Colorectal Cancer: Identification of a New Therapeutic Target

A study recently conducted by the Sapienza Department of Molecular Medicine in close collaboration with the Italian Institute of Technology (IIT) has identified a new molecular mechanism that can affect the development, progression and chemoresistance of colorectal cancer. The results of the study have been published on Cancer Research

The Notch Signalling Pathway is an important regulator of development, proliferation and differentiation processes in various tissues throughout our organism. Its alteration can lead to the insurgence of many different tumours, including colorectal cancer (CRC), a tumour with a high mortality rate worldwide. Recently, the scientific community has identified the existence of a new signalling pathway mediated by the ligand Jagged1, a molecule that induces biological functions independently from the Notch Receptor in a variety of tumoral contexts. Understanding the molecular mechanisms that regulate this signalling pathway and studying its involvement in the development of tumours is a key point for the development of new therapeutic approaches.

In particular, the research group guided by Diana Bellavia, in collaboration with Isabella Screpanti from the Department of Molecular Medicine and Maria Pelullo at the Centre for Life Nano Science of the Italian Institute of Technology (CLNS@Sapienza, IIT Roma) - thanks to co-financing by MIUR, AIRC and Sapienza - studied the role of Jagged1 in the development of colorectal cancer, identifying this molecule as an important therapeutic target to cure the tumour. The results of the study have been published on Cancer Research.

In greater detail, the research group demonstrated, through the use of experimental in vitro and in vivo models, the existence of a retrograde signalling in colorectal tumours characterized by specific genetic mutations. In this cellular context, Jag1-ICD is capable of regulating the proliferative events of the transformed cells, controlling the tumoral progression by favouring invasive and metastasis-forming processes and inducing chemoresistance against the main anti-tumour drugs in use today.

“In this study,” explains Sapienza Professor Diana Bellavia, “we added a new element to the function of Jag1-ICD in supporting the development and diffusion of colorectal cancer, demonstrating that by inhibiting the operation of this protein we can block the growth of tumoral cells and reduce both its invasiveness and chemoresistance, making the tumour cells more sensitive to anti-tumoral drugs.”

This new discovery allows us to identify Jag1-ICD as a new therapeutic target for the treatment of colorectal cancer and opens the road to new custom-tailored therapies.

References:

Kras/ADAM17-dependent Jag1-ICD reverse signalling sustains colorectal cancer progression and chemoresistance - Pelullo, M. Nardozza, F. Zema, S. Quaranta, R. Nicoletti, C. Besharat, Z. M. Felli, M. P. Cerbelli, B. d’Amati, G. Palermo, R. Capalbo, C. Talora, C. Di Marcotullio, L. Giannini, G. Checquolo, S. Screpanti, I. Bellavia, D. Cancer Research, (10 September 2019) DOI: 10.1158/0008-5472.CAN-19-0145