Dottorato in MEDICINA MOLECOLARE

Titolo della tesi: A Novel Role of Jag1-ICD in Sustaining Colorectal Cancer Progression and Chemoresistance

The colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. It develops through a series of known histopathological changes resulting from specific mutations in oncogenes and tumour suppressor genes, such as Wnt/β-catenin, KRAS, TP53, TGFβ, BRAF and Notch. Emerging data suggest that degenerated activations of Notch signalling contribute to the CRC onset and malignancy. Moreover, it has been demonstrated that the specific Notch ligand Jagged1 is aberrantly expressed in about 50% of human CRC and correlates with poor prognosis and recurrence. It is well described that Jagged1 is processed in the same manner of Notch receptors. In fact, Jagged1 is a substrate of the catalytic activity of ADAM17 that allows the shedding of Jag1-ECD ectodomain, necessary for the subsequent cleavage mediated by the PS/γ–secretase complex. These events end in the generation of the soluble intracellular fragments (Jag1-ICD) able to induce the transactivation of several target genes involved in tumorigenesis. The emerging idea is that Jag-ICD is able to provide its own contribution in tumour biology. In fact, it sustains the malignancies features of several tumors, such as leukemia, ovarian, cervical, breast and colon cancer. We provide new evidence that Jag1-ICD is a novel oncogene in CRC disease. The data presented in this thesis highlight a novel role for Jagged1 in colorectal cancer biology that may go beyond its effect on canonical Notch activation. We suggest that Jag1-ICD may behave as an oncogenic driver able to sustain tumor pathogenesis and to confer chemoresistance both in vitro and in vivo, through a noncanonical mechanism. Additionally, we explore the role of Jag1-ICD in chemoresistance mediated by γ-secretase inhibitor (GSIs).   Several GSIs have been developed to inhibit γ-secretase cleavage in human since they are therapeutical target in Alzheimer’s disease (AD), but their use has been also extended to cancer on the premise that they inhibit Notch activation. However, treatments with GSIs are still highly controversial due to their lack of specific action and thus the rationale to better characterize their use in therapy is strong. These finding could be useful to identify new therapeutical approaches in the colorectal cancer treatment and could provide to the scientific community novel information about a successful use of GSIs.