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Unravelling oncogenic defects in feedback control of receptor tyrosine kinases

Final Report Summary - ONCROBUST (Unravelling oncogenic defects in feedback control of receptor tyrosine kinases)

The major goal of the project, OncRobust, has been to uncover the natural richness of feedback regulation of receptor tyrosine kinases, in cancer, by developing in vitro models of normal mammary cells and introducing genetic, disease-mimicry manipulations, including stimulation with growth factors (to mimic autocrine and paracrine loops). Two time domains of feedback regulation have been addressed:
(i) The early (seconds/minutes) domain of post-translational modifications and endocytosis of ligand-receptor complexes. Both phosphorylation/dephosphorylation reactions and ubiquitination/deubiquitination processes were resolved in mammary cells and their relevance to breast cancer was uncovered.
(ii) The late domain, comprising alterations in transcription of coding and non-coding RNAs, as well as mRNA alternative splicing. Both microRNAs and long non-coding RNAs were studied and, as a result, a dense network of functional interactions was uncovered. For example, we identified multiple EGF-inducible lncRNAs in basal-like normal mammary cells and overlaid them with the transcriptomes of over 3,000 breast cancer patients. This led to the identification of several prognostic lncRNAs. Functional analyses of this group uncovered LINC01089 (renamed LncRNA Inhibiting Metastasis; LIMT), a highly conserved lncRNA, which is depleted in basal-like and in HER2-positive breast tumors, and the low expression of which predicts poor patient prognosis.
To exemplify the significance of feedback regulatory loops studied by OncRobust and their relevance to cancer research, one might refer to our observation of a strong negative crosstalk between glucocorticoids and growth factors. The mechanism underlying the ability of glucocorticoids to inhibit growth factor signaling, according to our studies, entails suppression of positive feedback loops and simultaneous triggering of negative feedback loops that normally restrain growth factor signaling. Our studies in mice revealed that the regulation of feedback loops by glucocorticoids translates to circadian control of growth factor signaling. In other words, growth factor signals are suppressed by high glucocorticoids during the active phase (night-time in rodents), while these signals are enhanced during the resting phase. Consistent with this pattern, anti-cancer drug treatment of animals bearing tumors driven by constitutive growth factor signals was more effective if administered during the resting phase of the day, when glucocorticoids are low. These findings support a circadian clock-based paradigm in cancer therapy.