MET is a crucial oncogene that encodes a protein regulating cell growth, survival, and migration. While it is well known that MET is overexpressed in the vast majority of cancers—even in the absence of genetic alterations—driving cancer progression and therapy resistance, the mechanisms underlying this upregulation have remained unclear.

To address this question, a team of researchers at IFOM, led by Prof. Paolo M. Comoglio and Dr. Dogus M. Altintas, in collaboration with Prof. Marco Foiani and Prof. Carla Boccaccio, discovered that the hostile tumour microenvironment unleashed MET overexpression. Their findings, recently published in The EMBO Journal, uncovered a novel molecular mechanism linking the cellular stress response to the overexpression of MET.

“Cellular stress arises when cells encounter adverse conditions such as nutrient deprivation, hypoxia (low oxygen levels), or chemotherapy exposure,” explains Dr Altintas. “In response, cells activate the Integrated Stress Response (ISR), an evolutionarily conserved defence mechanism designed to regulate protein synthesis and promote survival under challenging microenvironmental conditions. Given that cancer cells thrive in such hostile environments, our findings are particularly intriguing: cancer cells exploit the ISR to enhance MET expression, enabling them to adapt and transform these stressful conditions to their advantage.”

The study revealed that the ISR enhances the production of MET protein. Specifically, certain elements within MET’s mRNA act as molecular switches, increasing protein synthesis in response to stress. This upregulation enables cancer cells to survive, migrate, and resist oncological treatments.

The research employed advanced techniques, including CRISPR-based genetic models, to pinpoint the precise molecular elements in MET’s mRNA that respond to ISR activation. The team demonstrated that ISR-mediated MET upregulation provides a survival advantage under harsh microenvironmental conditions.

"Furthermore," adds Dr Altintas, "we demonstrated that inhibiting the ISR reduces MET protein levels, impairing cancer cell survival, migration, and treatment resistance. These findings suggest that targeting the ISR could represent a promising strategy for enhancing cancer therapy efficacy."

This work provides new insights into the intricate interplay between cancer cells and their microenvironment, marking a significant advancement in the field of cancer biology. As a next step, the team aims to investigate the ISR/MET pathway as a potential therapeutic vulnerability, offering new avenues to counteract cancer progression. 

This achievement aligns with IFOM’s mission to advance innovative cancer solutions. It was made possible by the generous support of AIRC (Associazione Italiana per la Ricerca sul Cancro, IG-19 Grant to Prof. Paolo M. Comoglio, Number 23820) and the Fondazione Umberto Veronesi (Post-doctoral Fellowship to Dr. Dogus M. Altintas, Number 4691).

Read more: doi.org/10.1038/s44318-024-00338-4 Cerqua et al. 2025