SMARCA4 loss in endometrial cancer induces cell fate chaos concomitant with the senescence associated secretory phenotype and aberrant regulation of mTOR

Endometrial cancer is the most common gynecological malignancy worldwide, and incidence has been steadily on the rise. While the prognosis for localized endometrial cancer is excellent, some patients develop dedifferentiated endometrial cancer (DDEC), wherein the five year survival rate is less than 25%. DDEC is an advanced, rare subtype of endometrial cancer characterized pathologically by the mix of dedifferentiated and well differentiated tissue. We have discovered that the loss of SMARCA4 , the catalytic subunit in the SWI/SNF complex, causes well differentiated endometrial cancer cells to form histologically undifferentiated lesions. SWI/SNF is a critical epigenetic modifier, which remodels chromatin by sliding and evicting nucleosomes. Evidence from our lab suggests that SMARCA4 loss causes epigenomic dysfunction in endometrial cells, leading to cell state chaos and the emergence of tissue that appears dedifferentiated. Interestingly, this chaos occurs only upon passaging in vivo , following an initial period wherein cells manifest a senescent-like phenotype. This phenotype is indicated by reduced growth, expression of Β-galactosidase, and manifestation of the Senescence Associated Secretory Phenotype (SASP). This suggests that features of the growing tumor, such as hypoxia, may enable cell state chaos and that the SASP may characterize a transitional cell state. The mTOR pathway, which regulates metabolism, survival, and mRNA translation, has been shown to promote the SASP and is normally inactivated in response to cell stress, such as hypoxia. We hypothesize that SMARCA4 loss promotes the senescent-like phenotype by altering mTOR signaling, and that by enabling adaptations in mRNA translation, aberrant mTOR signaling underpins the emergence of cell state chaos and disease progression. We have shown that, in contrast to other cell types, SMARCA4 deficient cells do not respond to hypoxia with a reduction in mTOR activity. SMARCA4 KO cells maintain high levels of phosphorylation of many key effectors, like 4EBP1, under hypoxia. Interestingly, phosphorylation of eIF4E (a cap binding protein involved in translation initiation) is significantly decreased with SMARCA4 KO, under hypoxia and in normoxia. These results suggest there may be modulation to the translational machinery upon SMARCA4 KO. Indeed, SMARCA4 deficient cells maintain high levels of protein synthesis in hypoxia, suggesting a strong resistance to stress-induced reductions in mRNA translation. In conclusion, our results suggest that dysregulated mTOR activity, leading to uncontrolled mRNA translation, may underpin the emergence of cell fate chaos an aggressive dedifferentiated histopathology in endometrial cancers.