Colorectal cancer (CRC) is a leading cause of cancer-related death in western countries. TGFb are a family of signaling molecules delivering crucial tumor-suppressive signals to different cell types. Lack of TGFb induced cytostasis is a hallmark of cancer, and mutations of key transducers of TGFb in Colorectal cancer (CRC), albeit found only in a subset of tumors, indicates a leading role for these signals in limiting tumor progression. In our lab we identified Ectodermin, a molecule that antagonizes TGFb responses by controlling Smad4 ubiquitination. Interestingly, Ectodermin is expressed in the normal and neoplastic human colon, and it plays a causative role in limiting the anti-mitogenic effects of Smad4 in tumor cells. Our preliminary data point at a fundamental role of Ectodermin in vivo as Smad4/TGF-b inhibitor, both during embryonic development and for adult tissue homeostasis. We propose here to exploit the genetic inactivation of Ectodermin in models of CRC progression to test if raising cellular responsiveness to tumor-suppressive signals (i.e. by disabling a key endogenous inhibitor) can oppose tumor formation/progression. Moreover, as part of the previous Marie Curie Fellowship to the applicant, we recently characterized the function of a novel Smad4 deubiquitinating enzyme (SADE), required for TGFb signaling, opposing Ectodermin functions in multiple cellular and development systems. We propose here to test the potential role of SADE as tumor-suppressor in CRC and to develop genetic tools to study the function of SADE in mammalian tissue homeostasis. This approach has the potential to generate novel genetic models of CRC, and to open the way for new avenues of therapeutic intervention targeting these novel enzymatic ‘druggable’ targets.