bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B14: Discoidin domain receptor 1 activity drives an aggressive phenotype in gastric adenocarcinoma
Authors: Hur Hoon , Ham In-hye , Lee Da Keun , Jin Hye-Jin , Y Aguilera Kristina , Oh Hae Jeong , Han Sang-Uk , Kwon Ji-Eun , Kim Young Bae , Ding Ke , Brekken Rolf 
Published: October 2016

Abstract
Purpose: Stromal content in gastric cancer patients inversely correlates with outcome. However, underlying molecular mechanisms for these clinical observations have not been determined. Here, we investigated the contribution of the collagen receptor, discoidin domain receptor-1 (DDR1), in the aggressive phenotype of gastric cancer induced by tumor stroma.
Experimental Design: We conducted immunohistochemical analyses with a tissue microarray of 217 gastric cancer specimens. We examined the effect of collagen-induced activation of DDR1 on cell signaling, tumorigenesis and cell migration in gastric cancer, and evaluated the effects of DDR1 inhibition in organotypic culture and xenograft animal models of gastric cancer.
Results: High DDR1 expression in gastric cancer tissue significantly correlated with poor prognosis. Gastric cancer patients were classified into two groups based on the stromal collagen and the expression of DDR1 was significantly associated with cancer invasion and lymph node metastasis in the collagen-positive group. Decreased expression of E-cadherin was associated with cancer progression in the collagen and DDR1 positive groups. We also demonstrated that collagen activated DDR1 and increased clonogenicity and cell migration. Importantly, we demonstrated that a DDR1 inhibitor, 7rh benzamide, reduced the invasiveness of gastric cancer in organotypic culture system and suppressed tumor growth in gastric cancer xenografts.
Conclusions: Taken together, these findings suggest that collagen enhances the aggressive phenotype of gastric cancer through the DDR1 signaling pathway and that inhibition of DDR1 is an attractive candidate for the therapy of aggressive gastric cancer.
Citation Format: Hoon Hur, In-hye Ham, Da Keun Lee, Hye-Jin Jin, Aguilera Kristina Y., Hae Jeong Oh, Sang-Uk Han, Ji-Eun Kwon, Young Bae Kim, Ke Ding, Rolf Brekken. Discoidin domain receptor 1 activity drives an aggressive phenotype in gastric adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B14.
Abstract B30: Discovery and functional characterization of novel anti-PD-1 antibodies using ex vivo cell-based assays, single-cell immunoprofiling, and in vivo studies in humanized mice
Authors: Scheuplein Felix , Ranganath Sheila , McQuade Thomas , Wang Lei , Spaulding Vikki , Vadde Sri , Watkins-Yoon Jennifer , Feng Bin , Mehta Shanu , Chiu Maria Isabel , Nguyen Cokey 
Published: October 2016

Abstract
Given recent approvals of anti-PD-1 inhibitors Keytruda (pembrolizumab) and Opdivo (nivolumab) for treatment of metastatic melanoma and non-small cell lung cancer NSCLC, we asked whether additional anti-PD-1 inhibitors with different epitopes or potentially differentiated mechanisms of action can provide clinical benefit beyond the two marketed therapies.
Using Enumeral's proprietary single cell technology, we generated more than 300 anti-PD-1 monoclonal antibodies from primary B cells. Bioinformatics analysis of sequences show these antibodies comprise 26 distinct clades, or families, that bind to PD-1. Results from binding studies further indicate we have discovered a family of novel antibodies that do not appear to compete with currently marketed antibodies for binding to PD-1, nor do they appear to compete with PD-L1, suggesting a differentiated mechanism of action. We have humanized two lead antibodies for preclinical testing and in preparation for clinical studies.
Here we describe functional characterization of the two lead antibodies using cell-based ex vivo assays, patient-derived tumor profiling assays using our single-cell platform, and in vivo studies in humanized NSG mice. Results show that the two lead anti-PD-1 antibodies exhibit a higher level of T cell activation in mixed lymphocyte reaction (MLR) assays using primary human immune cells. Second, these antibodies also demonstrated dose-dependent increases in T cell CD25 expression. Next, to test the effect of the two lead anti-PD-1 antibodies on tumor growth, we are conducting a study using a patient-derived tumor (PDX) model on humanized NSG mice. NSG mice reconstitute a full human immune system including a functional T, B cell repertoire, enabling the direct, in vivo evaluation of our human anti-PD-1 antibodies. Effects of drug treatment on tumor growth, transcriptome (RNA seq) and protein expression (IHC) will be described. Finally, results from ex vivo tumor profiling comparing the immmunomodulatory effects of our anti-PD-1 antibodies on tumor-infiltrating lymphocyte function will also be presented.
Citation Format: Felix Scheuplein, Sheila Ranganath, Thomas McQuade, Lei Wang, Vikki Spaulding, Sri Vadde, Jennifer Watkins-Yoon, Bin Feng, Shanu Mehta, Maria Isabel Chiu, Cokey Nguyen. Discovery and functional characterization of novel anti-PD-1 antibodies using ex vivo cell-based assays, single-cell immunoprofiling, and in vivo studies in humanized mice. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B30.
Abstract C10: The role of FIH in macrophage function
Authors: Gojkovic Milos , Rundqvist Helene , Veliça Pedro , Johnson Randall S. 
Published: October 2016

Abstract
The cells of the immune system have to be able to exert its functions in areas of low oxygen tension. In macrophages, functions such as phagocytosis, migration and antigen presentation has been shown to be partly dependent on the hypoxia sensitive transcription factor HIF-1 activation. Previous studies on tissue specific deletion of HIF-1 in macrophages showed decreased infiltration, activation and bacterial killing, as well as decreased cancer progression and growth in the MMTV-PyMT mouse model of breast cancer. However, the effects of increased HIF-1 expression and activity in macrophages are not fully understood. In light of the current literature, we hypothesize that increased activity of HIF-1 may lead to enhanced immunological activity in macrophages. When we knock down FIH (a hydroxylase that inhibits HIF-1 activity) in Raw cells, migration towards a PyMT derived tumor cell line increases. FIH knock down macrophages was characterized by increased MHC Class II surface expression and improved phagocytosis under normoxic conditions, however the difference between knock down FIH and wild type macrophages are less in hypoxic conditions, indicating that the enhanced immunological function may depend on increased HIF-1 activity.
Future work includes the use of a conditional cre-loxP knockout mouse, with cre expression driven by the myeloid specific promoter for LysM, knocking out either VHL (a negative regulator of HIF stability) or FIH. These mice will also be used to investigate the role of constitutively active myeloid HIF-1 in tumor progression.
Citation Format: Milos Gojkovic, Helene Rundqvist, Pedro Veliça, Randall S. Johnson. The role of FIH in macrophage function. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C10.
Abstract C28: Platelet-derived growth factor receptor-β (PDGFRβ) in the breast metastatic tumor microenvironment
Authors: Sizemore Gina , Mathur Anisha , Thies Katie , Bolyard Chelsea , Sizemore Steven , Kladney Raleigh , Trimboli Anthony , Kaur Balveen , Leone Gustavo , Ostrowski Michael 
Published: October 2016

Abstract
A role for the tumor microenvironment (TME) in cancer progression is irrefutable and our laboratory has been at the forefront of this field providing evidence for both tumor suppressive and oncogenic roles of the TME. The PDGF pathway is an exemplar for the study of tumor-stroma interaction as PDGF receptors (PDGFR) are frequently expressed in the fibroblasts and pericytes within the tumor-associated stroma of epithelial tumors including breast cancer. In contrast, PDGF ligands are expressed by the epithelial tumor cells themselves. However, beyond a few descriptive studies, the role of interactive PDGFRβ signaling in the TME during breast cancer initiation, progression and metastases is not understood. This can be attributed in part to limited in vivo models to study the complex TME, especially for breast cancer associated metastases. To overcome this limitation, we have established a transgenic knock-in mouse model that expresses constitutively active PDGFRβ in the stroma of the mammary gland as well in the lung and the brain, two common sites of metastatic breast cancer dissemination. We have found that these mice develop mammary gland hyperplasia highlighting the importance of PDGFRβ in the TME in driving mammary epithelial cell growth. To test whether activation of mutant PDGFRβ in either the lung or the brain increases metastatic growth at either site, two experimental metastases assays were performed: (1) tail vein and (2) intracranial injections to test for lung and brain metastatic outgrowth, respectively. Tail vein injection of the non-metastatic murine mammary cancer cell line DB7 cells led to pronounced lung metastases in PDGFRβ knock-in mice in less than 4 weeks. No macrometastases were seen in the control at this same time point. Similar to the surge in lung metastasis, intracranial injection of DB7 cells led to an increase in tumor growth in brains of the mutant versus wild type controls, revealing an important role for PDGFRβ signaling in the breast cancer metastatic microenvironment. In addition, knockdown of PDGF-B in mammary cancer cells represses intracranial growth in wild type animals. Combined these data support a role for PDGFRβ signaling in the breast cancer metastatic microenvironment. Ongoing investigation is aimed to delineate how activated PDGF-B to PDGFRβ signaling primes the metastatic niche.
Citation Format: Gina Sizemore, Anisha Mathur, Katie Thies, Chelsea Bolyard, Steven Sizemore, Raleigh Kladney, Anthony Trimboli, Balveen Kaur, Gustavo Leone, Michael Ostrowski. Platelet-derived growth factor receptor-β (PDGFRβ) in the breast metastatic tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C28.
Abstract IA03: Fibroblast heterogeneity in skin tumour stroma
Authors: Watt Fiona M. 
Published: October 2016

Abstract
The fibroblasts of mouse skin connective tissue arise from two distinct lineages during embryonic development. One forms the upper dermis, including the dermal papilla, dermal sheath and arrector pili muscle, and is required for hair follicle formation. The other forms the lower dermis, including the reticular fibroblasts that synthesize the bulk of the fibrillar ECM, and the skin adipocyte layer. The lower dermal lineage is responsible for the first phase wound repair. We have been investigating the changes in the composition of adult mouse dermis when epidermal tumors arise through oncogenic beta-catenin activation. Our studies highlight the contribution of different fibroblast subpopulations to the stroma of skin tumors.
Citation Format: Fiona M. Watt. Fibroblast heterogeneity in skin tumour stroma. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA03.
Abstract IA12: Stromal cells in the targeting and transport of tumor-penetrating peptides
Authors: Ruoslahti Erkki , Ruoslahti Erkki 
Published: October 2016

Abstract
This laboratory studies tissue-specific vascular markers, “vascular zip codes”, and their use in selective targeting of drugs to diseased tissues. Screening of phage libraries in live mice identifies peptides that direct phage homing to a specific target in the body. When the libraries are injected into the circulation, tissue-specific or tumor-specific differences in endothelial cells are primarily targeted. The endothelial target molecules are frequently also expressed by other tumor stromal cells and tumor cells, but not cells in normal tissues. Recently discovered tumor-penetrating peptides, through a complex mechanism that involves a proteolytic cleavage and binding to a second receptor, activate an endocytic transport pathway related to but distinct from macropinocytosis. This trans-tissue pathway, dubbed the CendR pathway, mediates the exit of payloads ranging from small molecule drugs to nanoparticles from the blood vessels and transport through extravascular tumor tissue. The CendR technology provides a solution to a major problem in tumor therapy, poor penetration of drugs into tumors. The tumor-penetrating peptides are capable of taking a drug, antibody, or nanoparticle payload deep into tumor tissue in mice, and they also penetrate into human tumors ex vivo. Remarkably the payload does not have to be coupled to the peptide; the peptide activates a bulk transport system that sweeps along any compound that is present in the blood. Treatment studies in mice show improved anti-tumor efficacy and less damage to normal tissues.
Citation Format: Erkki Ruoslahti, Erkki Ruoslahti. Stromal cells in the targeting and transport of tumor-penetrating peptides. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA12.
Abstract IA19: Microenvironmental regulation of breast cancer invasion, dissemination, and lung colonization
Authors: Ewald Andrew J. 
Published: October 2016

Abstract
The majority of cancer deaths are associated with the metastasis of epithelial tumors. This clinical reality presents an interesting conceptual puzzle: homeostatic epithelial cells are tightly adherent to each other and exhibit comparatively modest levels of proliferation and motility. Conversely, metastatic cancer cells must escape from the primary tumor, navigate the local stroma, access the systemic circulation, evade the immune system, and survive in distant sites with molecularly distinct microenvironments. We seek to understand the molecular changes that underlie this large change in epithelial cell behavior.
To accomplish this goal, we first developed a series of 3D organotypic assays to elucidate the specific molecular changes downstream of expression of genes associated with metastatic cell behaviors, such as Twist1. We found that Twist1 expression is sufficient to induce mammary cells to disseminate but, surprisingly, its major effectors are proteins that constitute, interpret, or modify the extracellular compartment. We further demonstrated that Twist1 induced dissemination occurs in the presence of membrane localized adherens junction components and requires E-cadherin (Shamir et al, JCB, 2014). We are currently leveraging our bioinformatic analyses to identify molecular targets that can be inhibited to block invasion and dissemination.
In addition to candidate gene approaches, we sought to identify invasion and metastasis associated genes in an unbiased fashion. We therefore developed 3D organotypic culture assays using primary and metastatic tumor tissue from mouse models and clinical breast cancer samples (n&gt;150). We discovered a conserved molecular program expressed in the most invasive breast cancer cells across molecular subtypes (Cheung et al, Cell, 2013). We next used lineage analysis in vivo to demonstrate that the majority of metastases in the MMTV-PyMT mouse model are founded by multicellular groups of cancer cells. Importantly, the keratin-14+ (K14+) invasive molecular phenotype is common in invasion strands, locally disseminated cancer cells, CTC clusters, and micrometastases but rare in the macrometastases. We are now focused on understanding how the microenvironment determines the likelihood of dissemination from the primary tumor and metastatic outgrowth in distant organs.
Citation Format: Andrew J. Ewald. Microenvironmental regulation of breast cancer invasion, dissemination, and lung colonization. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA19.
Abstract IA25: Hallmark capabilities modulated by the tumor microenvironment during tumor progression and adaptive resistance to therapy
Authors: Hanahan Douglas , Hanahan Douglas 
Published: October 2016

Abstract
The hallmarks of cancer constitute an organizing concept that may provide a rational basis for distilling the diversity and complexity of human cancers so as to better understand mechanisms of the disease and its manifestations. The integration of these hallmark capabilities in symptomatic disease involves multiple cell types populating the tumor microenvironment, including heterogeneous populations of cancer cells, and three prominent classes of stromal support cells - angiogenic vascular cells, cancer associated fibroblasts, and infiltrating immune cells. Dynamic interactions amongst these cell types convey hallmark capabilities whose roles and functional importance vary during multi-step tumorigenesis and tumor progression, and in the context of adaptive responses to hallmark-targeting therapies, suggesting potential benefits in multi-targeting the TME. A few examples from our research program will seek to be illustrative.
Citation Format: Douglas Hanahan, Douglas Hanahan. Hallmark capabilities modulated by the tumor microenvironment during tumor progression and adaptive resistance to therapy. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA25.
Abstract PR14: Epidermal neoplasms bypass immune evasion requirements via niche occupancy
Authors: Kubick Brad , Roop Dennis 
Published: October 2016

Abstract
Anti-tumor immune effectors exert selective pressure against transformed clones, ultimately permitting only mutation cascades that are either non-immunogenic or include immune-evasive adaptations. This evolutionary process often includes an equilibrium phase during which immunogenic transformed cells are prevented from outgrowth by the immune system without being eliminated. In most cases, escape from this state requires loss of antigen presentation and consequent loss of immunogenicity. To characterize this pre-outgrowth phase of cancer-immune interaction and test the efficacy of interventions during dormancy, we assembled a genetically-engineered mouse model (GEMM) of inducible, Kras-driven carcinogenesis coupled to a fluorescent reporter. Early characterization of this model revealed a confounding artificial tolerance mechanism that renders inducible alleles automatically non-immunogenic in autochthonous settings. To circumvent this tolerance, we transplant dissociated epidermal keratinocytes from the GEMM onto recipient animals that do not carry the inducible mutant Kras allele. This transplant step also enables the use recipient animals carrying various immune deficiencies. After graft healing, transformation is induced and the grafts are imaged repeatedly over time via intravital confocal microscopy. In immunocompromised recipients, transformation initiates the rapid growth of labeled cells and subsequent tumor formation. In immunocompetent cohorts, tumor formation does not occur. Instead, we observe establishment of a long-term equilibrium phase characterized by cyclic growth and regression of labeled clones originating exclusively from hair follicles, suggesting that the immune privilege of this stem cell niche provides a safe harbor for transformed cells. Surprisingly, the architecture of the normal tissue defines a protected reservoir for the survival of transformed cells, a fate that usually requires cell-intrinsic immune-evasive adaptations. This provides a mechanism by which a single source of anti-tumor activity could produce the observed biphasic nature of cancer-immune interaction, including both elimination of some clones and immune-mediated dormancy of others. Most importantly, we have identified a novel pre-malignant, immune-controlled state that may represent a vulnerable target population for rational cancer prevention strategies.
Citation Format: Brad Kubick, Dennis Roop. Epidermal neoplasms bypass immune evasion requirements via niche occupancy. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr PR14.
Impact of Left Ventricular to Mitral Valve Ring Mismatch on Recurrent Ischemic Mitral Regurgitation After Ring Annuloplasty
Authors: Capoulade Romain , Zeng Xin , Overbey Jessica R. , Ailawadi Gorav , Alexander John H. , Ascheim Deborah , Bowdish Michael , Gelijns Annetine C. , Grayburn Paul , Kron Irving L. , Levine Robert A. , Mack Michael J. , Melnitchouk Serguei , Michler Robert E. , Mullen John C. , O’Gara Patrick , Parides Michael K. , Smith Peter , Voisine Pierre , Hung Judy 
Published: October 2016

Background:
In ischemic mitral regurgitation (IMR), ring annuloplasty is associated with a significant rate of recurrent MR. Ring size is based on intertrigonal distance without consideration of left ventricular (LV) size. However, LV size is an important determinant of mitral valve (MV) leaflet tethering before and after repair. We aimed to determine whether LV-MV ring mismatch (mismatch of LV size relative to ring size) is associated with recurrent MR in patients with IMR after restrictive ring annuloplasty.

Methods:
Patients with moderate or severe IMR from the 2 Cardiothoracic Surgical Trials Network IMR trials who received MV repair were examined at 1 year after surgery. Baseline LV size was assessed by LV end-diastolic dimension and LV end-systolic dimension (LVESd). LV-MV ring mismatch was calculated as the ratio of LV to ring size (LV end-diastolic dimension/ring size and LVESd/ring size).

Results:

At 1 year after ring annuloplasty, 45 of 214 patients with MV repair (21%) had moderate or greater MR. In univariable logistic regression analysis, larger LVESd (
P
=0.02) and LVESd/ring size (
P
=0.007) were associated with recurrent MR. In multivariable models adjusted for age, sex, baseline LV ejection fraction, and severe IMR, only LVESd/ring size (odd ratio per 0.5 increase, 2.20; 95% confidence interval, 1.05–4.62;
P
=0.038) remained significantly associated with 1-year MR recurrence.

Conclusions:
LV-MV ring size mismatch is associated with increased risk of MR recurrence. This finding may be helpful in guiding choice of ring size to prevent recurrent MR in patients undergoing MV repair and in identifying patients who may benefit from MV repair with additional subvalvular intervention or MV replacement rather than repair alone.

Clinical Trial Registration:

URL:
http://clinicaltrials.gov
. Unique identifiers: NCT00806988 and NCT00807040.