Revelar o invisível: uma estratégia de combate à dormência no cancro gástrico

Our main GOAL is to advance a proof-of-concept of a dormancy signature associated with E-cadherin mediated gastric cancer. We will address the HYPOTHESIS that the microenvironment imposes a selective pressure to E-cadherin defective cancer cells, forcing their adaptation through cell cycle arrest and undifferentiated morphology, thus enabling their camouflage and silent propagation. This will have a CLINICAL impact by detecting early lesions that are prone to progress and improving our capacity to tackle cancer in a timely manner. The APPLICABILITY of our findings is also reflected on the development of innovative pharmacological approaches, either to eliminate vulnerable dormant cancer cells or to sustain cancer cells in a controlled dormant condition. To scrutinize our hypothesis, we will pursue the following SPECIFIC objectives: 1. Determine the effect of the ECM scaffold in the modulation of cell dormancy mediated by E-cadherin dysfunction using artificial and native matrices. In contrast to previous strategies which dismiss the non-cellular ECM component, we will be pioneers in dissecting how physical constrains and biochemical composition of the surrounding niche dictate cancer cell behavior. Of note, our project crosses the frontiers of knowledge, by intercepting Clinical Research with Engineering and Technological Sciences. In this scope, we will deconstruct morphological aspects of dormant cells that will be explored in innovative Artificial Intelligence-based frameworks to identify patients at risk of cancer progression. 2. Define the molecular profile of dormant cancer cells with loss of cell-cell adhesion through high-dimensional single-cell technologies. At this stage, it is crucial to reveal signaling programs underlying quiescent states of E-cadherin dysfunctional cells, while maintaining their three-dimensional (3D) context and spatial interactions with the ECM. For that, we will take advantage of powerful methods that combine the accuracy of mass cytrometry with high multiplexing imaging platforms, which will also consider functional states of proteins. 3. Establish a correlation between expression of dormancy hallmarks and gastric cancer progression in patient samples. It is our commitment to develop research programs that translate experimental findings into clinical practice. As members of the International Gastric Cancer Linkage Consortium, we have a unique opportunity to study specific E-cadherin mutations in vitro and in vivo, and validate the results in patient samples. By unraveling the intricacies of cancer latency, we will move one step closer to alternative treatment approaches that may spare patients from the drastic step of prophylactic total gastrectomy. 4. Delineate a pharmacological strategy to target dormant cancer cells in vivo. Our ultimate objective is focused on targeting cells that hold a unique capacity to grow and thrive under extreme environments. Indeed, for patients with early gastric cancer, surgery remains the primary line of treatment, while patients with advanced disease rely on chemotherapy alone or combined with targeted and immunotherapies. However, conventional treatment confers a median overall survival of around 12 months, reflecting high toxicity and drug resistance associated with HIDDEN malignant cells. With this project, we expect to make a remarkable progress in cancer treatment, devising ways to shape cells towards a continuous dormant state or into a vulnerable phenotype.