Revealing molecular pathways for cancer cell fitness through a genetic screen of the cancer translatome.

The major cap-binding protein eukaryotic translation initiation factor 4E (eIF4E), an ancient protein required for translation of all eukaryotic genomes, is a surprising yet potent oncogenic driver. The genetic interactions that maintain the oncogenic activity of this key translation factor remain unknown. In this study, we carry out a genome-wide CRISPRi screen wherein we identify more than 600 genetic interactions that sustain eIF4E oncogenic activity. Our data show that eIF4E controls the translation of Tfeb, a key executer of the autophagy response. This autophagy survival response is triggered by mitochondrial proteotoxic stress, which allows cancer cell survival. Our screen also reveals a functional interaction between eIF4E and a single anti-apoptotic factor, Bcl-xL, in tumor growth. Furthermore, we show that eIF4E and the exon-junction complex (EJC), which is involved in many steps of RNA metabolism, interact to control the migratory properties of cancer cells. Overall, we uncover several cancer-specific vulnerabilities that provide further resolution of the cancer translatome.

Clonal ZEB1-Driven Mesenchymal Transition Promotes Targetable Oncologic Antiangiogenic Therapy Resistance.

Glioblastoma (GBM) responses to bevacizumab are invariably transient with acquired resistance. We profiled paired patient specimens and bevacizumab-resistant xenograft models pre- and post-resistance toward the primary goal of identifying regulators whose targeting could prolong the therapeutic window, and the secondary goal of identifying biomarkers of therapeutic window closure. Bevacizumab-resistant patient specimens and xenografts exhibited decreased vessel density and increased hypoxia versus pre-resistance, suggesting that resistance occurs despite effective therapeutic devascularization. Microarray analysis revealed upregulated mesenchymal genes in resistant tumors correlating with bevacizumab treatment duration and causing three changes enabling resistant tumor growth in hypoxia. First, perivascular invasiveness along remaining blood vessels, which co-opts vessels in a VEGF-independent and neoangiogenesis-independent manner, was upregulated in novel biomimetic 3D bioengineered platforms modeling the bevacizumab-resistant microenvironment. Second, tumor-initiating stem cells housed in the perivascular niche close to remaining blood vessels were enriched. Third, metabolic reprogramming assessed through real-time bioenergetic measurement and metabolomics upregulated glycolysis and suppressed oxidative phosphorylation. Single-cell sequencing of bevacizumab-resistant patient GBMs confirmed upregulated mesenchymal genes, particularly glycoprotein YKL-40 and transcription factor ZEB1, in later clones, implicating these changes as treatment-induced. Serum YKL-40 was elevated in bevacizumab-resistant versus bevacizumab-naïve patients. CRISPR and pharmacologic targeting of ZEB1 with honokiol reversed the mesenchymal gene expression and associated stem cell, invasion, and metabolic changes defining resistance. Honokiol caused greater cell death in bevacizumab-resistant than bevacizumab-responsive tumor cells, with surviving cells losing mesenchymal morphology. Employing YKL-40 as a resistance biomarker and ZEB1 as a target to prevent resistance could fulfill the promise of antiangiogenic therapy. SIGNIFICANCE: Bevacizumab resistance in GBM is associated with mesenchymal/glycolytic shifts involving YKL-40 and ZEB1. Targeting ZEB1 reduces bevacizumab-resistant GBM phenotypes. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/7/1498/F1.large.jpg.

Recommendations for the design, implementation and evaluation of social support in online communities, networks, and groups.

A new model of health care is emerging in which individuals can take charge of their health by connecting to online communities and social networks for personalized support and collective knowledge. Web 2.0 technologies expand the traditional notion of online support groups into a broad and evolving range of informational, emotional, as well as community-based concepts of support. In order to apply these technologies to patient-centered care, it is necessary to incorporate more inclusive conceptual frameworks of social support and community-based research methodologies. This paper introduces a conceptualization of online social support, reviews current challenges in online support research, and outlines six recommendations for the design, evaluation, and implementation of social support in online communities, networks, and groups. The six recommendations are illustrated by CanConnect, an online community for cancer survivors in middle Tennessee. These recommendations address the interdependencies between online and real-world support and emphasize an inclusive framework of interpersonal and community-based support. The applications of these six recommendations are illustrated through a discussion of online support for cancer survivors.

Building a shared vision for an online cancer survivorship community.

In order to achieve comprehensive, closed-loop care for cancer survivors, new strategies are needed to bring together patients, providers, and support services in local communities. To address this challenge, an online community for cancer survivorship was envisioned and designed collaboratively by cancer survivors, family members, community professionals, and informatics researchers in middle Tennessee. The vision developed by the community members serves as a foundation for medical informatics systems to build capacity in local communities to improve cancer care and social support. Using ecological systems theory and social capital as theoretical frameworks, key themes are identified for the future of communication and collaboration in cancer survivorship.

Synthesizing community wisdom: A model for sharing cancer-related resources through social networking and collaborative partnerships.

Despite the availability of community-based support services, cancer patients and survivors are not aware of many of these resources. Without access to community programs, cancer survivors are at risk for lower quality of care and lower quality of life. At the same time, non-profit community organizations lack access to advanced consumer informatics applications to effectively promote awareness of their services. In addition to the current models of print and online resource guides, new community-driven informatics approaches are needed to achieve the goal of comprehensive care for cancer survivors. We present the formulation of a novel model for synthesizing a local communitys collective wisdom of cancer-related resources through a combination of online social networking technologies and real-world collaborative partnerships. This approach can improve awareness of essential, but underutilized community resources.

Blogs, wikis, and discussion forums: attributes and implications for clinical information systems.

Informaticians increasingly view clinical information systems as asynchronous communication systems instead of data processing tools. Outside of health care, popular web technologies like blogs, wikis, and discussion forums have proven to be platforms for effective asynchronous communication. These popular technologies have implications for improving the coordination of clinical care and social support. In order to appropriately evaluate these webbased tools for use in clinical information systems, it will be essential for the informatics community to formally identify the distinguishing attributes of these communication methodologies. The authors propose seven interpersonal and informational attributes to compare and contrast the purposes of blogs, wikis, and discussion forums. This attribute-based approach to analyzing emerging web technologies will lead to a better understanding of the design choices involved in web-based information systems. Two case studies demonstrate how informatics researchers and developers can consider these attributes in the design and evaluation of clinical information systems.

Challenges of social networking technologies for cancer care and social support.

Online communities and web-based messaging tools are valuable tools for cancer care and social support. Developers of these systems should be prepared to address the challenges of including social networking and emerging web technologies in clinical and consumer informatics systems. Experiences and challenges from a pilot test of a web-based messaging and social networking system for cancer patients will be discussed, and recommendations are offered for system design and adoption.

Interface design for patient-caregiver integrated network.

Communication surrounding cancer treatment involves clinicians, patients, families, friends and others affected by the illness. The aim of this work is to create an informatics system that can support the communication needs of cancer patients and their formal and informal caregivers. Based on interviews with patients and family/friend caregivers, a prototype web-based communication system was created with an emphasis on the interpersonal relationships between patients, families, and clinicians.

Online communication and support for cancer patients: a relationship-centric design framework.

Dealing with a cancer diagnosis and cancer treatment involves communication among clinicians, patients, families, friends and others affected by the illness. The hypothesis of this research is that an informatics system can effectively support the communication needs of cancer patients and their informal caregivers. Two design frameworks for online cancer communication are defined and compared. One is centered primarily on the users' interpersonal relationships, and the other is centered on the clinical data and cancer information. Five types of clinical and supportive relationships were identified and supported by in-depth interviews with cancer patients and their informal caregivers. Focusing the design of an online cancer communication system around the interpersonal relationships of patients and families may be an important step towards designing more effective paradigms for online cancer care and support.