Dias group
Therapeutic overactivation of mitogenic signaling
Our group studies cancer through the lens of evolutionary fitness. We investigate how Therapeutic OVERactivation of mitogenic signaling (TOVER) can turn oncogenic activity into a liability, reducing cancer cell fitness and viability. This rationale is fundamentally different from conventional strategies that focus on inhibiting oncogenic pathways, instead exploiting their excessive activation for therapeutic benefit. Our goal is to define how this approach can be applied in pediatric cancers to achieve effective treatments while minimizing long-term toxicity.
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Matheus Dos Santos Dias
Broad research topic
Cancer cells rely on elevated oncogenic signaling to sustain growth, but this comes at a cost. Increased signaling places cells under constant stress, requiring activation of multiple stress-response pathways to maintain viability. While this balance supports the malignant phenotype, it also defines cellular fitness, and creates vulnerabilities. Pushing signaling beyond its optimal range can overwhelm these compensatory mechanisms and compromise survival.
Our work is based on the concept of Therapeutic OVERactivation of oncogenic signaling (TOVER), in which this intrinsic vulnerability is deliberately exploited. By further increasing signaling output, we aim to overstress cancer cells, reduce their fitness, and enhance their sensitivity to therapies targeting stress response pathways.
A key question is whether such an approach would also affect normal tissues. However, in contrast to cancer cells, non-malignant cells retain functional feedback mechanisms that buffer excessive signaling and maintain homeostasis. Moreover, normal cells remain dependent on external growth cues, whereas cancer cells often operate closer to the limits of tolerable signaling. These differences suggest that TOVER may selectively reduce the fitness of cancer cells while preserving normal tissue function, a critical consideration in pediatric cancers where long-term toxicities must be avoided.
This framework also reflects a broader view of cancer as a context-dependent evolutionary process. The fitness advantage conferred by oncogenic alterations depends on the tissue environment and the level of signaling activity. Conditions that disrupt tissue homeostasis can increase the benefit of oncogenic mutations. Conversely, excessive signaling may shift this balance, turning a growth advantage into a liability. TOVER builds on this principle by increasing the cost of oncogenic alterations and reducing their selective advantage.
““Cancer cells depend on abnormal growth signals and control systems that do not work as they should. By increasing these signals beyond their limits, we can turn an advantage into a weakness and open new possibilities for cancer treatment.””
Matheus Dos Santos Dias
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