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eSymposia | Tissue Plasticity: Preservation and Alteration of Cellular Identity


Aggressive Dedifferentiated Endometrial Cancer can be Recapitulated from Cell Line Models with Chromatin Remodeling Protein SMARCA4 Deficiency and Treated with Synthetic Lethality Approaches


Oct 5, 2020 12:00am ‐ Oct 5, 2020 12:00am

Description

Aggressive Dedifferentiated Endometrial Cancer can be Recapitulated from Cell Line Models with Chromatin Remodeling Protein SMARCA4 Deficiency and Treated with Synthetic Lethality Approaches Mackenzie Coatham (1), Zhihua Xu (2), Guihua Zhang (2), Jiahui Liu (2), Edmund Su (3), Dylan Dieters-Castator (4), Gilles Lajoie (4), Franco Vizeacoumar (5), Martin Hirst (3), Cheng-Han Lee (3,6), Lynne-Marie Postovit (2) (1) University of Alberta, Department of Obstetrics and Gynecology, Edmonton, Alberta, Canada (2) University of Alberta, Department of Oncology, Edmonton, Alberta, Canada (3) University of British Columbia, Department of Pathology and Laboratory Medicine, Vancouver, British Columbia, Canada (4) University of Western Ontario, Department of Anatomy and Cell Biology, London, Ontario, Canada (5) University of Saskatchewan, Department of Pathology, Saskatoon, Saskatchewan, Canada (6) University of Alberta/Royal Alexandra Hospital, Department of Laboratory Medicine and Pathology, Edmonton, Alberta, Canada One of the most lethal yet rare subsets of uterine cancer is dedifferentiated endometrial carcinoma (DDEC). Less than 20% of patients diagnosed with DDEC survive compared to the over 80% of uterine cancer patients with high-grade endometrial cancer diagnoses. DDEC tumors possess both well-differentiated and undifferentiated regions. Previously, we demonstrated that 80% of the undifferentiated regions in DDEC lesions lack the expression of core chromatin remodeling proteins, SMARCA4 or ARID1A and ARID1B. We hypothesize that loss of these proteins, which are known regulators of transcription may lead to the induction and/or maintenance of gene expression programs that drive dedifferentiation, metastasis and therapy resistance. SMARCA4-deficient endometrial cancer (EC) cell line models were generated by CRISPR gene editing and were found to be less capable of self-renewal and anchorage-independent growth. SMARCA4 knockout cells were found to be more senescent than their wild-type counterparts, possessing more positive beta-galactosidase stained cells and expressing higher levels of p21 and H3K9me3. Existence of a senescent associated secretory phenotype (SASP) together with upregulation of interferon and IL2/STAT5 signaling in the absence of SMARCA4 were determined by mass spectrometry of conditioned media and RNA sequencing, respectively. Tumors formed from SMARCA4-deficient EC cell line models in immune-compromised mice recapitulated the mixed phenotype observed in patient DDEC lesions. Endometrial cancer cells lacking SMARCA4 expression were also found to be more sensitive to inhibition with clinically available therapeutics targeting CDK4 and EGFR. Synergistic effects upon combining therapies against CDK4 and EGFR were observed in SMARCA4 knockout cells. Response to CDK4 inhibition in the absence of SMARCA4 is likely mediated through dysregulation of the p16/cyclin D1/Rb pathway. Exome sequencing in addition to single cell RNA-Seq and ATAC-Seq will be carried out in the future to elucidate whether it is the consequence of acquired mutations, changes in gene expression or alterations to nucleosome occupancy that contribute to cellular dedifferentiation in the context of DDEC.

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