Investigating lineage plasticity and EMT through the ZEB1-GRHL2 axis in DSRCT
Desmoplastic small round cell tumors (DSRCTs) are rare, often incurable abdominal sarcomas that present in pediatric and young adolescent populations. It arises from a translocation, resulting in a fusion protein (FP). However, no current molecular targets against the FP exist. Although many patients respond to VAI-based chemotherapeutics, most will relapse within two years, and less than 20% of patients survive beyond five years.
Critically, DSRCT presents with multi-lineage expression with cells expressing markers from mesenchymal, epithelial, neural, and muscle lineages. Henon et al. showed that DSRCT patients with a higher epithelial signature have a better prognosis. This suggests that differentiation therapy may be a potential treatment to overcome the lack of treatment against the FP. Differentiation therapy has been successful in acute promyelocytic leukemia by all-trans retinoic acid and acute myeloid leukemia by menin inhibition leading to induction of differentiation and tumor growth arrest.
In our data, ZEB1 and GHRL2, two transcription factors responsible for epithelial-to-mesenchymal transition, were linked to the control of epithelial signatures and may have a role in lineage plasticity in DSRCT. ZEB1 decreased epithelial genes, and GRHL2 increased epithelial genes across different carcinomas, but this has not been confirmed in DSRCT. We hypothesize that ZEB1 acts as a negative regulator of epithelial signature, while GRHL2 acts as a positive regulator. Further, we hypothesize that a stronger epithelial signature may induce chemosensitivity.
This proposal focuses on understanding the role of ZEB1 and GHRL2 in DSRCT and if epithelial phenotype confers chemosensitivity. We will determine if ZEB1 and GRHL2 affect epithelial signatures in DSRCT by transcriptomic analyses. Next, we will evaluate how these two transcription factors orchestrate chromatin accessibility to control lineage plasticity and epithelial phenotype in DSRCT. If there is an induction of epithelial phenotype either by repression of ZEB1 or activation of GRHl2, we will study the downstream response to common chemotherapeutics used for DSRCT. These aims will help us better understand this poorly understood disease, combat therapeutic resistance in DSRCT upon recurrence, and improve patient survival.