Abstract 2104: 3D spheroid: A rapid drug screening model for epigenetic clinical targets against heterogenic cancer stem cells
Authors: Das Madhumita , Santana Maylet Cortes , Barraque Stephanie , Cardenas Jhoselyn , Galindo Johnny Amaya , Cortes Misael , Ramos Jose , Prado Alberto Sanchez , Castillo Melissa Tejeda , Villar Victor , Vincent Claudy , Justo Elizabeth , Mendez Mariano , Mera Indira , Pachon Juan , Perez Kamila , Marin Adara , Murmu Nabendu , Biswas Maharaj , Ruiz Marco , Das Jayanta Kumar 
Published: July 2021

Recent scientific studies showed that transcript start sequences (TSS) are regulated by epigenetic bivalent histone modifications (H3K4me3 and H3K27me3) of target genes for heterogenic cancer stem cells (CSCs) reprogramming. Most of these studies are based on monolayer or 2D culture grew cancer cells. Studies of 3D spheroid models showed a rapid screening of anticancer drugs against CSCs. The 3D-spheroid models closely mimic in vivo tumor microenvironment (TME). Hence, 3D spheroid in vitro model development is a standout amongst other portrayed cancer models regarding 3D cell culture based on its similitude to physiological tumor tissues. Our previous studies of 3D spheroid models showed the effectiveness of small molecules targeted to the bivalent histone modifications against the CSCs in pancreatic cancer. The current study is aimed to explore the epigenetic clinical targets of bivalent histone modifications with the expression of heterogenic CSCs (CD133, CD15 CD44, CD49f, CD24, ALDH1A3, CXCR4) of 3D spheroids in glioblastomas, oral, and colorectal cancers (CRC). The Cancer Stem Cells Therapeutic Target Database Version 2.0 (CSCTTv2.0) reported the highest expression of CSCs in glioblastomas, oral and CRCs that showed resistance to anticancer drugs (such as Bevacizumab, 5-FU, cisplatin, cetuximab, oxaliplatin). The biological informatics methods (String; Cytoscape, BioGrid, Reactome, MatrixDB, Pubchem database) were used in our current study. The NCBI Gene Expression Omnibus (GEO) database showed only 4 studies of 3D spheroids of CSCs which revealed drug-resistant heterogenic CSCs, in 7 samples of glioblastoma spheroids and 4 samples of CSCs in MCF-7 breast cancer spheroids from 6 samples; drug-resistant CSCs of MDA-MB 231 spheroids from 6 samples; CSCs of colorectal cancer (CRC) spheroids from 6 samples, but the clinical the target of bivalent histone modifications with heterogenic CSCs in the glioblastomas, oral and CRCs have not been explored earlier using 3D spheroids for rapid drug screening. The protein-protein interaction (PPI) network of the current study showed a relationship of closely related 17 significant genes. Among these 17 genes, a total of 6 CSCs was closely associated with epigenetic bivalent histone modifications through KDM7A, PHF1and EZH2. We also found from Cytoscape analysis of Reactome network that UniProtKB - P61073 (CXCR4_HUMAN) has significant interaction with other target network genes from 106 network data and it has been mentioned that Plerixafor, an antagonist inhibits CXCR4 activity. Therefore, it is important in designing any small molecules or drugs against heterogenic CSCs of glioblastomas, oral, and CRC with epigenetic target of histone bivalent modifications using a 3D spheroid model which could be rapid screening model for anticancer drug discovery and our current study highlighted this important relationship.

Citation Format: Madhumita Das, Maylet Cortes Santana, Stephanie Barraque, Jhoselyn Cardenas, Johnny Amaya Galindo, Misael Cortes, Jose Ramos, Alberto Sanchez Prado, Melissa Tejeda Castillo, Victor Villar, Claudy Vincent, Elizabeth Justo, Mariano Mendez, Indira Mera, Juan Pachon, Kamila Perez, Adara Marin, Nabendu Murmu, Maharaj Biswas, Marco Ruiz, Jayanta Kumar Das. 3D spheroid: A rapid drug screening model for epigenetic clinical targets against heterogenic cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2104.