Genetic changes in genes are the main reasons for the formation of a tumor, also called tumorigenesis. Apart from the genetic changes, epigenetic changes, reversible non-genetic alterations play an important role in tumorigenesis and disease progression. Since the epigenetic changes can induce tumorigenesis and can also reverse it, it is pivotal in cancer research to understand epigenetic cellular reprogramming that happens in various cancers, its role in disease progression, and explore potential to use in cancer therapy.
A comprehensive review paper published by Dr. Jungsun Kim from the Department of Molecular and Medical Genetics, Oregon Health & Science University School of Medicine, Portland, USA, in the journal Stem Cell Research, highlights the history and advances in the cellular reprogramming of cancer cells. Dr. Kim also draws attention to the epigenetic changes during tumorigenesis and shares her perspective on how studying these can help us reprogram cancer cells.
Dr. Kim’s paper initially demonstrates the evidence for cancer reversibility in mammalian embryonic cells by blastocyst injection, cell fusion, and nuclear transplantation experiments. These historical experiments have established that oocytes/embryonic cells can reset accumulated epigenetic modifications and control cancerous cells’ proliferation until the blastocyst stage. Using human cells in mice models, it has also been established that in later stages of embryonic development, especially during cell specification, epigenetic changes can be reactivated in a cell lineage-specific manner. These studies have paved the path for further investigation into the potential of cellular remodeling of cancer progression.
Apart from embryonic cells, somatic cells can be induced to reprogram into pluripotent stem cells (iPSC) by a set of master pioneer transcription factors (TFs) such as OCT4, SOX2, KLF4, and MYC that can control the expression of various genes in a cell. Models for various human cancers have been prepared using (iPSCs. Modeling human cancers using TFs mediated reprogramming of human cancer cell lines has demonstrated the potential to use reprogramming to study resistance or response to cancer therapies influenced by cellular states. TF-mediated cellular reprogramming in human cancer cell lines has also identified additional cancer-associated epigenetic changes responsible for gene expression control. Although epigenetic changes can be reset in differentiating programmed cells and suppress malignancy, some epigenetic changes are re-established only in the lineages corresponding to primary cancer. Dr. Kim has utilized the potential of cellular reprogramming and provided a human cell model to study the early stages of pancreatic ductal adenocarcinoma.
Successful reprogramming of normal somatic cells using TFs encompasses a plethora of molecular changes. Overexpression of OCT4, SOX2, KLF4 and MYC TFs induces highly dynamic chromatin remodeling, leading to the expression of silent genes in fibroblasts. Dr. Kim said to Science Featured that “These chromatin dynamics translate into distinct phenotypes at the very early and late stages, as well as in reprogramming intermediates that may follow diverse paths through transient states.” Further studies conducted to understand the nature of these chromatic changes have proved that OSKM-mediated epigenetic changes are similar to the changes observed during cancer development. In various cancers, important TFs are misregulated, which leads to epigenetic changes. Although chromatic changes induced by cellular reprogramming are like changes seen in cancer cells, pluripotent cells have an epigenetic landscape distinct and reciprocal of the cancer epigenome. This creates exciting possibilities for using cellular reprogramming to modulate abnormal cancer epigenome.
The extensive review summarises that a pluripotent environment can dominate cancer phenotype, indicating oncogenes can be reactivated during organogenesis. The ability to reprogram cancer cells to pluripotency and reverse back to their original stage provides an excellent model to understand epigenetic modification during disease progression.
“The biggest obstacles in cancer reprogramming mainly arise from the fact that tumors are highly heterogeneous, yet only a subset of cells is reprogrammed,” said Dr. Kim. Solid tumors are made of cancerous and non-cancerous cells, which show different proficiencies of cellular reprogramming. Cancer cells also have a low reprogramming efficiency. Some epigenetic changes persist in cancer cells and genetic mutations resistant to reprogramming cells, restricting them from being fully reprogrammed.
Dr. Kim emphasizes that further research in cellular reprogramming of cancer cells to understand dynamic epigenetic changes during tumorigenesis is crucial for a better understanding disease onset, progression, and therapy.
Journal Reference and Main Image Credit:
Kim, Jungsun. “Cellular reprogramming to model and study epigenetic alterations in cancer.” Stem Cell Research (2020): 102062. DOI: doi.org/10.1016/j.scr.2020.102062
About the Author
Dr. Jungsun Kim, Ph.D.
Dr. Jungsun Kim is an Assistant Professor in Molecular& Medical Genetics, Knight Cancer Institute, and Cancer Early Detection Advanced Research Center at the Oregon Health & Science University School of Medicine. She received her B.S. and Ph.D. in biochemistry from Hanyang University in South Korea under the mentorship of Dr. IL-Yup Chung and completed postdoctoral studies at the University of Pennsylvania under the mentorship of Dr. Kenneth Zaret.
Her lab studies the molecular mechanisms of cellular reprogramming and programming in cancer.