bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A47: A patient-derived xenograft model of pancreatic cancer in mice to develop novel adjuvant therapies
Authors: Mullen Matthew G. , Newhook Timothy E. , Lindberg James M. , Adair Sara J. , Blais Edik M. , Michaels Alex D. , Stelow Edward B. , Papin Jason A. , Parsons J. Thomas , Bauer Todd W. 
Published: May 2019

Abstract
Background: Eighty percent of patients with pancreatic ductal adenocarcinoma (PDAC) die from their disease within five years of surgical resection, likely due to presence of occult metastases at diagnosis. We have developed a patient-derived xenograft (PDX) model in mice to investigate the behavior of occult metastatic cells in the liver microenvironment and derive novel adjuvant therapies.
Methods: Five PDAC tumors (215, 366, 608, 654 and 738) were resected from patients and implanted orthotopically in mice. Tumors were harvested, cell lines generated and transduced with luciferase, then injected into spleens of mice to generate microscopic liver metastases, then primary tumors removed via splenectomy. Bioluminescence imaging of mice and histologic analysis and flow cytometry of livers were utilized to characterize each tumor's distinct pattern of cell clearance and outgrowth kinetics. Affymetrix gene expression of tumors was performed. Mice were treated with adjuvant therapy following resection of primary tumors in the spleen and time-to-progression (TTP) and overall survival (OS) were measured.
Results: Each PDX cell line demonstrated unique and reproducible clearance in the liver and outgrowth kinetics as measured by bioluminescence imaging. Distinct differences in gene expression were identified in tumors exhibiting rapid vs. delayed outgrowth. The MEK inhibitor trametinib (0.3 mg/kg oral daily) prolonged TTP and OS vs. control (OS - Tumor 608: 114 vs. 43 days, p&lt;0.001; Tumor 366: MS not achieved vs. 167 days, p=0.0488). In a randomized preclinical trial, sequential therapy with gemcitabine followed by trametinib provided a survival advantage and increased TTP when compared with control and single agent gemcitabine treatment.
Conclusions: This PDX PDAC model of occult metastasis allows characterization of hepatic clearance of tumor cells and outgrowth kinetics. Metastatic outgrowth appears to be dependent upon distinguishable tumor cell-specific factors. Trametinib effectively inhibits KRAS-MEK-ERK signaling, delays outgrowth of occult metastases and prolongs survival of mice. Utilization of this model will help further define the complex interaction of PDAC cells and the metastatic microenvironment of the liver.
Citation Format: Matthew G. Mullen, Timothy E. Newhook, James M. Lindberg, Sara J. Adair, Edik M. Blais, Alex D. Michaels, Edward B. Stelow, Jason A. Papin, J. Thomas Parsons, Todd W. Bauer. A patient-derived xenograft model of pancreatic cancer in mice to develop novel adjuvant therapies. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A47.
Abstract A66: Systemic effects of AC-T chemotherapy in breast cancer
Authors: DeCristo Molly J. , McAllister Sandra S. 
Published: May 2019

Abstract
Cytotoxic chemotherapy is the only standard of care treatment currently available for patients with triple negative breast cancer (TNBC) because this breast cancer subtype lacks expression of therapeutic targets, namely, estrogen receptor, progesterone receptor, and amplification of Her2. Despite the efficacy of neoadjuvant chemotherapy for some TNBC patients, approximately 60-80% of TNBC patients will still present with local and distant disease after therapy, and these patients suffer poor prognosis. In addition to direct effects on tumor cells, systemic chemotherapy also has the potential to impact patient physiology. However, the implications of tumor-cell independent effects of chemotherapy for metastatic progression are not well understood. We are using mouse models of TNBC to study the effects of chemotherapy on host physiology and how these effects impact metastasis. Treatment of TNBC tumor-bearing mice with doxorubicin (A), cyclophosphamide (C), and paclitaxel (T) decreased overall bone marrow cell counts; although, the degree of decrease and subsequent recovery of individual bone marrow and circulating cell populations varied among populations. Notably, parallel experiments in tumor-free mice demonstrated that chemotherapy-dependent effects on the bone marrow and circulating cell populations dominate tumor-dependent effects. These findings highlight the potential implications of the physiological effects of chemotherapy on metastasis and response to therapy.
Citation Format: Molly J. DeCristo, Sandra S. McAllister. Systemic effects of AC-T chemotherapy in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A66.
Abstract A67: Elucidating the impact of zoledronic acid on the bone microenvironment: Implications for breast cancer
Authors: Ubellacker Jessalyn M. , McAllister Sandra S. 
Published: May 2019

Abstract
Bisphosphonates, such as zoledronic acid (ZOL), are bone microenvironment modulators that work primarily by inhibiting the activity of bone resorbing osteoclasts and have demonstrated ability to reduce breast cancer risk and recurrence in the bone in clinical trials. Previous work in our laboratory has demonstrated the ability of tumor-derived factors (osteopontin) to activate pro-tumorigenic bone marrow hematopoietic cells, which subsequently promote tumor outgrowth. The aim of this current study is to determine whether ZOL inhibits the impact of such tumor-derived paracrine factors on the bone microenvironment, thus reducing metastatic outgrowth in the bone. A human bone-tropic breast cancer cell line (MDA-MB-231 BO2) was introduced into NU/J mice via intracardiac (IC) and intratibial (IT) injections 72 hours after treating the mice with ZOL. Cell seeding was assessed at 24 hours by CM-DiL staining, and subsequent tumor outgrowth was monitored weekly by bioluminescence. One ZOL pre-dose was sufficient to decrease both tumor cell seeding (via IC) and colonization (via IT) relative to the robust tumor outgrowth observed in mice treated with vehicle control. Additionally, subcutaneous ad-mixtures of MDA-MB-231 BO2 cells with bone marrow cells from ZOL-treated mice demonstrated a decreased incidence of tumor formation relative to control bone marrow cells, indicating that the tumor inhibitory effect of ZOL occurs via modulations to the bone marrow hematopoietic microenvironment. A second MDA-MB-231 bone-tropic cell line similar to the BO2 line, but with higher expression levels of CXCL1, G-CSF, GM-CSF and IL8, was not inhibited by ZOL in the IC and IT bone metastasis models. These results implicate the role of certain tumor-derived paracrine factors in mediating resistance to ZOL treatment. These findings are important for elucidating the therapeutic potential of bisphosphonates for treating at-risk patients in the adjuvant setting before they develop incurable metastatic disease.
Citation Format: Jessalyn M. Ubellacker, Sandra S. McAllister. Elucidating the impact of zoledronic acid on the bone microenvironment: Implications for breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A67.
Abstract B02: Silencing of semaphorin 7a attenuates breast tumor progression
Authors: Black Sarah , Nelson Andrew , Gurule Natalia , Futscher Bernard , Lyons Traci 
Published: May 2019

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR10) of the Conference Proceedings.
Citation Format: Sarah Black, Andrew Nelson, Natalia Gurule, Bernard Futscher, Traci Lyons. Silencing of semaphorin 7a attenuates breast tumor progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B02.
Abstract B26: Epigenetic master regulator EPC1 is a decisive factor for E2F1 to silence cell death and activate metastatic gene signatures in response to DNA damage
Authors: Engelmann David , Wang Yajie , Alla Vijay , Goody Deborah , Gupta Shailendra K. , Spitschak Alf , Pützer Brigitte M. 
Published: May 2019

Abstract
The transcription factor E2F1 is a key regulator of cell proliferation and apoptosis. Recently, it has been shown that aberrant E2F1 expression often detectable in advanced-stage metastatic and chemoresistant cancers contributes essentially to malignant progression and characterizes the aggressive potential of a tumor. Conceptually, this requires a subset of malignant cells capable of evading apoptotic death through anticancer drugs. The molecular mechanism by which the pro-apoptotic activity of E2F1 is antagonized is widely unclear. Here we report a novel function for enhancer of polycomb homolog 1 (EPC1) in DNA damage protection. Depletion of EPC1 potentiates E2F1-mediated apoptosis in response to genotoxic treatment and abolishes tumor cell motility. We found that E2F1 directly binds and activates the EPC1 promoter and EPC1 vice versa physically interacts with bifunctional E2F1 to modulate its transcriptional activity in a target gene-specific manner. Remarkably, nuclear-colocalized EPC1 activates E2F1 to upregulate the expression of anti-apoptotic survival genes such as BCL-2 or Survivin and inhibits death-inducing targets including p27 and Bim. Mechanistically, we observed that EPC1 is required for recruitment of Tip60, a subunit of the NuA4 acetyltransferase complex, to E2F sites of the Bcl-2 promoter, causing increased activating histone acetylation levels. In contrast, ablation of EPC1 removes the PRC2 component EZH2 from the p27 promoter, resulting in decreased histone methylation for E2F1-mediated gene activation. In this scenario, EPC1 acts as a crucial bridging factor to connect E2F1 with essential components of the chromatin remodeling complexes Nu4A and PRC2. The uncovered cooperativity between EPC1 and E2F1 triggers a gene signature in advanced cancers that predicts metastatic behavior and poor patient survival. These findings unveil a novel oncogenic function of EPC1 for inducing the switch into tumor progression-relevant gene expression that may help to set novel therapies.
This work was supported by German Cancer Aid, Dr. Mildred Scheel Stiftung (109801 to B.M.P. and D.E.) and German Federal Ministry of Education and Research (BMBF) as part of the eBio:SysMet project (0316171 to B.M.P.).
Note: This abstract was not presented at the conference.
Citation Format: David Engelmann, Yajie Wang, Vijay Alla, Deborah Goody, Shailendra K. Gupta, Alf Spitschak, Brigitte M. Pützer. Epigenetic master regulator EPC1 is a decisive factor for E2F1 to silence cell death and activate metastatic gene signatures in response to DNA damage. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B26.
Abstract B28: Identification of breast cancer metastasis promoting genes by next generation sequencing
Authors: Szczepanek Karol , Hunter Kent 
Published: May 2019

Abstract
Breast cancer is a leading cause of cancer-related mortality of women in the United States. The majority of cancer deaths are due to metastases rather than the primary tumor, therefore a better understanding of the mechanisms that lead to metastatic disease is critical to reducing breast cancer-related mortality. A majority of cancer cells that leave the primary tumor are either removed by the immune system or fail to survive in distant organs. However, some cancer cells acquire molecular features that allow them to survive and proliferate in secondary sites, such as lung, liver, brain, and bone. In order to design highly efficient anti-metastatic therapies, it is crucial to address metastasis-specific mechanisms of growth and survival. One of the major hurdles to developing these therapies is the genotypic and phenotypic heterogeneity between primary tumors and metastases, as well as between individual metastases. The goal of this project is to characterize the transcriptomic landscape of breast cancer metastases using Next Generation Sequencing (NGS) tools in order to identify potential genes that drive (metastasis promoters) or inhibit (metastasis suppressors) the metastatic outgrowth in distant organs. Therefore, RNA sequencing was performed on breast cancer primary tumors and matching lung metastases from two different mouse models: Polyomavirus Middle-T antigen (PyMT) transgenic mice, a model of spontaneous and highly aggressive breast cancer, as well as from mouse mammary cancer cells orthotopically injected into FVB mice. RNA sequencing using the NGS platform revealed genes that were highly expressed in metastases compared to primary tumors. Interestingly, overlapping the RNA-seq datasets from these two distinct models revealed a shared subset of upregulated genes, strongly suggesting that these genes are likely to be common metastatic outgrowth promoters. To validate these candidate genes, we are currently developing a CRISPR sgRNA library for orthotopic transplant experiments. The genes displaying in vivo effects on metastatic outgrowth in the lungs will be further explored for the development of targeted anti-metastatic therapies.
Citation Format: Karol Szczepanek, Kent Hunter. Identification of breast cancer metastasis promoting genes by next generation sequencing. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B28.
Abstract B39: PI3K therapy-induced adaptive mitochondria reprogramming fuels metastatic traits
Authors: Caino M. Cecilia , Altieri Dario C. 
Published: May 2019

Abstract
Tumors rewire cell metabolism and autophagy to adapt to environmental stress conditions, including hypoxia, starvation and oxidative stress. Such adaptive reprogramming includes a switch from oxidative phosphorylation to glycolysis, use of glutamine as fuel instead of glucose and increased biosynthesis of lipids and nucleotides. Although these processes promote resistance to apoptosis and support biomass expansion, they are also energetically inefficient, making it unclear how transformed cells accomplish highly energy-demanding tasks, including invasion and metastasis. Scattered evidences suggest that mitochondrial oxidative phosphorylation may be important for cancer traits, including stemmness, tumor repopulation and drug resistance. We recently demonstrated that targeting of the universal cancer node phosphatidylinositol-3 kinase (PI3K) induces extensive bioenergetics and transcriptional reprogramming in tumor cells, paradoxically culminating with preservation of homeostatic mitochondrial bioenergetics, opposing permeability transition and tumor cell death. Here we sought to understand how tumors adapt to molecular therapy as it pertains to tumor progression. Our results show that PI3K inhibitors used in the clinic induce global changes in activation of growth factor receptor kinases, reactivation of Akt and mTOR signaling, and dramatically increased tumor cell invasion. This involves the trafficking of energetically active mitochondria to the cortical cytoskeleton of tumor cells, supporting membrane lamellipodia dynamics, heightened turnover of focal adhesion complexes and increased velocity and distance of random cell migration. Furthermore, a single dose of PI3Ki increased liver metastasis after intrasplenic-injection of tumor cells in mice. Mechanistic studies pinpoint the role of Akt, mTOR, mitochondrial Hsp90s, the autophagy initiating complex ULK1/FIP200 and focal adhesion kinase (FAK) in the adaptive response to PI3Ki. Blocking oxidative phosphorylation by targeting mtHsp90s prevented the repositioning of mitochondria to sites of cell movements, impaired membrane dynamics and suppressed tumor cell invasion. Our results suggest a potential drawback for PI3K therapy, namely the increased risk of metastasis in patients. Targeting mitochondrial reprogramming is feasible, and could provide a novel therapeutic strategy to limit disease dissemination.
Note: This abstract was not presented at the conference.
Citation Format: M. Cecilia Caino, Dario C. Altieri. PI3K therapy-induced adaptive mitochondria reprogramming fuels metastatic traits. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B39.
Abstract B46: Biomechanical preconditioning of circulating tumor cell adhesion during metastasis
Authors: Spencer Adrianne , Zhu Zhiying , Lee Katerina , Lee Jason , Spruell Chris , Williams Chad , Voyvodic Peter , Ramaswami Ashwin , Jiang Ning , Baker Aaron 
Published: May 2019

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR08) of the Conference Proceedings.
Citation Format: Adrianne Spencer, Zhiying Zhu, Katerina Lee, Jason Lee, Chris Spruell, Chad Williams, Peter Voyvodic, Ashwin Ramaswami, Ning Jiang, Aaron Baker. Biomechanical preconditioning of circulating tumor cell adhesion during metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B46.
Abstract B63: Cell surface vimentin (CSV) serves as markers and targets for EMT, stem cancer cell and metastatic cells
Authors: Mitra Abhisek , Noh Hyangsoon , Li Shulin 
Published: May 2019

Abstract
The presence of cancer stem–like cells and the epithelial–mesenchymal transition (EMT) cancer cells serves as one of the primary mechanisms for causing metastasis in cancer. However, there is no clear and universal cell surface markers for identifying these types of cells though multiple intracellular markers for EMT or non-universal markers for cancer stem cells are reported. A clear, functional and universal EMT and cancer stem cell marker will assist our understanding in cancer cell metastasis. Recently, we discovered that Vimentin, an intracellular EMT tumor cell marker, is present on the surface of circulating tumor cells and on the surface of colon metastatic tumor nodules in the liver. In this study, we examined the potential of using this marker as a capturing target to isolate EMT stem–like cancer cells using a cell surface Vim-binding antibody, 84-1, which was developed in-house. Using this antibody, we purified the csVim+CD133- cell population from primary liver and GBM tumor cell suspensions. Stem cell characterization assays demonstrated that csVim+CD133- cells have stem–like properties similar to the csVim-CD133+ population. This population also showed tumorigenicity under both in vitro and in vivo conditions. Moreover, csVim+CD133- cells stained with classical EMT markers Twist and Slug to validate their metastatic phenotypes. In vivo inoculation further revealed that the csVim+CD133- population supported EMT-like phenotypes and aggressive metastasis in livers as compared to the csVim-CD133+ population. In the era of personalized cancer therapy, this population should also be considered a promising target for the treatment and prevention of metastatic carcinoma.
Citation Format: Abhisek Mitra, Hyangsoon Noh, Shulin Li. Cell surface vimentin (CSV) serves as markers and targets for EMT, stem cancer cell and metastatic cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B63.
Abstract IA05: Where the wild things are: Perivascular regulation of disseminated tumor cell dormancy and chemoresistance
Authors: Ghajar Cyrus M. 
Published: May 2019

Abstract
In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumor cells (DTCs) are kept dormant, and what wakes them up, are fundamental problems in tumor biology. To address these questions, we use metastasis assays in mice and zebrafish and have determined that the perivascular niche of distant sites like the lung, bone marrow, liver and brain regulate DTC dormancy. We have developed organotypic microvascular niches to specify that endothelial cells regulate breast cancer cell growth, and applied proteomics to identify endothelial-derived mediators of DTC dormancy. More recently, we have begun to explore whether the perivascular niche confers therapeutic resistance to DTCs. I will present data that suggests strongly that the perivascular niche regulates therapeutic resistance of DTCs in a manner that is independent from its role in regulating DTC growth. Our goal is to uncover these mechanisms to guide strategies to eradicate dormant DTCs without affecting their growth status. We believe this will result in a viable strategy to prevent metastasis.
Citation Format: Cyrus M. Ghajar. Where the wild things are: Perivascular regulation of disseminated tumor cell dormancy and chemoresistance. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr IA05.