Filippo G. Giancotti, MD, PhD

The Giancotti laboratory has been at the forefront of major discoveries in the area of cell adhesion, cell signaling, and tumor progression to malignancy. We have elucidated the signaling mechanisms that enable tissue cells to respond to extracellular matrices of different composition by migrating and proliferating or withdrawing from the cell cycle and differentiating. In addition to elucidating integrin signaling pathways and defining their roles in tumorigenesis, we have discovered that the tumor suppressor NF2 mediates contact inhibition of proliferation and studied its connection to the Hippo-YAP pathway in mammalian cells. A major component of our current research program focuses on metastatic dissemination and colonization. We have identified oncogenic alterations that drive the Epithelial-to-Mesenchymal Transformation and, hence, dissemination in breast and prostate cancer. Furthermore, we have developed powerful gain-of-function genetic screens that enable the identification of mediators of metastatic reactivation. By using this approach, we have begun to identify the major signaling pathways that trigger metastatic reactivation. Our most recent findings indicate that the metastasis-initiating cells undergo dormancy and reactivation in response to the activation of signaling pathways and transcriptional circuits that govern these processes in adult stem cells, including niche signals organized by the extracellular matrix and stromal cells. We are currently studying the origin of metastatic cells and the molecular basis of dormancy and reactivation. Our research program spans several cancer types - including breast, prostate and pancreatic cancer - and multiple target organs, and it aims to not only shed light on the biology of the most mysterious phase of metastasis but also to bring to the clinic an entire new class of therapeutics.

Questions:

·    What is the origin of metastatic cells?

·    Which tumor cell-intrinsic mechanisms govern metastatic dormancy and reactivation?

·    What is the composition, architecture, and network of intercellular signals in dormant and metastatic niches?

·    What is the role of immune and non-immune niche components?

·    How do metastatic cells evade the immune system and resist stress?

·    Which mechanisms link therapy resistance to metastasis?

Toolbox:

·    Gain-of-function and loss-of-function genetic screens in mice.

·    Syngeneic transplantation models of dormancy and inducible reactivation (iREACT mice).

·    Somatic cell genetics, biochemistry, and molecular biology.

·    Metastatic niche labeling and single cell RNA-seq and ATAC-seq.

·    Isolation of tissue progenitors, propagation as organoids, and direct transformation with combinations of oncogenic drivers.

·    Bioinformatic analysis of patient datasets.