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SELECTBIO Conferences Circulating Biomarkers World Congress 2019

Circulating Biomarkers World Congress 2019 Agenda

Co-Located Conference Agendas

Circulating Biomarkers World Congress 2019 | Liquid Biopsies 2019 | 

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Wednesday, 27 March 2019


Conference Registration, Materials Pick-Up, Morning Coffee and Breakfast Pastries

Session Title: Conference Plenary Session -- Emerging Themes in Circulating Biomarkers and Liquid Biopsies

Plenary Session Chairperson: Lucia R. Languino, Ph.D., Professor of Cancer Biology, Thomas Jefferson University


Jennifer JonesKeynote Presentation

Mt-SEA Pipeline: High Throughput Flow Cytometric Analysis of Exosomes in Clinical Biofluids
Jennifer Jones, Staff Clinician, Molecular Immunogenetics & Vaccine Research Section, National Cancer Institute (NCI), United States of America

Because Extracellular Vesicles (EVs) carry surface receptors that are characteristic of their cells of origin, EVs have tremendous potential as non-invasive biomarkers for diagnosis, risk-stratification, treatment selection, and treatment monitoring. We developed a first-in-class pipeline to characterize EV heterogeneity and provide high-sensitivity quantification of informative EVs in biofluids before, during, and after treatment. By combining multiplex assays with high-resolution, single EV flow cytometric methods together into a Mutiplex-to-Single EV Analysis (Mt-SEA) pipeline, we are able to characterize a broad range of relevant EV subsets, while also accurately measuring the concentration of specific EV populations.  Detection of tumor-associated EVs and detection of EV repertoire changes during treatment paves the way to future evaluation of EVs as as biomarkers for use in personalized, adaptive therapies.


Erkki RuoslahtiKeynote Presentation

Disease-Specific Vascular Markers for Cancer, Atherosclerosis and Brain Diseases
Erkki Ruoslahti, Distinguished Professor and Former President, Sanford Burnham Prebys Medical Discovery Institute, United States of America

We study peptides that home to specific targets in the body. We discover the homing peptides by screening phage libraries for peptides that direct homing of phages to the target tissue in vivo. The homing peptides, which usually bind to receptors in the vessels of the target tissue, can be used to selectively deliver diagnostic probes and drugs to the target. The latest development is the discovery of tumor-penetrating peptides. These peptides activate an endocytic bulk transport pathway we have dubbed the CendR pathway, which can enhance the exit from blood and tissue penetration co-administered compounds even without chemical coupling to the peptide (Ruoslahti, Adv Mater. (2012) 24 3747). We have also identified peptides specific for atherosclerotic plaques, accumulate at the site of a brain injury or recognize the blood vessels in Alzheimer’s disease brain. Our homing frequency have an intrinsic biological active I the disease they target. Examples of the peptide discovery process from initial screening to clinical trials will be given.


Coffee Break and Networking in the Exhibit Hall


Jan LötvallKeynote Presentation

Diversity of Extracellular Vesicles to Understand their Diagnostic and Therapeutic Potential
Jan Lötvall, Professor, University of Gothenburg; Founding President of ISEV, Sweden

This presentation will discuss the diversity of extracellular vesicles, primarily from a clinical perspective. Specifically, the presentation will show the presence of extracellular vesicles in tissues, specifically healthy tissues as well as different types of tumors.  Data showing the presence of multiple types of EVs in different types of tissues will be presented, as well as the opportunities of utilizing that knowledge for clinical use.


Steve SoperKeynote Presentation

Title to be Confirmed.
Steve Soper, Foundation Distinguished Professor, Director, Center of BioModular Multi-scale System for Precision Medicine, Adjunct Professor, Ulsan National Institute of Science & Technology, William H. Pryor Emeritus Chair of Chemistry, The University of Kansas, United States of America


Hollis ClineKeynote Presentation

Exosome Signaling in Brain Development
Hollis Cline, Chair of Neuroscience and Hahn Professor of Neuroscience, The Scripps Research Institute, United States of America

Exosomes are thought to be secreted by all cells in the body and could to be involved in intercellular communication. I will describe experiments in which we tested whether neural exosomes regulate the development of neural circuits and whether exosome-mediated signaling may be aberrant in in vitro models of a neurodevelopmental disorder using human induced pluripotent stem cells (hiPSC) and in vivo rodent models. I will describe results of quantitative proteomic analysis of exosomes. Together our studies indicate that exosomes have the capacity to influence neuron and circuit development.


Networking Lunch in the Exhibit Hall and Poster Viewing

Session Title: Intercellular Communication Mediated by Exosomes/EVs - An Emerging Class of Circulating Biomarkers


Yves A. DeClerckKeynote Presentation

Tumor-derived Exosomes Contribute to a Pro-inflammatory Tumor Microenvironment through the Stimulation of Chemokines and Cytokines in Mesenchymal Stromal Cells and Macrophages
Yves A. DeClerck, Professor of Pediatrics and Biochemistry & Molecular Medicine, Children’s Hospital Los Angeles, University of Southern California, United States of America

Exosomes are members of a large family of extracellular vesicles involved in cell-cell communication that play important regulatory functions in physiological and pathological conditions. Using neuroblastoma (NB), the second most common solid tumor in children and a cancer that is highly metastatic to the bone marrow and the liver as a model, we show that NB-derived exosomes contribute to the stimulation of several protumorigenic cytokines and chemokines (IL-6, IL-8, MCP-1, VEGF) by mesenchymal stromal cells (MSC) and macrophages via ERK1/2 activation.  In vivo NB-derived exosomes are also preferentially captured by macrophages at the site of metastasis (bone marrow and liver).  Altogether these cytokines promotes the proliferation of tumor cells, their resistance to chemotherapy and immune escape via STAT3 and ERK1/2 activation.


Cancer–Host Crosstalk Through Exosomal miRNA
Shizhen Emily Wang, Associate Professor, Department of Pathology, University of California, San Diego, United States of America

Extracellular microRNAs (miRNAs) that can be detected in the circulation are novel mediators of intercellular communication and are considered emerging biomarkers for human diseases. Using cell-secreted extracellular vesicles (e.g., exosomes) as vehicles, miRNAs secreted by cancer cells can travel to and enter various types of niche cells in primary and pre-metastatic tumor microenvironments. Upon entering niche cells, miRNAs regulate gene expression to prepare the niche for cancer progression. Our lab focuses on defining the roles of breast cancer secreted miRNAs in adapting local and distal niche cells and tissues in cancer progression and metastasis. Through de novo sequencing and PCR of circulating small RNAs in the sera of breast cancer patients we identified circulating miRNAs as biomarkers for cancer progression to metastatic disease. Subsequent mechanistic studies revealed important functions of breast cancer secreted miRNAs in various aspects of cellular behaviors. Our findings reveal (1) vascular leakiness and enhanced metastasis caused by cancer-secreted miR-105, which downregulates endothelial tight junctions; (2) miR-105-induced metabolic plasticity in cancer-associated fibroblasts to convert cancer-produced metabolic wastes (e.g., lactate and ammonia) into energy-rich metabolites to re-enter cancer bioenergetics; (3) suppressed glucose utilization by lung fibroblasts and astrocytes in favor of glucose uptake by metastasized cancer cells mediated by cancer-secreted miR-122.


Modulation of Extracellular Vesicle Release and Content in SCC Cells
My Mahoney, Professor and Vice Chair, Thomas Jefferson University, United States of America

Emerging as critical in the pathobiology of cancer are nanosized extracellular membrane vesicles (EVs) secreted by tumor cells into the blood and other bodily fluids carrying molecular constituents to modulate local and distant tumor microenvironment. EVs can be taken up by recipient cells and can modulate diverse biological processes including cell polarity and tissue morphogenesis and represent novel and valuable circulating biomarkers for tumor prognosis and diagnosis. Thus, defining factors that affect the release or modify the content of EVs is critical to our understanding of not only normal tissue development but also malignant transformation and progression. We have shown that the cadherin desmoglein 2 (Dsg2), an important regulator of growth and survival signaling pathways, drives tumorigenesis in experimental models, and clinical samples confirm that Dsg2 is indeed overexpressed in those cancers. We observed that Dsg2 is enriched in EVs derived from SCC cells and patient sera. Dsg2 modulates EV release and mitogenic content including EGFR and c-Src. Dsg2-labeled EVs are taken up by dermal fibroblasts, activating Erk1/2 and Akt signaling and promoting cell proliferation. Our work thus far defines a mechanism by which cancer cells can modulate the tumor microenvironment, a step critical for tumor progression.


Coffee Break and Networking in the Exhibit Hall


Utkan DemirciKeynote Presentation

Chemistry-Free Microfluidic Technologies to Sort Cells for Health and Disease
Utkan Demirci, Professor, Stanford University School of Medicine, United States of America

Micro- and nano-scale technologies can have a significant impact on medicine and biology in the areas of cell manipulation, diagnostics and monitoring. At the convergence of new technologies and biology, our research is centered on enabling solutions to real world problems at the clinical level. Emerging nano-scale and microfluidic technologies integrated with biology offer innovative possibilities for creating intelligent and mobile medical lab-chip devices that could transform diagnostics and monitoring, tissue engineering and regenerative medicine. In this talk, we will first present an overview of our laboratory's work in the areas focused on applications in magnetic levitation methods for assembling cells and chemistry free sorting of rare cells from whole blood. Cells consist of micro- and nano-scale components and materials that contribute to their fundamental magnetic and density signatures. Previous studies have claimed that magnetic levitation can only be used to measure density signatures of non-living materials. Here, we demonstrate that both eukaryotic and prokaryotic cells can be levitated and that each cell has a unique levitation profile. Furthermore, our levitation platform uniquely enables ultrasensitive density measurements, imaging, and profiling of cells in real-time at single-cell resolution. This method has broad applications, such as the label-free identification and sorting of CTCs and CTM with broad applications in drug screening in personalized medicine. Second, we will present some of our efforts on developing new tools to isolate extracellular vesicles from blood, urine and cell cultures. I will also share some of the clinical implications of these technologies indicating the broader potential that chemistry-free and label-free microfluidic-based technologies have in medicine.


The HSP-Accessorized Exosome: Presence in States of Danger, Disease, and Disruption
Michael Graner, Associate Professor, Dept of Neurosurgery, University of Colorado Anschutz School of Medicine, United States of America

Heat shock proteins (HSPs) function as chaperones under both normal and pathologic conditions. As chaperones they assist in protein folding, in holding protein complexes for current or future activation, and in the degradation of senescent proteins for recycling of components and display for immune surveillance. During stressful situations, HSP quantities and/or activities are increased as cells and tissues seek protection from insults. On occasion, these insults can result in the cell surface display of HSPs, which can then lead to the surface display of HSPs on exosomes, membrane-enclosed vesicles released extracellularly after passage thru the endosomal system. HSPs present on the cell surface or in the extracellular space are regarded as “danger signals” in an ancient biologic paradigm. HSP-accessorized exosomes may act as “danger boli”, carrying not only the HSPs, but hundreds of components of the stressed parental cell, capable of prompting immune responses, or possibly immune suppression, depending on the status of the recipient cell. Here we show that exosomes from the blood of patients suffering from neurologic maladies (cancer, brain injury, multiple sclerosis) are precipitated by peptides designed to bind HSPs. The metabolome of such exosomes is distinct from that of blood exosomes from healthy donors. Such HSP-accessorized exosomes possess inflammatory properties and may serve as biomarkers in a “liquid biopsy” setting.


Dominique PV de KleijnKeynote Presentation

Title to be Confirmed.
Dominique PV de Kleijn, Professor Experimental Vascular Surgery, Professor Netherlands Heart Institute, University Medical Center Utrecht, The Netherlands, Netherlands


Networking Reception with Beer and Wine in the Exhibit Hall


Close of Day 1 of the Conference.

Thursday, 28 March 2019


Morning Coffee Break and Breakfast Pastries Served in the Exhibit Hall

Session Title: Technologies for the Interrogation and Modulation of Exosomes/EVs


Michael HellerKeynote Presentation

Rapid Simultaneous Isolation and Detection of Exosome/EV and cfDNA Biomarkers from Cancer Patient Blood Samples
Michael Heller, Distinguished Scientist - Knight Cancer Institute at Oregon Health & Science University (OHSU), Center for Cancer Early Detection and Research (CEDAR); Professor, University of California-San Diego, United States of America

Multi-omic approaches using different types of biomarkers will be a viable strategy for liquid biopsy diagnostics and early cancer detection. A novel electrokinetic sample to answer device (ACE chip, Biological Dynamics, San Diego, CA) was used to isolate exosomes, extracellular vesicles (EVs) and cell free (cf) DNA from 20-50 µL of cancer patient plasma samples. Fluorescent detection of the cf-DNA and immunostaining for exosome/EV protein biomarkers could then be rapidly carried out directly on-chip. Subsequently, cf-DNA and exosome/EV entrapped RNA could be eluted from the ACE chip, whereupon PCR and sequencing analysis is conducted to identify cancer-related point mutations. Our results show correlation of immunofluorescent detection of exosome/EV glypican-1 and cf-DNA KRAS mutations (G12V, G12D) determined by digital PCR for a number of patient samples from pancreatic and colorectal cancers, where lung cancer patient samples were used as a negative control. This provides further advancement towards integrating multi-omics analysis as a single, on-chip platform, with an ultimate goal of providing seamless sample-to-answer point-of-care liquid biopsy diagnostics.


Silicon Chip Nanofluidics for Extracellular Vesicle Enrichment
Benjamin H. Wunsch, Research Staff Member, T.J. Watson Research Center, IBM, United States of America

Silicon lithography provides a high resolution and scalable route to fabricating nanofluidic structures on a chip. We describe a silicon chip based on the nanoscale deterministic lateral displacement (nanoDLD), for enriching extracellular vesicles from biological fluids based on size. We report on our pilot efforts to use high- throughput extraction of EVs from urine and serum to aid in the identification of cancer-specific biomarkers.


Hsian-Rong TsengKeynote Presentation

NanoVelcro Rare-Cell Assays for Detection and Characterization of Circulating Tumor Cells
Hsian-Rong Tseng, Professor, Crump Institute for Molecular Imaging, California NanoSystems Institute, University of California-Los Angeles, United States of America

Circulating tumor cells (CTCs) are cancer cells shredded from either a primary tumor or a metastatic site and circulate in the blood as the potential cellular origin of metastasis. By detecting and analyzing CTCs, we will be able to noninvasively monitor disease progression in individual cancer patients and obtain insightful information for assessing disease status, thus realizing the concept of “tumor liquid biopsy”. Over the past decade, our research team at UCLA pioneered a unique concept of “NanoVelcro” cell-affinity substrates, in which CTC capture agent-coated nanostructured substrates were utilized to immobilize CTCs with remarkable efficiency. Five generations of NanoVelcro CTC assays have been developed over the past decade for a variety of clinical utilities, including CTC enumeration for prognosis and staging, single-CTC mutational analysis for tracking tumor origin, and CTC-based molecular analysis for treatment monitoring.  In this presentation, I will summarize the development of the new generations of NanoVelcro CTC assays and the clinical applications of these new diagnostic devices.


Coffee Break and Networking in the Exhibit Hall


Exosome Engineering for Delivery of Cytosolic Proteins: Principles and Therapeutic Applications
Chulhee Choi, Professor and Chair, BioMedical Imaging Center, Korea Advanced Institute of Science and Technology (KAIST), President, Cellex Life Sciences, Korea South

Our group has recently developed an opto-genetically engineered exosome system, named ‘exosomes for protein loading via optically reversible protein–protein interaction” (EXPLOR) that can deliver soluble proteins into the cytosol of target cells via controlled, reversible protein–protein interactions (PPI). By integrating a reversible PPI module controlled by specific wavelength of light with the endogenous process of exosome biogenesis, cargo proteins of our interest can be loaded into newly generated exosomes. Protein-loaded exosomes were shown to significantly increase intracellular levels of cargo proteins and their function in recipient cells in both a time- and dose-dependent manner. In this presentation, I will introduce the basic principles of EXPLOR technology and follow-up studies for therapeutic applications including sepsis.


Dolores Di VizioKeynote Presentation

Biological Functions and Methods of Detection of Large Oncosomes in Cancer
Dolores Di Vizio, Professor, Cedars Sinai Medical Center, United States of America

Extracellular Vesicles (EVs) are important mediators of intercellular communication pathways that lead to tumor progression, and potential sources for discovery of novel cancer biomarkers. Recent studies have shed light on the existence of different populations of cancer-derived EVs. These heterogeneous EV populations exhibit distinct molecular cargo, thus pointing to the possibility that the various EV populations might play diverse roles in cancer and that this does not happen randomly. However, data attributing cancer specific intercellular functions to given populations of EVs are still limited. A deeper functional, biochemical and molecular characterization of the various EV classes might identify more selective clinical markers, and significantly advance our knowledge of the pathogenesis and disease progression of many cancer types. We demonstrated that atypically large EVs can be shed from highly migratory and metastatic cancer cells. These EVs, named large oncosomes, play distinct functions and contain a specific repertoire of molecules that can be used for detection of tumor-derived cargo in plasma.


Networking Lunch in the Exhibit Hall and Poster Viewing

Session Title: Studies on the Biology of Exosomes/EVs in Cancer and Beyond


Lucia LanguinoConference Chair

Exosomes: Novel Opportunities for the Diagnosis and Therapy of Cancer
Lucia Languino, Professor of Cancer Biology, Thomas Jefferson University, United States of America


Paul RobbinsConference Chair

Extracellular Vesicles and Aging
Paul Robbins, Professor, Department of Biochemistry, Molecular Biology, and Biophysics, and the Institute on the Biology of Aging and Metabolism, University of Minnesota Medical School, United States of America


Afternoon Coffee Break in the Exhibit Hall


Extracellular Vesicles Go Nuclear
Aurelio Lorico, Professor of Pathology, Touro University Nevada, United States of America

Molecular mechanisms regulating EV biogenesis, their release, and subsequent uptake by target cells have emerged during the last two decades. How their cargo molecules are selectively delivered to their intracellular sites of action, including the intra-nuclear compartment, is still obscure. This issue is particularly important given that the biogenesis and functionality of EVs are dysregulated under pathological conditions. Recently, we described a novel sub-nuclear compartment which is created by the entry of small GTPase Rab7-containing late endosomes in the nucleoplasmic reticulum. The latter is shaped by superficial and deep nuclear envelope invaginations (NEI) penetrating into the nucleoplasm. Given that late endosomes in NEI has often an elongated appearance and resembles a sword in its scabbard, we proposed to name this dual-structure “spathasome” from Greek/Latin words “spathi/spatha” for sword. This structure appears to act as an intermediate compartment for the delivery of the content of endocytosed EVs (e.g., CD9/CD133 protein complexes and RNA molecules) to the nucleoplasm of their host cell. The NEI-associated late endosomes and nuclear localization of EV-derived proteins were observed in cancer cells and mesenchymal stromal cells in cultures and in breast cancer patient biopsies. A molecular complex, investigated by indirect immunofluorescence, fluorescence resonance energy transfer, immunoisolation techniques and RNA interference, was found to be responsible for the entry of EV cargo into the nucleoplasmic reticulum.


Cell-to-Cell Propagation of Pathogenic Aberrant Dipeptide Repeat Proteins in C9orf72-Linked Amyotrophic Lateral Sclerosis
Davide Trotti, Professor, Scientific Director, Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University, United States of America

Nucleotide repeat expansions (NREs) are prevalent mutations in a multitude of neurodegenerative diseases. Abnormal translation of these repeat regions produces proteins that contribute to the pathogenesis of these diseases. However, the mechanisms and drivers of the aberrant translation are not well understood. Here we analyzed whether different cellular stressors promote these aberrant translations of peptides associated with the G4C2 hexanucleotide expansions in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that activating glutamate receptors or increasing neuronal activity trigger these aberrant translation of  neurotoxic peptides. In addition, we postulate that cell-to-cell transmission of these disease-linked aberrant peptides could be a modality by which toxic insults spread in disease-afflicted CNS areas in ALS and FTD. We are presenting evidence here using in vitro and in vivo approaches that indeed transmission of these aberrantly translated peptides occurs via exosomes and that transfer of injury could happen from the neuron of peptide formation to neighboring neurons but also to neurons connected in neuronal networks.


Customized Circulating Tumor DNA Platform for Cancer Research
Cheng-Ho Jimmy Lin, Chief Scientific Officer, Oncology, Natera, United States of America

We have created a ctDNA assay custom-built for treatment monitoring and minimal residual disease (MRD) assessment. Our methodology identifies 16 unique, clonal, somatic variants individualized to each patient’s tumor, followed by multiplex PCR and ultra-deep sequencing for longitudinal ctDNA analysis of whole blood samples. In this talk, I will be presenting data across four cancer types -  including lung, colorectal, bladder, and breast, and show how determining ctDNA status longitudinally can be important for patient management and decision-making.


Close of Day 2 of the Conference.

Friday, 29 March 2019


Morning Coffee and Breakfast Pastries Served in the Exhibit Hall


Nanodiagnostic Tool for Comprehensive Assessment of Cancer in Blood
Shan Wang, Leland T. Edwards Professor in the School of Engineering, Stanford University, United States of America

Blood borne biomarkers, such as secreted proteins, circulating tumor DNA (ctDNA) and circulating tumor cell (CTC), have garnered much attention as minimally invasive cancer biomarkers for the “liquid biopsy” of tumors over the past decade. In this talk, we will describe three magnetic-nanoparticle-based diagnostic tools that have been used to assess cancer in peripheral blood successfully: 1) Stanford spin-off MagArray Inc. has launched REVEAL, a cancer-specific blood test that may aid clinicians in characterizing indeterminate pulmonary nodules (4-30mm) in current smokers aged 25-85. The REVEAL Score is calculated using an algorithm based on the measurement of 3 clinical factors and 3 blood proteins associated with the presence of lung cancer. The assay is optimized to rule out lung cancer with a negative predictive value (NPV) of = 95%.  2) We have developed sequence-specific capture of hypermethylated or mutated genes of interest from cfDNA for early detection of NSCLC and colorectal cancer (CRC). With downstream analysis of PCR products on giant magnetoresistive (GMR) biosensors and high-resolution melt analysis for a highly multiplexable assay, we have achieved a sensitivity of 0.01% mutant/methylated allele fractions. Our optimized assay has the ability to detect down to 16 pg (~4 genome equivalents) of hypermethylated DNA spiked-in to 3.5 mL of plasma. 3) We have utilized the MagSifter and immunocytochemistry combined with automated image analysis and machine learning techniques (random forest, transfer learning) for the enumeration and diagnosis/prognosis of NSCLC derived CTCs in patient samples, which are well suited for therapy selection and monitoring.


exRNA Biomarkers: Challenges in Methodology
Srimeenakshi Srinivasan, Research Fellow, University of California, San Diego, United States of America

The study of exRNAs and their roles in biological functions and potential biomarkers require robust and reproducible methods for quantification of exRNAs in biofluids, a task that is made more challenging by multiple sources of technical and biological variability. A number of factors including the variety of cells/tissues from which the exRNAs are produced, the low concentrations of exRNAs in the biofluids, the presence nucleases and association with multiple different extracellular compartments impact the reproducibility of exRNA measurements, and are likely a significant reason that the field has encountered difficulties with validation of findings both within and among different research groups. Here we compare various exRNA isolation methods used on standardized samples in multiple laboratories and evaluate their performance using qRT-PCR and small RNA sequencing. The results show that different methods enrich for different subsets of exRNAs depending on their association with extracellular carriers and the reproducibility of each method varies widely. Thus selection of the RNA isolation method is a critical consideration to be taken into account when planning a study to identify exRNA biomarkers.

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