bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY37-01: Dissecting the canonical and noncanonical interactions of the BCL-2 family for therapeutic benefit
Authors: Walensky Loren D. 
Published: May 2015

Abstract
BCL-2 family proteins are key regulators of apoptotic and other signaling pathways in health and disease. Discrete amphipathic alpha-helices embedded within the protein infrastructure are essential interaction motifs that can inhibit or activate their physiologic targets. The canonical complex between a pro-apoptotic BCL-2 homology domain 3 (BH3) helix and a surface groove on anti-apoptotic members portrayed a molecular wrestling match between pro- and anti-apoptotic signals. If anti-apoptotic grooves are sufficient in number to bind and sequester the pro-apoptotic BH3 signals, cell survival prevails. In contrast, if the capacity to withstand pro-apoptotic assault is breached, cell death ensues. Not only did this protein interaction paradigm provide a mechanism for apoptotic regulation, but it also informed the development of drugs to reactivate cell death through targeted inhibition of anti-apoptotic BH3-binding pockets. Given the critical roles of amphipathic alpha-helices in mediating signal transduction, we advanced all-hydrocarbon stapling to refold bioactive alpha-helical peptides for use as research tools and prototype therapeutics. Depending on their amino acid composition and design, “stapled peptides” have proven to be structurally stable, protease resistant, and cell permeable agents capable of interrogating and modulating protein interactions in vitro and in vivo. Here, I present our latest applications of Stabilized Alpha-Helices of BCL-2 domains (SAHBs) to dissect the canonical and noncanonical interactions that directly regulate the functional activity of BCL-2 family proteins and their targets. Our findings broaden the opportunities to pharmacologically modulate cell death and other physiologic processes by revealing new protein terrain for therapeutic targeting.
Citation Format: Loren D. Walensky. Dissecting the canonical and noncanonical interactions of the BCL-2 family for therapeutic benefit. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY37-01. doi:10.1158/1538-7445.AM2014-SY37-01
Abstract SY37-04: Bcl-2 family proteins as a paradigm for protein:protein interactions as chemotherapy targets
Authors: Andrews David W. 
Published: May 2015

Abstract
Many aspects of cell signaling are regulated by protein:protein interactions including growth factor receptor signal transduction pathways, transcriptional regulatory complexes and programmed cell death. The Bcl-2 family proteins regulate programmed cell death via a series of protein:protein interactions that occur in the cytoplasm and in membranes. These interactions are regulated by the amount of the proteins, their locations and by post-translational modifications. The multi-domain pro-apoptotic Bcl-2 family members Bax and Bak directly regulate mitochondrial outer membrane permeabilization (MOMP), an event widely accepted as committing most cells to apoptosis. MOMP results from an ordered series of steps beginning with activation of one or more Bcl-2 homology 3 proteins (BH3-proteins). Once activated, BH3-proteins bind to mitochondria, directly recruit and activate Bax and the constitutively membrane bound Bak. In some cases ‘activation’ involves releasing a previously activated Bax or Bak from inhibition by an anti-apoptotic protein of the Bcl-2 family. Oligomerization of integral membrane Bax and/or Bak culminates in membrane permeabilization. The embedded together model describes these interactions as a series of dynamic equilibria that change when the proteins interact with membranes. Because of their role regulating apoptosis in cancer cells and in response to chemotherapy, Bcl-2 family proteins are attractive targets for the development of small molecule inhibitors. The rational development of small molecules requires understanding in detail the molecular interactions that regulate activity. However, studying protein:protein interactions for membrane bound proteins is fraught with difficulties. I will describe some of the challenges of studying this family of proteins and the successes and surprises that resulted from our analyzing and perturbing their interactions for a variety of Bcl-2 family proteins in live cells. I will highlight recent data that suggests new avenues to targeting Bcl-2 family protein:protein interactions therapeutically.
Citation Format: David W. Andrews. Bcl-2 family proteins as a paradigm for protein:protein interactions as chemotherapy targets. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY37-04. doi:10.1158/1538-7445.AM2014-SY37-04
Abstract SY40-04: Immune control of spontaneous tumor development
Authors: Li Ming 
Published: May 2015

Abstract
Long recognized as an evolutionarily ancient cell type to control development, tissue homeostasis, and immune responses to pathogens, macrophages are being rediscovered as regulators of several chronic disorders including cancer. Using a spontaneous mammary tumor model, here we show that tumor growth induces the differentiation and expansion of a unique subset of tumor-associated macrophages (TAMs) that are phenotypically and functionally distinct from mammary tissue macrophages (MTMs). Compared to MTMs, TAMs do not exhibit an “alternatively activated macrophage” phenotype, but express the adhesion molecule Vcam1, and have high proliferative capacity upon their differentiation from CCR2-expressing inflammatory monocytes. Importantly, TAM differentiation is dependent on the transcriptional regulator of the Notch signaling pathway, RBPJ; and TAM, but not MTM, depletion restores tumor-infiltrating cytotoxic T cell responses, and suppresses tumor growth. These findings demonstrate that TAMs represent a novel lineage of mononuclear phagocytes with critical regulatory functions in promoting T cell tolerance to tumors.
Citation Format: Ming Li. Immune control of spontaneous tumor development. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY40-04. doi:10.1158/1538-7445.AM2014-SY40-04
Abstract SY42-03: Novel DNA repair inhibitors for radiosensitization and cancer therapy
Authors: Glazer Peter M. 
Published: May 2015

Abstract
There is growing interest in the development of molecules that can inhibit DNA repair or disrupt DNA damage response pathways for application to cancer therapy. Such inhibitors offer the potential to achieve synthetic lethality in the context of DNA repair deficient cancers and/or to sensitize tumors to chemotherapy and radiation. We have identified a series of structurally related small molecules that demonstrate increased toxicity to human cancer cells deficient in BRCA2, PTEN, ATM, and the Fanconi pathway. These compounds are not PARP inhibitors but rather impact DNA damage response pathways at upstream steps, causing impairment of both homology-dependent DNA repair (HDR) and non-homologous end-joining (NHEJ) repair of DNA double-strand breaks. The molecules also reduce the formation of DNA repair foci by several damage response factors, including 53BP1, BRCA1, and DNA-PK, following ionizing radiation treatment of cancer cells. Efforts to identify the molecular target of these compounds are underway.
In addition, we have found that a highly unusual lupus-derived, cell-penetrating autoantibody, 3E10, preferentially binds DNA single-strand tails, inhibits key steps in DNA single-strand and double-strand break repair, and sensitizes tumor cells and human tumor xenografts to DNA-damaging therapy, including doxorubicin and radiation. Moreover, we find that 3E10 alone is synthetically lethal to BRCA2-deficient human cancer cells and selectively sensitizes such cells to low dose doxorubicin. These findings identify a new antibody that may have clinical application in cancer, particularly in BRCA-related malignancies. Because lupus is associated with circulating autoantibodies reactive against host DNA, the work also suggests that lupus autoantibodies may be a valuable source of other potential therapeutic agents. In addition, our findings raise the possibility that lupus autoantibodies may be partly responsible for the unexpectedly low rates of breast and ovarian cancers observed in lupus patients.
Citation Format: Peter M. Glazer. Novel DNA repair inhibitors for radiosensitization and cancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY42-03. doi:10.1158/1538-7445.AM2014-SY42-03
Abstract A07: Breast tumor microenvironment shapes vascular response to endothelial HoxA5 expression
Authors: Northcott Josette , Cuevas Ileana , Layman Hans , Boudreau Nancy 
Published: May 2015

Abstract
Current anti-angiogenic therapy for the treatment of solid tumors is based on directed inhibition of growth factor signaling pathways essential for the development of new blood vessels. Despite evidence showing a positive correlation between angiogenesis and breast cancer progression, existing anti-angiogenic therapies have not proven effective at clinically managing breast tumors or prolonging patient survival. Several studies have shown that tissue microenvironment shapes local angiogenic responses and tumor progression - a finding that may partially explain the refractoriness of breast tumors to anti-angiogenic therapy. Data from our laboratory supports an anti-angiogenic role for the HoxA5 homeodomain containing transcription factor. Using the KRT14-HPV16 mouse model of skin cancer crossed with our tetracycline-regulated mouse line that expresses HoxA5 in the endothelium, we observed that HoxA5 reduced angiogenesis and slowed tumor progression in the skin. Thus, we hypothesized that constitutive endothelial expression of HoxA5 during mammary tumor development would prevent tumor growth and metastasis via modulation of the endothelial phenotype. Surprisingly, in the MMTV-PyMT mouse model of breast cancer, we observed that endothelial HoxA5 expression increased both primary tumor growth and lung metastasis. Mammary tumors from PyMT/HoxA5+ mice had larger areas of hypoxia and necrosis, as compared to primary tumors from control mice. Although we did not detect any change in intra-tumoral vascular staining (CD31+), we observed an increased number of large vessels and reduced vascular leakage in the primary tumors from PyMT/HoxA5+ mice. In contrast, subcutaneous injection of MMTV-PyMT mammary tumor cells into HoxA5 transgenic mice displayed significantly reduced tumor growth and decreased intra-tumoral vascularization, as compared to controls. This suggests that, unlike the anti-angiogenic properties of HoxA5 in the skin microenvironment, within the context of the mammary gland HoxA5 has vascular normalization effects. We conclude that the tissue microenvironment shapes the vascular response to anti-angiogenic agents and thereby controls tumor progression.
Citation Format: Josette Northcott, Ileana Cuevas, Hans Layman, Nancy Boudreau. Breast tumor microenvironment shapes vascular response to endothelial HoxA5 expression. [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 A07. doi:10.1158/1538-7445.CHTME14-A07
Abstract A43: Systemic tumor-stroma interactions are prognostic indicators of breast tumor invasiveness
Authors: Frankenberger Casey A. , Bainer Russell O. , Rabe Daniel C. , Saleh Sadiq , Park Morag , Gilad Yoav , Rosner Marsha R. 
Published: May 2015

Abstract
Cancer progression is critically dependent on specific molecular interactions between tumor cells and their microenvironment, but little is known about the global dynamics of this crosstalk within and across individuals. Here, we used an RNA sequencing approach with species-of-origin information in a xenograft mouse model to computationally resolve and compare tumor versus stromal transcriptional changes. Our study employed a triple-negative breast cancer (TNBC) model in which primary tumor invasiveness is controlled by the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP) allowing systemic observation of stromal response to invasive or noninvasive breast tumours at both proximal and distal sites.
Initially, we observed that expression levels of gene homologs in human tumor and mouse stroma are highly synchronized. Surprisingly, the set of genes most prognostic for metastasis-free survival in multiple clinical data sets were those whose mRNA expression was inversely correlated between tumor and stroma. These results were confirmed in an independent set of microarray data from tumor and stroma micro-dissected from primary human breast cancer patient tissue. Additionally, we found broad-based and invasion-specific gene expression changes in stromal tissues far from the primary lesion, with these results being confirmed in an independent set of samples. Of note, genes differentially expressed in the tumor-associated stroma were better classifiers of tumor phenotype than genes differentially expressed in the tumor alone. As well, stromal genes differentially expressed both locally and distally, are significant predictors of patient prognosis.
These findings demonstrate the potential for using patient tissue remote from the primary tumor as indicators of disease aggressiveness. Furthermore, these results suggest that stromal gene expression, acting to compensate for changes in the tumor, may have both prognostic and therapeutic implications.
Citation Format: Casey A. Frankenberger, Russell O. Bainer, Daniel C. Rabe, Sadiq Saleh, Morag Park, Yoav Gilad, Marsha R. Rosner. Systemic tumor-stroma interactions are prognostic indicators of breast tumor invasiveness. [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 A43. doi:10.1158/1538-7445.CHTME14-A43
Abstract A47: IL-4 receptor-targeted delivery of liposomal doxorubicin and siRNA to tumor
Authors: Padmanaban Guruprasath , Vadevoo Sri Murugan Poongkavithai , Chi Lianhua , Lee Byung-Heon 
Published: May 2015

Abstract
Targeted delivery of imaging agents and therapeutics to tumors would provide early detection and increased therapeutic efficacy against cancer. Using phage displayed-random peptide libraries, we have identified IL4RPep-1 (IL-4 receptor-binding peptide-1), CRKRLDRNC, that binds to IL-4 receptor (IL4R). IL4R is over-expressed on many types of cancer cells including lung cancer and breast cancer. Peptides have smaller size and in turn may exert better tissue penetration than bulky antibodies. IL4RPep-1 bound to H226 lung tumor cells that over-express IL4R, while little binding was observed in H460 lung tumor cells that express IL4R at low levels. When injected intravenously into nude mice bearing a subcutaneous H226 tumor, Cy7.5 near-infrared fluorescence dye-conjugated IL4RPep-1 selectively homed to tumor. IL4RPep-1-labeled liposomes containing doxorubicin showed more efficient anti-tumor growth activity than untargeted liposomes. In addition, IL4RPep-1-labeled, branched-type polyethyleneimine nanoparticles containing Bcl-xL siRNA more efficiently knocked down Bcl-xL expression and showed higher cytotoxic effect on cancer cells over-expressing IL4R than cancer cells expressing IL4R at low levels. These results suggest that IL4RPep-1 could be a useful probe for affinity-based imaging and drug delivery to tumor that over-expressing IL4R.
Citation Format: Guruprasath Padmanaban, Sri Murugan Poongkavithai Vadevoo, Lianhua Chi, Byung-Heon Lee. IL-4 receptor-targeted delivery of liposomal doxorubicin and siRNA to tumor. [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 A47. doi:10.1158/1538-7445.CHTME14-A47
Abstract A71: TMPRSS4 proteolytically activates pro-uPA to induce cancer cell invasion
Authors: Min Hye-Jin , Kim Semi 
Published: May 2015

Abstract
The invasive nature of tumor cells is critical for cancer metastasis. Urokinase-type plasminogen activator (uPA), which is usually derived from stromal cells, is a well-known serine protease involved in invasion and metastasis. uPA is produced as an inactive single-chain protein (known as pro-uPA or sc-uPA) that is processed into the active disulfide-linked two-chain form of uPA by a proteolytic event. TMPRSS4 is a novel type II transmembrane serine protease that is highly expressed on the cell surface in pancreatic, thyroid, colon, and other cancer tissues. Previously, we demonstrated that TMPRSS4 mediates colorectal tumor cell invasion, migration, and metastasis and increased TMPRSS4 expression is associated with colorectal cancer progression. We also demonstrated that TMPRSS4 upregulates uPA gene expression through c-Jun N-terminal kinase signaling activation to induce cancer cell invasion. However, it remains unknown how proteolytic activity of TMPRSS4 contributes to invasion. Here, we report that TMPRSS4 directly converted inactive pro-uPA into the active form through its proteolytic activity. Analysis of conditioned medium from cells overexpressing TMPRSS4 demonstrated that the active TMPRSS4 protease domain is released from the cells and is associated with the plasma membrane. Furthermore, TMPRSS4 could increase pro-uPA-mediated invasion in a serine proteolytic activity-dependent manner. These observations suggest that TMPRSS4 is an upstream regulator of invasion through the regulation of uPA. This study provides valuable insights into the proteolytic function of TMPRSS4 as well as mechanisms for the control of invasion.
Citation Format: Hye-Jin Min, Semi Kim. TMPRSS4 proteolytically activates pro-uPA to induce cancer cell invasion. [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 A71. doi:10.1158/1538-7445.CHTME14-A71
Abstract A79: Mouse models of breast cancer identify oncogene-associated stroma subtypes
Authors: Saleh Sadiq M. , Savage Paul , Laferrière Julie , Cory Sean , Bertos Nicholas , Souleimanova Margarita , Zhao Hong , Zacksenhaus Eldad , Muller William , Hallett Michael , Park Morag 
Published: May 2015

Abstract
Breast Cancer is a highly heterogeneous disease involving complex crosstalk between tumor cells and their surrounding microenvironment (stroma). Previous work in our lab utilized laser capture microdissection and gene expression analysis to separate Breast Cancer stromal samples into distinct subtypes. Although this and other data demonstrate the importance of the stroma in tumor progression, the cause of these stromal changes are still poorly understood. We hypothesize that changes within stroma are related to individual oncogenic events within the tumor epithelium. Analyzing human data does not allow us to draw causative conclusions due to the presence of compounding factors such as genetic variance and living conditions. In an attempt to circumvent this challenge we used transgenic mouse models of breast cancer in the same strain of mice (FVB) with oncogenes driven by a mammary specific promoter (MMTV). By keeping these variables constant and only varying the oncogene: using either Neu-NDL-2-5, PyVMT or Wnt1 - allowed us to test the aforementioned hypothesis.
Class discovery and distinction confirmed that the epithelial and stromal samples from each mouse model were distinct, which validated our hypothesis. Pathway analysis of the genes that distinguish the stroma of the mouse models identifies genes linked to recruitment and activation of different stromal cells. Interestingly our findings corroborate with results from other labs using these mouse models.
Citation Format: Sadiq M. Saleh, Paul Savage, Julie Laferrière, Sean Cory, Nicholas Bertos, Margarita Souleimanova, Hong Zhao, Eldad Zacksenhaus, William Muller, Michael Hallett, Morag Park. Mouse models of breast cancer identify oncogene-associated stroma subtypes. [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 A79. doi:10.1158/1538-7445.CHTME14-A79
Abstract B02: Matrix stiffness regulates local metabolism of breast carcinoma cells
Authors: Burkel Brian , Ponik Suzanne , Morris Brett , Eliceiri Kevin , Keely Patricia 
Published: May 2015

Abstract
Dense breast tissue is one of the single largest risk factors for the development of breast cancer, and one of the primary proteins responsible for increased breast density is the core extracellular matrix (ECM) component, collagen. Similar to other ECM proteins, collagen plays a structural role underlying tissue organization and increased collagen deposition correlates to a stiffer ECM and cellular microenvironment. Interestingly, changes to the stiffness of the ECM or microenvironment have profound and poorly-understood effects on cell migration, cell proliferation, and cancer progression. Consistent with an expanding role of ECM stiffness in cell signaling, we report that increased matrix stiffness also affects cellular metabolism and respiration. Using specific pharmacological inhibitors and quantitative imaging modalities like fluorescence lifetime microscopy, we are able to show that changes in collagen stiffness can cause a metabolic shift towards a more glycolytic, Warburg-like equilibrium in breast carcinoma cells. Matrix stiffness regulates the expression of several metabolic enzymes, including PDHK-1, which is poised to regulate this shift.
Note: This abstract was not presented at the conference.
Citation Format: Brian Burkel, Suzanne Ponik, Brett Morris, Kevin Eliceiri, Patricia Keely. Matrix stiffness regulates local metabolism of breast carcinoma cells. [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 B02. doi:10.1158/1538-7445.CHTME14-B02