quickly to injury in order to fuel rapid tissue regeneration. How stem cells balance self-renewal and differentiation is of fundamental importance to our understanding of normal tissue maintenance and wound repair. The regulatory circuitry governing this normal balancing act must be intricately regulated in normal homeostasis and then transiently altered to cope with injury responses. Increasing evidence suggests that the mechanism goes awry in inflammation and becomes hijacked in cancers. Skin epithelium is an excellent model system to understand how stem cells remain quiescent during times of minimal wear and tear, how these cells become mobilized during the cyclical bouts of hair growth and wound repair, and how the normal process of stem cell activation goes awry in cancer and inflammation. We have identified and characterized at a molecular level the skin’s stem cells and shown that they reside in distinct niches that impart to the stem cells their behavior both in task and in the molecular properties they display. We use high-throughput genetic and genomic approaches to dissect at a molecular level how stem cell interactions with their niches differ in homeostasis, wound repair, and inflammation, and how heterogeneity in the tumor microenvironment can confer on stem cells resistance to chemotherapy and immunotherapy. Our global objective is to apply our knowledge of the basic science of epithelial stem cells to unfold new avenues for therapeutics.
Citation Format: Elaine Fuchs. Stem cells: Coping with stress and cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA04.
Abstract IA06: The tissue-specific microenvironment in primary tumors and metastases
Authors: Werb Zena , Gonzalez Hugo , Winkler Juliane , Berens Eric 
Published: June 2020

Abstract
Cancer cells within tumors exist in specialized niches in the microenvironment. The tumor cells are heterogeneous and can have properties as divergent as self-renewal, tumor initiation and repopulation potential, dormancy, evasion of cell death, and metastasis. Metastasis is the major cause of poor outcome in breast cancer. The microenvironment is critical for regulating multiple aspects of tumor progression and metastasis. Understanding the processes involved in metastasis is critical for developing new preventative and therapeutic strategies. We have analyzed the matrix environment and its function in tumor progression using in vivo imaging, genetic models of breast cancer, patient-derived xenografts, organotypic cultures, and patient samples. We have found that the matrix environment and the innate immune cells responding to the primary tumor and infiltrating the metastatic sites are critical for regulating tumor invasion and metastasis. Indeed, the inflammatory microenvironment of metastatic sites was distinct from that of the parental tumor and the normal tissue, even before metastasis takes hold. Interplay between nonmetastatic primary breast cancer and innate immune response acts to control metastatic progression. At the single-cell level, early-stage metastatic cells possess a distinct stemlike gene expression signature. The metastatic cells and the microenvironment are distinct in different metastatic sites and from the primary tumor. Micrometastatic cells are distinct due to their increased expression of basal, stem cell, prosurvival, and dormancy-associated genes. In contrast, cells from macrometastases are similar to primary tumor cells, which are more differentiated and heterogeneous. We validated our findings with a large primary breast cancer tissue microarray and pleural effusions from breast cancer patients. These results suggest that novel cancer immunotherapies that activate and augment the function of antitumoral myeloid subpopulations could have therapeutic potential and be clinically important for patients with advanced breast cancer.
Citation Format: Zena Werb, Hugo Gonzalez, Juliane Winkler, Eric Berens. The tissue-specific microenvironment in primary tumors and metastases [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA06.
Abstract IA12: From mouse to man: Dissecting cancer mechanisms using mouse models
Authors: Abate-Shen Cory 
Published: June 2020

Abstract
I have a longstanding interest in understanding how basic cellular mechanisms become co-opted in cancer. I have approached this problem by studying the transcriptional regulatory mechanisms of homeobox genes with the goal of understanding their roles in development, differentiation, and cancer. Over the years, my research program has evolved towards its current focus in which we have undertaken a multidisciplinary approach to investigate genitourinary malignancies, which includes using mechanism-based studies, analyses of genetically engineered mouse models (GEMMs), and state-of-the-art systems biology approaches. My research focus on prostate cancer has its origins in our discovery of Nkx3.1, a prostate-specific homeobox gene that is essential for prostate differentiation and whose loss of function predisposes to prostate cancer. The culmination of our studies over many years has led to a model in which NKX3.1 functions as a gatekeeper that promotes prostate differentiation and protects against prostate cancer initiation. Our recent work has shown that Nkx3.1 is sufficient to fully reprogram non-prostate epithelium to form prostate in vivo. Our work showing that Nkx3.1 mutant mice accurately model indolent prostate cancer led to the discovery of a 3-gene panel that distinguishes indolent and aggressive human prostate cancers, which we are now advancing to the clinic. Moreover, our coclinical prevention study of Nkx3.1 mutant mice led to the identification of a gene signature that predicts response to antiandrogens for men on active surveillance. Furthermore, our analysis of Nkx3.1 mutant mice provided the foundation for our extensive series of GEMMs that are based on genomic alterations that are prevalent in human prostate cancer and that represent the full spectrum of prostate cancer phenotypes, ranging from preinvasive to lethal metastatic disease. To capitalize on these GEMMs, we have generated genome-wide regulatory networks for mouse and human prostate cancer, which have enabled cross-species analyses that have identified key drivers of the specific stages of prostate cancer. We have expanded these computational approaches to integrate preclinical data from GEMMs with human clinical data to predict drug response and optimize drug combinations for human prostate cancer. These studies have identified cellular plasticity as a mechanism of drug resistance in prostate cancer.
Citation Format: Cory Abate-Shen. From mouse to man: Dissecting cancer mechanisms using mouse models [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA12.
Abstract IA13: Identification, validation, and therapeutic targeting of a driver gene in poor-prognosis breast cancer
Authors: Kang Yibin 
Published: June 2020

Abstract
Breast cancer remains a significant health concern worldwide. Integrative genomic analysis of clinical breast cancer samples identified Metadherin (MTDH) as a driver gene that promotes breast cancer initiation, progression, and treatment resistance. Using genetically engineered mouse models, we found that MTDH sustains breast cancer progression and metastasis via interacting with SND1, and acute Mtdh loss inhibits breast cancer development. Using a structure-based small-molecule screen, we obtained a serial of MTDH/SND1 inhibitors. Treatments of the compounds suppress breast tumor growth and metastasis and sensitize breast cancer to chemotherapy by sensitizing cancer cells to stress-induced apoptosis. This series of studies illustrates the use of mouse models to validate clinically relevant novel therapeutic targets for breast cancer and illustrates the functional mechanism of driver genes in cancer progression and metastasis.
Citation Format: Yibin Kang. Identification, validation, and therapeutic targeting of a driver gene in poor-prognosis breast cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA13.
Abstract IA14: Deconstructing the origins of PDAC development
Authors: Flowers Brittany , Xu Hang , Hanson Kathryn , Curtis Christina , Vogel Hannes , Wood Laura , Attardi Laura D. 
Published: June 2020

Abstract
The TP53 gene, which encodes the p53 transcription factor, is mutated in ~75% of human pancreatic ductal adenocarcinomas (PDACs), underscoring the fundamental role of p53 as a barrier to PDAC development. Despite this critical function, however, the cellular and molecular programs through which p53 acts in pancreatic cancer suppression remain poorly understood. To gain a better understanding of the pathways through which p53 acts to suppress PDAC development, which will provide key insight into how the disease develops, we have taken combined mouse genetic and genomic approaches. First, we have sought to determine whether p53 acts in acinar and/or ductal cells to restrain PDAC development. Importantly, for these experiments we have used adult mice to more accurately mimic the development of PDAC in humans. Second, we have sought to systematically deconstruct the role of p53 deletion and p53 missense mutations in driving cancer from these different cells of origin. This comprehensive analysis of large adult mouse cohorts has helped to define the cell of origin for PDAC and the effects of different p53 mutations on spontaneous PDAC development. To gain additional insight into the programs that become dysregulated during pancreatic cancer development, we have performed RNA-sequencing analysis on tumors arising from different compartments and driven by different genetic lesions. These studies have revealed the molecular profiles of tumors arising from acinar versus ductal cells as well those driven by different types of p53 mutations. Through comparison to human pancreatic cancer data, our studies are helping us to better understand the paths to PDAC development in humans and the underlying origins of different subtypes of this disease.
Citation Format: Brittany Flowers, Hang Xu, Kathryn Hanson, Christina Curtis, Hannes Vogel, Laura Wood, Laura D. Attardi. Deconstructing the origins of PDAC development [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA14.
Abstract IA16: The International Human Cancer Models Initiative is generating models annotated with clinical and molecular data
Authors: Gerhard Daniela S. 
Published: June 2020

Abstract
For the past 60 years, cancer research has relied heavily on established cancer cell lines. Their genomes are known to have evolved in vitro and therefore may not reflect well the various salient features of patient tumors (e.g., sensitivity/resistance to cancer therapeutics, etc.). Novel model generation technologies promise to create the next-generation cancer models (NGCMs) to facilitate and enhance studies in various areas of cancer research. The Human Cancer Models Initiative (HCMI) is an international consortium that is developing ~1,000 NGCMs for use in a wide range of cancer-relevant discoveries, from genomic research, cell biology or bio/chemistry studies, to improvements in preclinical and clinical applications. Our goal is to make these models available broadly to the academic and industry researchers (community resource). Therefore, we established a process that ensures the quality of the models and the data associated with them. In my presentation I will describe the Initiative’s pipeline, status (e.g., tumor types, molecular characterization), challenges encountered, and how to obtain the models and associated data.
Citation Format: Daniela S. Gerhard. The International Human Cancer Models Initiative is generating models annotated with clinical and molecular data [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA16.
Abstract IA18: Genetic dissection of breast cancer development and therapy resistance in mouse models
Authors: Jonkers Jos 
Published: June 2020

Abstract
Genetically engineered mouse models (GEMMs) of human cancer not only permit us to gain a detailed insight into the specific genetic changes that drive tumor development and metastasis but also provide powerful tools to study the mechanisms underlying drug response and acquired resistance. Once these processes are understood in sufficient detail, it may be possible to design combination therapies that not only cause complete remissions but also eliminate remnant cells that elicit recurrent disease.
We have developed GEMMs of E-cadherin mutated lobular breast cancer. These mice develop mammary tumors that closely resemble the lobular morphology and the metastatic spectrum of the cognate tumors in humans. Using Sleeping Beauty (SB) transposon-based insertional mutagenesis in conditional E-cadherin mutant mice, we have found that heterozygous loss of MYH9 or overexpression of hyperactive truncated forms of MYPT1/2 and ASPP2 reduces actomyosin contractility and thereby promotes malignant transformation of E-cadherin-deficient mammary epithelial cells, resulting in ILC formation in mice. This work highlights actomyosin hypercontractility induced by E-cadherin loss as a critical barrier to ILC development.
We have also developed several GEMMs for somatic modeling of BRCA1-mutated triple-negative breast cancer using intraductal injection of lentiviral vectors for stable overexpression of exogenous genes and CAS9-mediated disruption or APOBEC-CAS9n-UGI (BE3)-mediated base editing of endogenous genes. We have used these GEMMs to validate RB, PTEN, PIK3CA, MYC, and MCL1 as bona fide driver genes in BRCA1-associated breast cancer. Moreover, MCL1 inhibition potentiated the in vivo efficacy of the PARP inhibitor (PARPi) olaparib, underscoring the therapeutic potential of this combination for treatment of BRCA1-associated cancer patients with poor response to PARPi monotherapy.
The BRCA1-deficient mammary tumors from our mouse models are characterized by genomic instability and hypersensitivity to DNA-damaging agents, including platinum drugs and PARP inhibitors. Nevertheless, none of these drugs are curative: tumors grow back after drug treatment and eventually become resistant. We found that PARPi resistance of BRCA1-deficient GEMM tumors can be induced by several mechanisms, including activation of drug efflux transporters, type of BRCA1 mutation, and loss of components of the 53BP1-RIF1-shieldin and CST complexes that govern end-protection of DNA double-strand breaks.
Citation Format: Jos Jonkers. Genetic dissection of breast cancer development and therapy resistance in mouse models [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA18.
Abstract IA25: Modeling cancer in the CRISPR era
Authors: Ventura Andrea 
Published: June 2020

Abstract
Chromosomal rearrangements are common cancer-associated mutations that often result in the generation of therapeutically actionable gene fusions. Unfortunately, until recently this class of mutations has proved challenging to recapitulate using conventional gene-targeting methods. To overcome this limitation, we have recently developed a CRISPR-based strategy to model a broad range of chromosomal rearrangements, including inversions, deletions, translocations, and tandem duplications (Maddalo et al., 2014). Since this strategy can be used to induce the desired chromosomal rearrangement in somatic cells—ex vivo or directly in vivo—of adult animals, it enables the rapid and cost-effective generation of novel mouse models of human cancer. As proof of concept, we have applied this strategy to generate a novel model of EML4-ALK driven lung adenocarcinoma, and to show that a novel gene fusion observed in a few human gliomas is a potent oncogenic driver and therapeutic target (Cook et al., 2017; Maddalo et al., 2014; Ventura, Dow, 2018). In my presentation, I will discuss how my group is using these novel technologies, as well as conventional gene-targeting methods, to recapitulate the genetic complexity of human cancers in vivo. I will present new and unpublished models of pediatric brain cancers driven by BRAF gene fusions we have recently generated using in vivo and ex vivo CRISPR-mediated chromosomal engineering and show how we are using these models to test novel therapeutic strategies and to gain insights into the molecular pathogenesis of human cancers.
References: Cook PJ, Thomas R, Kannan R, de Leon ES, Drilon A, Rosenblum MK, Scaltriti M, Benezra R, Ventura A. Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target. Nat Commun 2017;8:15987. Maddalo D, Manchado E, Concepcion CP, Bonetti C, Vidigal JA, Han YC, Ogrodowski P, Crippa A, Rekhtman N, de Stanchina E, et al. (2014). In vivo engineering of oncogenic chromosomal rearrangements with the CRISPR/Cas9 system. Nature 2014;516: 423-27. Ventura A, Dow LE. (2018). Modeling cancer in the CRISPR era. Annu Rev Cancer Biol 2018;2: 111-31.
Citation Format: Andrea Ventura. Modeling cancer in the CRISPR era [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA25.
Mature Vascular Smooth Muscle Cells, but Not Endothelial Cells, Serve as the Major Cellular Source of Intimal Hyperplasia in Vein Grafts
Authors: Wu Weiwei , Wang Chunyan , Zang Huimei , Qi Lei , Azhar Mohamad , Nagarkatti Mitzi , Nagarkatti Prakash , Cai Guoshuai , Weiser-Evans Mary C.M. , Cui Taixing 
Published: June 2020

Objective:
Neointima formation is a primary cause of intermediate to late vein graft (VG) failure. However, the precise source of neointima cells in VGs remains unclear.

Approach and Results:
Herein we clarify the relative contributions of mature vascular smooth muscle cells (SMCs) and endothelial cells (ECs) to neointima formation in a mouse model of VG remodeling via the genetic-inducible fate mapping approaches. Regardless of the magnitude of neointima formation, the recipient arterial and the donor venous SMCs contributed ≈55% of the neointima cells at the anastomotic regions, whereas only donor venous SMCs donated ≈68% of the neointima cells at the middle bodies. A small portion of the SMC-derived cells became non-SMC cells, most likely vascular stem cells, and constituted 2% to 11% of the cells in each major layer of VGs. In addition, the recipient arterial ECs were the major cellular source of re-endothelialization but did not contribute to neointima formation. The donor venous ECs donated ≈17% neointima cells in the VGs with mild neointima formation and conditional media from ECs after endothelial-to-mesenchymal transition suppressed vascular SMC dedifferentiation.

Conclusions:
The recipient arterial and donor venous mature SMCs dominate but contribute distinctly to intimal hyperplasia at the anastomosis and the middle body regions of VGs. The recipient arterial ECs are the major cellular source of re-endothelialization but do not donate neointima formation in VGs. Only the donor venous ECs undergo endothelial-to-mesenchymal transition. Endothelial-to-mesenchymal transition is marginal for generating neointima cells but is likely required for controlling the quality of VG remodeling.