bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA05: Granulocytic cells in metastasis
Authors: Acharyya Swarnali 
Published: May 2015

Abstract
Cancer progression is a complex process that involves tumor growth at the primary site coupled with dissemination and outgrowth at distant sites also known as metastasis. Majority of the cancer-related deaths are due to metastasis commonly occurring in the bone, lung, liver and brain. Although progress has been made in deciphering the process of tumor initiation and primary tumor growth, the molecular underpinnings and mechanisms of metastasis remain poorly understood. Given the role of the tumor microenvironment in cancer progression, there has been a growing interest in understanding the function of granulocytic myeloid cells, an abundant component of the peripheral blood and tumor microenvironment. Using multiple models of breast cancer metastasis, we have characterized two distinct subpopulations of CD11b+Ly6G+ granulocytic myeloid cells in peripheral blood by RNA sequencing and proteomic profiling. The first subpopulation is abundant early before any detectable metastasis. A second subpopulation is abundant late coinciding with systemic metastasis. We have identified a network of paracrine signals between carcinoma and CXCR2 expressing CD11b+Ly6G+ granulocytic cells that drive metastasis. We find that CXCL1/2 chemokines from metastatic cells attract CD11b+Ly6G+ granulocytic myeloid cells, which in turn produce survival factors called S100A8/9 that promotes metastatic progression. Pharmacological inhibition of the CXCR2 axis in combination with chemotherapeutic agents significantly reduces multi-organ metastasis. We envision that a delicate balance exists between different granulocytic populations that function as a determinant of metastatic progression.
Citation Format: Swarnali Acharyya. Granulocytic cells in metastasis. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA05. doi:10.1158/1538-7445.CHTME14-IA05
Abstract IA10: Targeting master regulators of damage responses in the tumor microenvironment
Authors: Nelson Peter S. 
Published: May 2015

Abstract
The armamentarium of therapeutics used to treat cancer patients relies heavily on ionizing radiation and chemotherapeutic drugs that severely damage DNA. The responses of tumor cells to these treatments is heavily influenced by their tumor micro environment (TME): physical contacts with structural elements comprising tissues, associations with resident and transient non-malignant cells, and interactions with numerous soluble endocrine and paracrine-acting factors all influence tumor cell behavior. Importantly, this TME is not static and dynamically responds to a variety of stimuli. This discussion will detail emerging data indicating that genotoxic cancer treatments activate highly conserved damage response programs in benign cells comprising the TME. These damage signals culminate in a developmentally conserved, powerful and diverse secretory program, the DNA Damage Secretory Program (DDSP) that generates a proangiogenic, pro-inflammatory microenvironment, and also promotes adverse tumor cell phenotypes including enhanced resistance to treatment. Key master regulators of the DDSP have been identified and offer opportunities for therapies co-targeting tumor cells along with key survival mediators from the TME. A detailed understanding of these survival signals induced in the context of genotoxic stress provides a platform to develop combinatorial strategies to improve outcomes that consider malignant cells, the tumor microenvironment, and the dynamics exerted by the treatment itself.
Citation Format: Peter S. Nelson. Targeting master regulators of damage responses in the tumor microenvironment. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA10. doi:10.1158/1538-7445.CHTME14-IA10
Abstract IA13: A hypoxic microenvironment influences pancreatic cancer progression
Authors: Simon M. Celeste 
Published: May 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths in the United States and one of the most lethal human cancers. Chronic pancreatitis, which is characterized by inflammation of the pancreas, is a well-known risk factor for PDAC in humans. However, the precise mechanisms whereby chronic pancreatitis promotes pancreatic tumorigenesis remain elusive. Hypoxia, a condition of insufficient oxygen availability, occurs in the context of pancreatic cancer as well as chronic pancreatitis, suggesting that hypoxia is a link between chronic inflammation of the pancreas and carcinogenesis. Hypoxia inducible factor 1α (HIF-1α) is a principal mediator of hypoxic responses. HIF-1α has also been shown to tightly regulate inflammatory responses of myeloid cells. To elucidate the effects of HIF-1α on chronic inflammatory injury and regeneration of the pancreas, and define the role of HIF-1α in pancreatic cancer development, we generated mice that spontaneously develop PDAC with HIF-1α ablated. Our results indicate that HIF-1α impacts both the resolution of pancreatitis as well as the progression of pancreatic neoplasia and inflammatory cell recruitment.
Citation Format: M. Celeste Simon. A hypoxic microenvironment influences pancreatic cancer progression. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA13. doi:10.1158/1538-7445.CHTME14-IA13
Abstract IA17: Intratumoral heterogeneity in glioblastoma
Authors: Seoane Joan 
Published: May 2015

Abstract
Cells within tumours have diverse genomes, epigenomes, and interact differentially with their surrounding microenvironment generating intratumour heterogeneity, which has critical implications for treating cancer patients. I will present our current approach to understand the intratumour heterogeneity in glioblastoma through the analysis of patient-derived models. I will present examples of how we perform functional analysis to understand genomic alterations in the context of inter- and intra-tumoral heterogeneity taking special interest on their therapeutic implications. Linked to the concept of intratumor heterogeneity in the cellular state of differentiation, I will explain our studies related to cancer-initiating cells in glioblastoma, and I will focus on the TGF-beta pathway which has a critical role in glioblastoma.
Citation Format: Joan Seoane. Intratumoral heterogeneity in glioblastoma. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA17. doi:10.1158/1538-7445.CHTME14-IA17
Abstract IA18: A brain metastasis-promoting role for cathepsin S identified from analysis of tumor- and stroma-supplied proteolytic networks
Authors: Sevenich Lisa , Bowman Robert , Mason Steve , Quail Daniela , Rapaport Franck , Elie Benelita , Brogi Edi , Brastianos Priscilla , Hahn William , Holsinger Leslie , Massagué Joan , Leslie Christina , Joyce Johanna A. 
Published: May 2015

Abstract
Cancer cells in an aggressive primary tumor are adept at exploiting their local tissue microenvironment. In contrast, when metastatic cells leave these favorable surroundings, they must possess or acquire traits that will allow them to survive and colonize foreign, potentially hostile tissue environments. The obstacles that metastasizing tumor cells encounter vary from organ to organ, and are highly influenced by non-cancerous stromal cells of the tumor microenvironment. For example, the blood-brain barrier, composed of endothelial cells, astrocytes and pericytes, presents a far more formidable structure for tumor cells to penetrate, compared to the fenestrated capillaries in the bone marrow.
While the primary tumor microenvironment has emerged as an important regulator of cancer progression, it is less well understood how different tissue environments influence metastatic processes. We used a dual species-specific microarray platform to uncover tumor-stroma interactions that modulate organ tropism of brain, bone and lung metastasis in animal models of cancer. Among the differentially regulated tumor- and stroma-specific genes, we identified cathepsin S as a novel regulator of breast-to-brain metastasis. In breast cancer patients, high cathepsin S expression at the primary site correlated with decreased brain metastasis-free survival. Both macrophages and tumor cells produce cathepsin S, and only the combined depletion significantly reduced brain metastasis in experimental models in vivo. We show that cathepsin S specifically mediates blood-brain barrier transmigration via proteolytic processing of the junctional adhesion molecule (JAM)-B. Pharmacological inhibition of cathepsin S significantly reduced experimental brain metastasis, supporting its consideration as a therapeutic target for this disease.
Citation Format: Lisa Sevenich, Robert Bowman, Steve Mason, Daniela Quail, Franck Rapaport, Benelita Elie, Edi Brogi, Priscilla Brastianos, William Hahn, Leslie Holsinger, Joan Massagué, Christina Leslie, Johanna A. Joyce. A brain metastasis-promoting role for cathepsin S identified from analysis of tumor- and stroma-supplied proteolytic networks. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA18. doi:10.1158/1538-7445.CHTME14-IA18
Abstract IA19: Multiplexing TGFβ in the tumor microenvironment
Authors: Barcellos-Hoff Mary Helen 
Published: May 2015

Abstract
The dynamics of TGFβ biology is context dependent. TGFβ is controlled at many levels with a major mechanism in its production as a latent complex from which TGFβ is released extracellularly. TGFβ production and activity is greatly increased in many cancer cells. Tumor microenvironment can also be a significant TGFβ source, particularly bone marrow derived cells (BMDC). TGFβ regulates malignant behaviors and cell phenotype of tumor microenvironment constituents locally and the hematopoietic and immune systems at a distance. We investigated the contribution of TGFβ to the effects of radiotherapy in breast, brain and lung cancer murine models. Our studies show that radiation induces rapid TGFβ activation that can persist for days. Radiation induced TGFβ promotes rapid and effective DNA damage response, mediates tumor microenvironment composition, regulates BMDC recruitment and phenotype, and augments immune evasion. Inhibition of TGFβ during radiotherapy provides significant therapeutic benefit by molecular and microenvironmental mechanisms. TGFβ inhibition during radiotherapy impedes DNA damage recognition, which promotes tumor cell death and thus, tumor growth control. Continued TGFβ inhibition prevents vascular remodeling necessary for tumor regrowth, and blocks BMDC recruitment, which limits an exogenous TGFβ source. Multiplexing these actions with those on tumor immunity suggest potent therapeutic potential of TGFβ inhibition during radiotherapy to eliminate tumor cells and eradicate tumor promoting microenvironments.
Citation Format: Mary Helen Barcellos-Hoff. Multiplexing TGFβ in the tumor microenvironment. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA19. doi:10.1158/1538-7445.CHTME14-IA19
Abstract PR01: Rebastinib, a selective TIE2 kinase inhibitor, decreases TIE2-expressing macrophages, reduces metastasis, and increases survival in murine cancer models
Authors: Flynn Daniel L. , Kaufman Michael D. , Leary Cynthia B. , Hood Molly M. , Lu Wei-Ping , Turner Benjamin A. , Wise Scott C. , Rudoltz Marc S. , Smith Bryan D. 
Published: May 2015

Abstract
In the tumor microenvironment, TIE2 expression on tissue macrophages, bone marrow derived TIE2-expressing monocytes (TEMs), osteoclasts, and vascular endothelial cells promotes tumor invasiveness, dissemination, and metastasis. Additionally, a subset of TIE2-expressing macrophages, located within specialized vascular structures known as tumor microenvironment for metastases (TMEMs), are linked to intravasation of cancer cells into circulation and dissemination to metastatic sites. Rebastinib is a picomolar inhibitor of TIE2 kinase, and exhibits an extraordinarily long off-rate from TIE2, measured to be over 24 hours in a cell-based assay. Herein, we examine the efficacy of rebastinib in the polyoma middle-T antigen (PyMT) syngeneic mouse breast cancer model. In this model, PyMT breast cancer cells are implanted in the mammary fat pad, and primary tumor growth leads to lung metastasis, which is known to be modulated by TEMs and TMEM vascular structures. We examined multiple dosing schedules of rebastinib in combination with anti-tubulin agents (ATAs). Rebastinib treatment in this model significantly ablated TEMs in the primary tumor stroma and caused a significant decrease in lung metastases. Furthermore, the combination of rebastinib with ATAs, even with once or twice weekly oral dosing of rebastinib, led to a significant further decrease in lung metastases compared to single-agent treatment with ATAs. Rebastinib also enhanced the activity of ATAs in reducing primary tumor growth and regrowth of tumor post-resection. TIE2 inhibition with targeted therapy represents a novel treatment approach for metastatic breast cancer and other cancers that rely on TEMs and TMEMs for growth and metastasis. As such, rebastinib has been selected for further clinical development in solid tumors with a Phase 1b trial being planned for 2014.
This abstract is also presented as Poster A5.
Citation Format: Daniel L. Flynn, Michael D. Kaufman, Cynthia B. Leary, Molly M. Hood, Wei-Ping Lu, Benjamin A. Turner, Scott C. Wise, Marc S. Rudoltz, Bryan D. Smith. Rebastinib, a selective TIE2 kinase inhibitor, decreases TIE2-expressing macrophages, reduces metastasis, and increases survival in murine cancer models. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr PR01. doi:10.1158/1538-7445.CHTME14-PR01
Abstract PR11: Hematopoietic system aging has profound effects on the breast tumor microenvironment and cancer progression
Authors: Marsh Timothy , Wong Irene , Barakat Amey , Qin Yuanbo , McAllister Sandra S. 
Published: May 2015

Abstract
The majority of breast neoplasms are diagnosed in patients who are between the ages of 65 and 80. Although tumor growth is generally less aggressive and metastasis is less prevalent in older patients than in younger patients, elderly patients suffer the highest mortality and morbidity associated with breast cancer and breast cancer treatment. The reasons for age-dependent differences in incidence and aggressiveness of breast cancer are not understood. Treatment of breast cancer patients therefore presents age-specific challenges.
We recently established mouse and human xenograft breast tumor models that mimic the age dependent disease progression that is observed in breast cancer patients, whereby tumor cells implanted into aged mice had lower incidence and slower growth kinetics than when implanted into young mice. Moreover, alpha-smooth muscle actin-positive myofibroblasts within the tumor microenvironment were significantly less prevalent in the tumors from aged mice than in size-matched tumors from young mice.
We discovered that bone marrow derived cells from aged mice were significantly less effective in supporting breast cancer progression than the counterpart cells from young mice. Strikingly, bone marrow derived cells from young mice rescued tumor growth and stromal desmoplasia in aged mice. We are elucidating some of the molecular and phenotypic differences between young and aged tumor-promoting bone marrow cells. For example, we found that bone marrow cells from aged mice express lower levels of the cytokine, granulin, which is known to activate normal mammary fibroblasts in young mice.
Our findings indicate that the age of the host hematopoietic system is a powerful determinant of breast tumor progression. Defining functional and molecular differences between tumor supportive hematopoietic cells in young and aged hosts should lay a foundation for further work in this relatively uncharted area of cancer research. Understanding tumor support mechanisms that exist in young and aged hosts should suggest new ideas for preclinical development of age-stratified breast cancer therapies.
Citation Format: Timothy Marsh, Irene Wong, Amey Barakat, Yuanbo Qin, Sandra S. McAllister. Hematopoietic system aging has profound effects on the breast tumor microenvironment and cancer progression. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr PR11. doi:10.1158/1538-7445.CHTME14-PR11
Abstract A18: Uncovering molecular subgroups and a novel cancer driver, ACVR1, in diffuse intrinsic pontine gliomas
Authors: Buczkowicz Pawel , Hoeman Christine , Rakopoulos Patricia , Pajovic Sanja , Morrison Andrew , Bouffet Eric , Bartels Ute , Becher Oren , Hawkins Cynthia 
Published: May 2015

Abstract
Diffuse intrinsic pontine glioma (DIPG) is a devastating paediatric brain tumor with no effective therapy and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and choosing therapies based on assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unravelled the unique genetic make-up of this brain cancer with nearly 80% harbouring a K27M-H3.3 or K27M-H3.1 mutation. However, DIPGs are still thought of as one disease with limited understanding of the genetic drivers of these tumors. Here we apply methylation profiling, whole genome sequencing, expression profiling, and copy number analysis to discover that DIPGs are three molecularly distinct subgroups (H3-K27M, Silent, and MYCN) and uncover a mutations in a novel driver, ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of downstream activin signalling targets ID1 and ID2. The MYCN subgroup is not associated with histone mutations and is instead characterized by hypermethylation and chromothripsis of chromosome 2p with high-level amplifications of MYCN, ID2, and KIDINS220. The Silent subgroup affects younger children, has genomes with minimal genomic instability and fewer mutations, over-expresses WNT pathway genes, as well as genes with known cancer association such as MDM2, MSMP and ADAM33. The H3-K27M subgroup is highly K27M-H3 mutated and associated with additional hits including activating mutations in ACVR1, frequent RB1 and TP53 deletions, PVT-1/MYC or PDGFRA gains/amplifications, genomic instability and alternative lengthening of telomeres. Our results show that this seemingly homogeneous entity in fact comprises three distinct subgroups with different demographic and molecular features. This complexity needs to be considered when designing new therapeutic approaches in order to improve outcome for these children.
Citation Format: Pawel Buczkowicz, Christine Hoeman, Patricia Rakopoulos, Sanja Pajovic, Andrew Morrison, Eric Bouffet, Ute Bartels, Oren Becher, Cynthia Hawkins. Uncovering molecular subgroups and a novel cancer driver, ACVR1, in diffuse intrinsic pontine gliomas. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A18.
Abstract A22: Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis in Wilms tumors
Authors: Rakheja Dinesh , Chen Kenneth S. , Liu Yangjian , Shukla Abhay A. , Hildebrand Sara , Schmid Vanessa , Sun Xiaoyong , Feng Xin , Chang Tsung-Cheng , Khokhar Shama , Karandikar Nitin J. , Malter James S. , Mendell Joshua T. , Amatruda James F. 
Published: May 2015

Abstract
Wilms tumor is the most common pediatric kidney cancer and the fourth most common childhood cancer overall. It is treated with a combination of surgery, chemotherapy, and radiation, and while most children are cured, survival remains poor in those with advanced-stage disease. Known driver mutations (in WT1, WTX, and CTNNB1) account for only one-third of Wilms tumor cases. To better define the genomic landscape of Wilms tumor, we performed whole-exome sequencing of 44 Wilms tumors. We also sequenced matched germline DNA by whole-exome sequencing (15 cases) or targeted Sanger sequencing (29 cases) to identify somatic mutations. Through this approach, we identified recurrent somatic mutations in MYCN, DROSHA, and DICER1, which were mutually exclusive with known Wilms tumor mutations in WT1 and CTNNB1. The ribonucleases DROSHA and DICER1 perform two key steps in the biogenesis of microRNAs (miRNAs), which are ∼22-nt non-coding RNAs that regulate the stability and translation of target mRNAs. DROSHA and DICER1 mutations occurred at or near conserved metal-binding residues in their ribonuclease (RNase) IIIB domains. In vitro processing assays modeling these mutations showed that they partially or completely disrupted the ribonuclease activity of DROSHA and DICER1. In addition, next-generation sequencing of small RNAs in these tumors revealed that the DICER1 mutations preferentially impaired processing of miRNAs derived from the 5′ arm of pre-miRNA hairpins, including the let-7 tumor suppressor miRNA family. Processing of 5′-derived miRNAs is specifically dependent on DICER1 RNase IIIB activity. Although DROSHA-mutant tumors did not exhibit skewed expression of 5′ vs. 3′-derived miRNAs, expression of let-7 and other putative tumor suppressor miRNAs was reduced in these tumors as well. While germline and somatic mutations in DICER1 have been reported in some cancers, this is the first report of recurrent DROSHA mutations in any human tumor type. Moreover, these results suggest that impairment of miRNA processing by somatic mutation of DROSHA and DICER1 defines a novel subclass of Wilms tumor.
Citation Format: Dinesh Rakheja, Kenneth S. Chen, Yangjian Liu, Abhay A. Shukla, Sara Hildebrand, Vanessa Schmid, Xiaoyong Sun, Xin Feng, Tsung-Cheng Chang, Shama Khokhar, Nitin J. Karandikar, James S. Malter, Joshua T. Mendell, James F. Amatruda. Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis in Wilms tumors. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A22.