Cancer Biology

YAP/TAZ in tissue homeostasis and cancer Duplicate 0

YAP/TAZ in tissue homeostasis and cancer

YAP and TAZ are two transcriptional co-activators originally identified as regulated by the Hippo pathway and later recognized as key effectors of cytoskeletal tension, cell polarity, cell-to-cell contacts and G-protein coupled receptors. As such, YAP/TAZ are emerging as essential genes that are able to integrate chemical and mechanical signals in order to regulate tissue growth during development, regeneration and cancer. In several cancer types, YAP/TAZ activity has been linked to mesenchymal-like features, metastatic potential, chemo-resistance and cancer stem cell properties. We have two major research lines:

Genomic study of YAP function in the control and cell identity. In the liver, activation of YAP supports proficient cell proliferation and triggers de-differentiation of hepatocytes towards a bi-potent progenitor-like state. How YAP may control such a large number of cellular processes is still to be fully understood. To address this, we are conducting a genome-wide studies in vivo. This will provide a genome scale understanding of how YAP controls gene expression and will reveal principles in gene regulation which account for YAP ability to orchestrate development, regeneration and cell reprogramming.

Upstream regulation of YAP/TAZ. While YAP/TAZ are frequently stabilized and activated in cancer, pathways leading to their deregulation are yet to be fully identified. To address this, we recently conducted a genetic screen where we identified novel genes that modulate YAP/TAZ activity. We are investigating these genes to gain insights on mechanisms of YAP/TAZ regulation and to assess their functional relevance in cancer development.

Targeting Myc in cancer

Targeting Myc in cancer

c-Myc (Myc) is an oncogenic transcription factor that, given its essential role in cancer cells, is receiving considerable attention as a therapeutic target. Yet, its biochemical properties hamper its direct inhibition by small molecules. We are circumventing this, by exploiting genetic dependencies in Myc-driven cancers. We are focusing on two aspects:

Therapeutic induction of replicative stress. This research line stems from our early discovery that Myc, while promoting DNA replication, also restrains inherent replicative stress by actively engaging “safeguarding pathways”. This renders Myc-driven tumors liable to undergo deadly replicative stress responses when such mechanisms are disengaged. Based on this rationale, we are conducting genetic screens to identify genes essential for genome stability in Myc over-expressing cells. We are now focusing on transcriptional regulators and on their role in the maintenance of genome stability during DNA replication.

Transcriptional addiction in cancer cells. Oncogenic Myc controls the expression of a thousand transcripts linked to cell cycle regulation and cellular metabolism, thus promoting tumor cells proliferation and fitness. This widespread transcriptional control leads to oncogenic addiction and implies that the selective pharmacological targeting of Myc transcriptional activity would represent an effective avenue to decommission Myc in cancer cells.

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