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Pro-tumorigenic effects of TGFb - elucidation of mechanisms and development of selective inhibitors

Periodic Reporting for period 1 - SelectiveTGFb-inhib (Pro-tumorigenic effects of TGFb - elucidation of mechanisms and development of selective inhibitors)

Reporting period: 2018-11-01 to 2020-04-30

The multifunctional cytokine transforming growth factor beta (TGFbeta) has important functions during embryonal development and in tissue homeostasis. However, in cancer TGFbeta is often overexpressed and has both tumor suppressive (induction of growth arrest and apoptosis) and tumor promoting(stimulation of epithelial-mesenchymal transition (EMT) of tumor cells, and stimulation of angiogenesis and inhibition of the immune system) activities. Our aim is to elucidate the mechanisms for the pro-tumorigenic effects of TGFbeta and to develop selective inhibitors which can be used to suppress tumor cell invasiveness and metastasis in animal models, and later on for the treatment of patients with malignancies. We think that it is important to identify selective inhibitors, which do not affect the tumor suppressive effects of TGFbeta, since complete suppression of TGFbeta activity may give severe side affects and even promote tumorigenesis.
During the first 18 months, the cooperation between TGFbeta-induced Smad signaling and transcription factors of the AP-1 family, and its role in tumorigenesis, has been elucidated. The mechanism whereby TGFbeta activates the pro-tumorigenic Src signaling pathways and its role in TGFbeta-induced tumor cell migration has also been determined. In addition, we have determined how the long non-coding RNA TGFB2-AS controls TGFbeta signaling. We have also inserted tags in the genes encoding the type I and type II TGFbeta receptors using cRISPR-Cas9 technique and are now in the process of identifying interactors of the receptors as well as posttranslational modifications of the receptors, with the aim of determining how these contribute to the control of TGFbeta signaling.
We expect to have a clear picture of the mechanisms whereby TGFbeta induces its pro-tumorigenic effects, and to have developed ways of selectively inhibiting such pathways, leaving the tumor suppressive signaling pathways unperturbed.
Tumor suppressive and tumor promoting signaling pathways induced by TGFbeta