CARE: Center for Advanced REsearch on lung cancer

Our Research:

CARE, the Center for Advanced Research on lung Cancer, is a FAMRI Center of excellence, established in 2003. Our Center brings together cancer researchers from the Weizmann Institute of Science and the Sheba Medical Center in Israel. The long-term goal of the Center is to elucidate the molecular genetic basis for lung cancer development and provide clues towards better diagnosis, prognosis and therapy of this fatal disease. The member scientists of our Center seek to make substantial progress towards this goal, building upon prior achievements as well as incorporating new developing techniques.

Specifically, the Center seeks to address the following central goals:

The Livneh group seeks to resolve the interplay between error-free and error-prone DNA repair, mutagenesis and apoptosis in lung cancer. This is being addressed by screening for novel genes involved in DNA damage tolerance, and by using novel assays for various DNA repair activities along the path of carcinogenesis in a human cell culture model system for lung carcinogenesis and in human tissue specimens. These studies are expected to lay the foundation for the integration of DNA repair, mutagenesis, and apoptosis biomarkers, as a novel tool in risk assessment and early detection of lung cancer.

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The Wallach group is exploring in depth the intracellular and extracellular mechanisms that participate in the regulation of cell function, inflammation, and immune regulation by receptors of the TNF/NGF family. This group systemically studies the functional consequences of caspase-8 deficiency, and has already obtained new insights into the mechanisms by which this deficiency facilitates tumor development in the lung and in other tissues. They now intend to further extend our knowledge of these mechanisms and explore the impact of additional molecular determinants of signaling regulation by receptors of the TNF/NGF family on inflammation and cancer in the lung.

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The Alon group is developing a mouse model for COPD to study the involvement of endothelial NF-κB signaling in leukocyte trafficking to smoke-exposed lungs and its role in disease onset. It is anticipated that this study will lead to an understanding of the nature that underlies the involvement and function of different subsets of effector and regulatory lymphocytes in disease progression, and the development new immunomodulatory strategies to attenuate COPD.

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The Kimchi group is seeking to deepen the understanding of the various molecular mechanisms underlying programmed cell death and the involvement of their deregulation in lung cancer development. Specifically, they search for genes and pathways that participate in the less studied types of cell death including the autophagic and programmed necrotic modules, and discover the molecular mechanisms that cause a switch from one cell death modality to the other. This project leans on a tight collaboration with the other partners who contribute their expertise and knowledge both in basic molecular biology and in medical science. In the long run, they aim to model the programmed cell death system and be able to predict the outcome of cell death in response to a given drug, thus enabling a better-guided choice of therapy regimens.

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The involvement of p53 in tumor-stroma interactions in lung cancer is addressed jointly by the Oren and Rotter groups. This entails setting up co-culture models of human lung-derived fibroblasts and lung cancer cells, and monitoring the impact of fibroblast p53 on the properties of the adjacent tumor cells, as well as that of the tumor cells on p53 activity within the stromal cells. The involvement of microRNAs in lung cancer is being studied through identification of miRNAs whose expression is suppressed in lung tumor cells, with particular emphasis on p53-regulated miRNAs.

The team will also study the impact of p53 mutations on the biological properties of lung cancer cells in culture as well as in animal models. Relevance to human cancer will be addressed through the analysis of human lung cancer specimens, done in collaboration with the clinical members of the FAMRI Center. The Rotter group has previously established a unique in vitro model to study lung cancer development and obtained genomic information that led to the identification and characterization of specific gene signatures corresponding to early and late steps of lung cancer development. They are now examining the prognostic and diagnostic value of these in vitro-derived gene signatures when applied to actual human lung cancer cases.

Epigenetic alterations modify gene expression without affecting the primary DNA sequence. In this context, A-to-I RNA editing emerges as a new type of epigenetic regulatory mechanism. The Rechavi group showed that various tumors, including lung cancer, are characterized by global hypoediting when compared to paired normal tissues. In addition, both hyper and hypo editing of specific gene transcripts are found in cancer. They now are studying the underlying mechanisms and their consequences, in order to attain a better understanding of the role of RNA editing in normal and pathological conditions and an insight into new mechanisms of gene expression control.

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It is expected that by providing a more comprehensive view of the molecular and genetic basis that drive lung cancer, the knowledge accumulated through the complementary projects of the center may lead to the development of new diagnostic tools and lay the foundation to the development of novel knowledge-based therapeutic approaches.