Anirban K. Mitra, PhD

Role of reciprocal interactions between cancer cells and their microenvironment in regulation of ovarian cancer metastasis and relapse.

Ovarian cancer is the most lethal of all gynecologic malignancies primarily because most ovarian cancer patients present with extensive metastasis when they are first diagnosed. There has been no significant improvement in survival rates over the last three decades. Metastasis is responsible for most cancer related deaths and is one of the least understood aspects of the disease. Therefore, it is imperative to understand the process of ovarian cancer metastasis and devise new therapies targeting metastatic disease. Ovarian cancer has a unique metastasis, which rarely takes the hematogenous route. During the process of abdominal dissemination, the cancer cells floating in the peritoneal fluid have to attach to the mesothelial cells lining the peritoneal organs and interact with the microenvironment at the site of metastasis to successfully establish metastatic colonies. The cross talk between the cancer cells with the microenvironment of the metastasis site and the regulation of the initial steps of colonization is crucial and largely unknown.

My laboratory seeks to understand the paracrine and juxtacrine interactions between cancer cells and their microenvironment that regulate metastatic colonization in ovarian cancer. We are using an in vitro organotypic 3D culture model of early ovarian cancer metastasis, heterotypic 3D culture models of the tumor microenvironment, matched ovarian cancer patient primary tumors and metastasis, ovarian cancer spheroids, mouse models of metastasis and live 3D time-lapse microscopy to study the reciprocal interactions between the metastasizing cancer cells with their microenvironment at the site of metastasis. We have developed novel assays including a proximal culture assay and a 3D time-lapse confocal microscopy-based assay for co-invasion of cancer cells and stromal cells. We have led the field in understanding the master regulators of gene expression that respond to these paracrine/juxtacrine signaling from the microenvironment, and the mechanism by which they drive metastatic colonization in ovarian cancer. We were the first to identify the microenvironment-induced epigenetic downregulation of metastasis suppressor microRNAs, miR-193b-3p and miR-4454 that promote metastatic colonization of ovarian cancer. We have also identified microenvironment-induced c-Jun and Ets1, along with microenvironment-induced changes in chromatin accessibility, as important drivers of ovarian cancer metastatic colonization. We are currently using scRNA-seq, scATAC-seq and spatial transcriptomics to characterize the metastasis initiating cells and their key regulators.

We were the first to determine the mechanism of reprogramming of normal fibroblasts into CAFs by a set of microRNAs and have continued to study the role of CAFs in various tumor promoting functions, including serving as a cancer stem cell niche. We are studying the specific CAF subpopulations that serve as the cancer stem cell niche and subpopulations of cancer cells that respond to the signals from these CAFs using scRNA-seq and spatial transcriptomics.