Cell State Chaos Underpins the Evolution of SMARCA4-Deficient Dedifferentiated Endometrial Cancer

Dedifferentiated endometrial carcinoma (DDEC) is a histologically unique cancer type, wherein well-differentiated regions lie adjacent to morphologically distinct, high-grade lesions that are histologically undifferentiated. Previous studies have determined that in nearly half of the cases dedifferentiation is associated with the genomic inactivation of SMARCA4, a catalytic subunit belonging to the SWI/SNF chromatin remodelling complex (SWI/SNF CRC), suggesting that SMARCA4 loss causes dedifferentiation. Herein, using gene editing, we reveal that when serially passaged in mice, SMARCA4-deficient endometrial cancer cells repeatably and predictably generate heterogeneous admixtures of differentiated and undifferentiated cells, resembling human DDEC. Surprisingly, despite this metamorphosis, SMARCA4 loss does not induce lineage plasticity nor reprogramming to a less differentiated fate. Rather, single-cell sequencing combined with barcoding demonstrated that SMARCA4 loss induces a dysregulated epigenome that allows cells to randomly move through cellular states that are otherwise shared with SMARCA4-expressing well-differentiated cancer cells. This finding was validated using a cohort of patient samples, such that epithelial fate markers (E-CADHERIN) can be detected in morphologically undifferentiated cells. Collectively, this work constitutes the first repeatable model of human dedifferentiated cancer and suggests that histological dedifferentiation is not due to the acquisition of a stem cell-like fate. Rather, undifferentiated tissue emerges due to epigenomic dysfunction concomitant with the arbitrary movement of cancer cells between cellular states.