Colorectal cancer (CRC) is a heterogeneous disease with a complex biology and a wide number of genetic alterations. CRC is second leading cause of cancer death in Europe that affect widely women and men worldwide, this disease counts over 600000 of patients die every year. 5-year survival rate
The 5-year survival rate is related to tumour stage, moving from the 90% for stage I to only the 10% for IV stage. Current CRC treatment consists in surgery, targeted therapy, neoadjuvant radiotherapy and adjuvant chemotherapy.
Nonetheless drug-resistance often occur and is the most important challenge for CRC treatment, thus understanding molecular mechanisms driving resistance is an important asset for drug development.
I hypothesize that the subpopulation of colorectal cancer cells with stemness features, the colorectal cancer stem cells (CR-CSCs), together with an aberrant activation of the Hedgehog-GLI (HH-GLI) pathway are involved in CRC resistance to therapy. This proposal arises from my preliminary studies suggesting that HH-GLI signaling pathway has a role in CR-CSCs maintenance and, in this project, I aim to investigate whether HH-Gli and CR-CSCs are involved in the mechanisms underlying treatment resistance.
Colorectal cancer is one of the most common type of cancer that account over 1 million of new patients every year. The survival is strikingly related to the stage of tumour at the time of diagnosis. Indeed, later stages of CRC are more difficult to treat because of their resistance to drug treatments. Thus, this project aims to put the light on mechanisms that are responsible of drug resistance. HH-GLI signaling involves a wide variety of cellular mechanisms, such as protein trafficking, protein-protein interactions, positive and negative feedback loops and post translational modifications. Most importantly this pathway in physiological condition is involved in embryogenesis and organogenesis orchestrating cell fate, differentiation and reciprocal communicative events between cells and tissues. Unfortunately, it is known that HH-GLI plays also a pivotal role in tumorigenesis and its misactivation in CSCs is related to malignancies in both liquid and solid tumors.
The inability to fully eradicate CSCs is a significant clinical problem and leads to tumour recurrence, therapy resistance and metastatic spread of disease.
In this project I will study the regulation of the ABC-transporters operated by HH-GLI pathway. Understanding the molecular mechanisms that lead the drug resistance is an important issue, for treatment of CRC later stages, thus identifying new molecular targets for the development of more efficient drugs.