HYBRID EVENT: You can participate in person at Orlando, USA or Virtually from your home or work.

Global Conference on Gynecology & Women's Health

April 20-22, 2023 | Orlando, USA

April 20 -22, 2023 | Orlando, Florida, USA
Gynec 2023

Subramanyam Dasari

Speaker at Gynecology & Women's Health 2023 - Subramanyam Dasari
Indiana University Bloomington, United States
Title : Targeting microenvironment induced microRNAs to treat ovarian cancer metastasis

Abstract:

Metastasis and frequent relapse contribute to the high mortality rate of ovarian cancer (OC) patients. However, the mechanisms of regulation of critical steps during metastasis is poorly understood and treatment strategies have not been developed to specifically target them. Using an organotypic 3D culture model of the human omentum, we have studied the productive cross-talk between metastasizing OC cells and the metastatic microenvironment that is essential for establishment of metastasis. To identify the clinically relevant microRNAs that can regulate both early and advanced metastasis, we combined our 3D omentum culture approach with the end point analysis of microRNA expression profiles of 42 matched primary and metastatic tumors from OC patients. miR-193b and miR-4454 was thus identified as an important metastasis suppressor, downregulated by signals from the metastatic microenvironment.

Both miR-193b and miR-4454 were downregulated by signals from the site of metastasis. Decreased microRNA expression promoted metastatic colonization by enhancing the ability of the OC cells to attach and invade through the outer layers of the omentum. These metastasis initiating cells have cancer stem cell like characteristics. The induction of cancer stem cell-like phenotype by the decreased expression of miR-193b was important for establishment of metastatic tumors, and could potentially regulate chemoresistance and recurrent disease in OC. Stably overexpressing miR-193b resulted in a significant decrease in metastases in OC xenografts while stable inhibition had the opposite effect. Moreover, treating a chemoresistant OC patient derived xenograft (PDX) model of metastasis with miR-193b significantly reduced metastasis. Using heterotypic coculture models, conditioned medium experiments, secretome analysis, inhibition, and rescue experiments, we have identified the microenvironmental signals and the mechanism of miR-193b downregulation via the ERK/EZH2/DNMT1 axis. By performing RNA-seq in OC cells overexpressing miR-193b, we identified cyclin D1 (CCND1) as a key target. Knockdown and functional rescue experiments confirmed CCND1 as the functional effector of miR-193b responsible for the metastasis initiation phenotype.

miR-4454 was downregulated in the metastasizing ovarian cancer cells through paracrine signals from microenvironmental fibroblasts, which promoted migration, invasion, proliferation, and clonogenic growth in ovarian cancer cells as well as their ability to penetrate through the outer layers of the omentum. Stable overexpression of miR-4454 decreased metastasis in ovarian cancer xenografts. Its mechanism of action was through the upregulation of its targets, secreted protein acidic and cysteine rich (SPARC) and BCL2 associated athanogene 5 (BAG5), which activated focal adhesion kinase (FAK) signaling, promoted mutant p53 gain of function by its stabilization, and inhibited apoptosis. Our studies suggest the possible application of miR-193b and miR-4454 replacement therapy as a novel approach to treat OC metastasis.

 

What will audience learn from your presentation?

  • Cross-talk between cancer cells and its tumor microenvironment (mesothelial cells and fibroblasts)
  • Epigenetic regulation by microenvironmental signals
  • Potential clinical application of microRNAs to treat OC metastasis

Biography:

Dr. Subramanyam Dasari completed his PhD (2014) in Cancer Biology (Gynecological cancers) at the School of Herbal Studies and Naturo Sciences, Department of Biotechnology from Dravidian University, Andhra Pradesh (India).  During his doctoral studies, he studied the use of potential serum protein biomarkers used to evaluate the diagnosis and prognosis of the gynecological cancers (cervical cancer, ovarian and endometrial) and Breast Cancers. The study also focused on the role of microbial flora and their enzymes as risk factors in the development of gynecological cancers. Then he joined as Postdoctoral research fellow at UIC, College of Medicine at Rockford, USA (2015-2017) to study the anticancer effects and their mechanism of biotherapeutic compounds against prostate cancer and cervical cancers. Then he moved to Indiana University, School of medicine, Bloomington, Indiana as a Post-doctoral research associate (2017-till). Dr. Dasari is seeking to understand the reciprocal interactions between ovarian cancer cells and their tumor microenvironment for the regulation of metastatic colonization in ovarian cancer. They used in vitro organotypic 3D culture models, live 3D time-lapse microscopy and mouse xenograft models of metastasis along with cell and molecular biological approaches to study the reciprocal interactions between the metastasizing cancer cells with their microenvironment at the site of metastasis.

Dr. Dasari is author of over 38 original papers, reviews, and book chapters, and presented numerous national and international conferences. In addition, Dr. Dasari is serving in several international organizations: member of the American association of cancer research (AACR), Indiana Science congress. Dr. Dasari is topic editor for journal Biomolecules, cells (MDPI), topic editor for Frontiers in Molecular Biosciences and Review Editor for Molecular Diagnostics and Therapeutics.

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