Breakthroughs at IOR in the search for anti-metastatic therapies

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Breakthroughs at IOR in the search for anti-metastatic therapies

The Molecular Oncology research group at USI has identified, through the use of bioinformatics and artificial intelligence, a new way to selectively identify and kill a specific type of cells involved in metastasis dissemination.

The problem

Metastasis, the spreading of tumor cells from a primary site to their progressive outgrowth at a distant organ, is ultimately what kills almost 90% patients with cancer. Yet, we are only at the cusp of our understanding of the biology of metastasis. So far little is known about why and how cancer cells migrate and invade away from the primary tumor. Nowadays, the clinic lacks an effective therapy to prevent this detrimental stage. Martina Troiani and Manuel Colucci two Ph.D. students in the team of Prof. Andrea Alimonti , MD at the Institute of Oncology Research (IOR, affiliated to USI and member of Bios+) have therefore identified a novel therapy to impairs metastasis formation.

Recently, Prof. Andrea Alimonti’s team has demonstrated that standard chemotherapies drive senescence. Senescence is a biological process where the cells do not proliferate, even if they are still metabolically active. Senescence limits tumor progression by arresting cancer cells and promoting immune surveillance. However, after an initial beneficial phase, persistent senescent tumor cells can promote tumor growth, migration, and even metastasis.

Martina Troiani and Manuel Colucci, by using bioinformatics and artificial intelligence, have identified a class of compounds that selectively eliminates senescent tumors cells (Senolytic Therapy) and impair metastatic dissemination. The results of this research were published in April 2022. ’022 -29824-1#Sec36 https://doi.org/10.1038/s41467’022 -29824-1

Background

Most common chemo and radiotherapy have secondary effects triggering a senescent response. Senescent tumor cells that persist in the tumor microenvironment remain metabolically active, possess a peculiar secretory phenotype, and if not removed from the tumor, can promote tumor proliferation and metastatic dissemination to distant organs. Therefore, removing those senescent tumor cells has emerged as a key therapeutic approach. By using Single-cell transcriptomic, the scientists have developed for the first time a bioinformatic tool to describe and identify novel vulnerabilities to fight cancer.

The discovery

The scientists at the IOR have developed a novel bioinformatic tool to identify and describe senescent tumor cells called Senescence Index Tool, SIT. These findings created an unprecedented opportunity to describe senescent cancer cells. In fact, for the first time, the researchers have described senescent tumor cells as a highly heterogeneous population that ultimately relies on the same pro-survival gene: MCL-1. Nowadays, the gold standard in senolytic therapy targets BCL-2 (Navitoclax). However, about 50% of senescent cells do not rely on this factor but survive thanks to MCL-1.

Therefore, Martina Troiani and Manuel Colucci, Ph.D. students co-first authors of this research, pharmacologically and genetically inhibit MCL-1 upon standard chemotherapy. The treatment results in growth inhibition and, more importantly, a significant decrease in metastatic formation.

This big discovery could ameliorate the current chemotherapy done in the Molecular Oncology department, led by Prof. Andrea Alimonti, MD. "Cells subjected to elevated stress such as treatment with anti-cancer therapies can make two choices: either die or remain suspended in between life and death, a condition known as cellular senescence. Thanks to the use of bioinformatic and machine learning algorithms, we have identified a novel target to eliminate senescent tumor cells and, therefore, prevent metastatic dissemination."

Outlook

The possibility to identify senescent tumor cells in terms of single cells and as a heterogeneous population will shed light on novel, precise therapy to ultimately ameliorate the potency of current chemotherapy. This idea was the rationale behind tailoring a bioinformatic approach to spot and describe senescent tumor cells. Andrea Alimonti laboratory has already paved the road to the tight connection between senescence and metastatic dissemination (Guccini et al, Cancer Cell 2021). Thanks to the SIT, we can deepen the knowledge, develop highly precise senolytic therapy to ameliorate oncological research, and could be an important starting point to fight aging and age-related diseases, therefore ultimately improving the lives of both oncological and elderly patients.


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