The modern day cancer treatments are a battle of destruction with methods like chemotherapy, radiation, and targeted drugs aimed to destroy the cancer cells. Amidst this, after various trials and errors, an emerging treatment has surfaced that focuses on transforming cancer cells into normal cells without destroying them. This research was carried out by Dr. Kwang Hyun Cho and his team at KAIST University, South Korea.
A Paradigm shift: From Destruction to Reversion
Dr. Kwang Hyun Cho’s research plays on the intricacies of cellular differentiation. Cellular differentiation is a complex process heavily relying on the transcriptional regulators of gene expression. These regulators work as genetic switches influencing the cellular gene expression by either turning it on or off. Cellular differentiation allows immature, unspecialised cells to become specific types of cells, such as muscle cells, nerve cells, skin cells, mucosal cells, etc. However, pinpointing the key players of this process, i.e., master regulators is not an easy feat. As a solution, the team at KAIST has developed a computational framework for single-cell Boolean network inference and control (BENEIN) that can identify the master regulators or switches of cell differentiation. They hypothesised that targeting these switches can aid in reprogramming the cancer cells into normal cells.
To understand the work on BENEIN, imagine the cell as a factory where genes are the workers who follow protocols and instruction manuals. In a cancerous state, the factory is thrown into chaos. Some workers (genes) stop working, some work overtime leading to uncontrolled growth, poor functioning with no checks – causing cancer. This is where BENEIN comes into the picture. It acts as a supervisory entity, keeping record of the workers in the factory. It maps out how all the workers (genes) interact in the cell, identifies the key controllers (master regulators) – essentially the bosses of the genes in the cancer stage. Lastly, it also suggests ways to reset the system by targeting these bosses so the factory returns to normal functioning.
The Breakthrough
Using this data given by BENEIN, the team at KAIST identified three master regulators – MYB, HDAC2, and FOXA2 in intestinal cell differentiation. MYB and FOXA2 are transcription factors. MYB is overexpressed in cancers while FOXA2 can either take on the role of tumor suppressor or an oncogene depending on the situation. HDAC2, on the other hand, is an enzyme contributing to oncogenesis by silencing tumor suppressor genes when it is dysregulated. Together, these three master regulators were identified as cues that prevent cellular differentiation in colorectal cancer. In vitro and in vivo experiments demonstrated suppressed proliferation of colorectal cancer cells when MYB, HDAC2, and FOXA2 were simultaneously inhibited.
Implications Beyond Colorectal Cancer
Apart from its obvious role in identifying regulators of colorectal cancer, the scope of BENEIN was also tested in neural differentiation using mice. BENEIN identified Tcf4, KIf9, and Etv4 as key regulators in mouse hippocampus cell differentiation. These genes are often disrupted in cancers such as glioblastoma and other brain tumors. This finding implies the flexibility of BENEIN across diverse biological systems. It further suggests that cancer reversion can be the ‘universal strategy’ to combat various cancer types.
A Path to Cancer Reversion as Hope for the Future
From this study it can be discerned that the key to this method lies in identifying master regulators of cellular differentiation. It differs from the traditional therapies of cancer cell destruction and aims to establish normal cellular functions in the cancer cells. Reversion as a cancer combat method reprograms cancer cells to look and function like normal cells, thereby switching off the oncogenes. The case of recurrence of the cancer is highly unlikely, distinguishing this method as a long-lasting treatment strategy. It also does not cause any intended or unintended harm to cells, as is often the case with traditional treatment methods. With minimal side effects, reversion offers an exciting prospect for cancer treatment.
The findings of this research pave the way for novel therapies targeting master regulators. While the current results show promise, further investigation is needed in this direction to establish the broader clinical applications. Considering the diverse types and causes of cancers, their genetic landscapes should be examined to ascertain the feasibility and limitations of this reversal treatment. Nevertheless, shifting the focus from elimination to reversion may allow us to view cancer not as a destructive disease, but as a challenge of transformation. Hence, the research by Dr. Kwang Hyun Cho and his team represents a new frontier in cancer research and is a ray of hope that could save millions of lives without side effects.
Deeksha, is a Biochemist and an aspiring neuroscientist. Her research interest lies at the intersection of molecular neuroscience and drug discovery.
