Metastasis is the leading cause of cancer-associated mortality, yet to my knowledge, no clinically approved therapy specifically targets the metastatic process itself. Most therapeutic approaches focus on countering the general progression of primary cancers, without considering the metastatic spread of tumor cells, and sometimes paradoxically inducing them. Metastatic potential (MP) is the initial property of primary tumor cells that defines their propensity to acquire metastatic behavior. Its inhibition represents an unmet therapeutic need. The aim of this thesis was to identify transcriptional and small molecule inhibitors of MP. Two complementary strategies were employed. First, starting from transcriptional analyses of subpopulations from colon cancer population CC14, putative transcriptional inhibitors of high-MP were identified and functionally validated in vitro and in vivo. Second, we carried out metabolomic profiling of low-MP and high-MP subpopulations to identify metabolites capable of restraining high-MP.
Through this integrated approach, we identified VGLL1 as a metastatic suppressor which controls the acquisition of high-MP. Genetic knockout of VGLL1 led to enhanced migration, invasion, and lung metastases from xenograft in vivo, whereas its expression correlated with restrained metastatic behaviour. Mechanistically, we show that VGLL1 interacts with TEAD4, acting as a transcriptional competitor that limits TEAD4-driven pro-metastatic gene expression programs typically associated with YAP/TAZ activity.
In parallel, we uncovered a crucial role for endoplasmic reticulum (ER) stress signaling in modulating MP. The stress-induced transcription factor DDIT3 (CHOP) was found to function as a suppressor of metastasis, while the transcription factor XBP1 exerted the opposite effect, promoting migratory traits. These findings highlight a dual and antagonistic contribution of distinct pathways of the unfolded protein response to the regulation of MP: CHOP restrains and XBP1 facilitates metastatic progression.
Through metabolomic profiling and functional tests, we identified α-Lipoic acid (α-LA) as a safe and bioavailable small molecule with MP suppressing abilities. α-LA treatment markedly reduced the number of migrating cells effectively restraining both pre-existing high-MP and post-chemotherapeutic induced high-MP. Given its favourable pharmacological profile, established clinical safety and use as an oral supplement, α-LA emerges as a promising preventive or adjuvant compound for future studies aimed at limiting metastatic relapse following chemotherapy.
