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A group of scientists at VCU Massey Comprehensive Cancer Center has revealed a new genetic code that acts like a cancer ringleader, recruiting and deploying a gang of tumor cells to incite a biological turf war by invading healthy organs and overpowering the normal cells. This discovery — published today, Dec. 9, in Nature Biotechnology — could unveil an entirely different understanding of the origins of cancer within the body, as well as offer groundbreaking insight into new treatment strategies that could target the growth of tumors in their earliest stages. 

The study authors have also developed an intravenous therapy that empowers healthy cells to mount an immune response and build up a defensive resistance against these invading tumor cells. This treatment has already been proven effective in ovarian tumors, but the implications of this research could be universal to all cancer types.

“We identified a biological mechanism through which cancer cells gaslight the human body, altering the genome of the host cells and forcing them into a state of low fitness, creating an enormous advantage for the cancer to take over,” said study author Esha Madan, Ph.D., member of the Cancer Biology research program at Massey and an assistant professor in the Department of Surgery at the VCU School of Medicine. “We have developed a monoclonal antibody which can stop this process. There are many targeted drugs already available to treat tumors, but for the first time ever we are enabling our entire body, beyond the immune system, to fight back against cancer.”

Through previous research, Madan, study co-author Rajan Gogna, Ph.D., and their collaborators found that, in addition to the immune system, the human body has an inherent neighborhood watchdog function, where healthy cells detect abnormal cells and alert other normal cells to effectively prevent invasive cells from doing any damage. However, somewhere along the way, this function fails during cancer progression.

A cancer cell’s journey can take many years before it becomes a tumor that is diagnosed in the clinic, needing time to take up residence in an organ and multiply. When cancer cells show up in an organ, they participate in a territorial standoff with normal cells through a process called cell competition. They have the ability to communicate with each other using “fitness fingerprints,” proteins on the cell surface that act as messengers between the two groups by using a series of codes.

Every cell in the human body carries a code on its surface. Gogna and Madan identified a previously unknown protein called the Flower gene, which is responsible for delivering a fitness code that can be expressed in two forms: Flower-Win and Flower-Lose. Like the names imply, cells expressing the Flower-Win code are more dominant and overpower cells expressing the Flower-Lose code. Essentially, when they encounter each other, a ‘winner’ cell will kill a ‘loser’ cell and occupy its space in an organ. Cancer cells were found to express high levels of the Flower-Win code, where normal cells more often expressed the Flower-Lose code.

“Cancer basically functions as a local bully, and these Flower proteins give it the tools to behave like that,” said Gogna, member of the Developmental Therapeutics research program at Massey and assistant professor in the Department of Human and Molecular Genetics at the VCU School of Medicine. “When they overexpress this Flower-Win code, they intimidate the host cells by signaling that they are the bosses, flashing their genetic weapons to communicate to the cellular neighborhood that they’re here to survive and thrive.”

The Massey researchers have patented a monoclonal antibody, a laboratory-manufactured drug administered by infusion that specifically targets and binds to the Flower gene, which has significantly reduced cancer growth and improved survival in models of ovarian cancer. The drug works by masking the expression of the Flower-Lose code among healthy cells, allowing for the body to effectively continue its regular biological neighborhood watchdog routine and turn away invading tumor cells.

“We know that early detection is paramount to favorable patient outcomes,” said study co-author Robert A. Winn, M.D., cancer center director and Lipman Chair in Oncology at Massey. “The findings from this groundbreaking research could forge the path for new treatments that are able to target tumors in the first, most curable stages of disease.”

Looking ahead, the study authors hope to be able to investigate the efficacy of this antibody in clinical trials, and many other reputable institutions have already expressed interest in partnering with Massey on a multicenter effort.

Although the monoclonal antibody has shown promise in ovarian cancer, the researchers believe the study findings will have broad implications for treating all types of tumors in their earliest forms.

"The collaboration between VCU School of Medicine and Massey holds unlimited value and impact. Our scientists continue to make progress by confronting and studying the hard questions,” said study co-author Arturo P. Saavedra, M.D., Ph.D., dean of the VCU School of Medicine. “Though it can often seem daunting, risky and expensive, innovative research performed by our teams has shown that no challenge is too big when it comes to advancing the health of our community and our nation."

Additional VCU collaborators on this study include Massey research members Tytus Bernas, Ph.D., Swadesh Das, Ph.D., Paul Fisher, Ph.D., Adam Hawkridge, Ph.D., Michael Idowu, MBBS, Jennifer Koblinski, Ph.D., Andrew Poklepovic, M.D., Arun Sanyal, M.D., Jose Trevino, M.D., and David Turner, Ph.D.; Charles Lyons of Massey’s Proteomics Shared Resource; and Karthikeya Bhoopathi, Praveen Bhoopathi, Ph.D., Gaurav Bilolikar, Sahil Chaudhary, MBBS, David Chelmow, M.D., Keshav Gogna, Gaurav Gupta, M.D., Kartik Gupta, Ph.D., Katherine Klein, M.D., Sambhav Khurana, Amit Kumar, Ph.D., Amy Lu, Santanu Maji, Ph.D., Padmanabhan Mannangatti, Ph.D., Antonio Palma, Anjan Pradhan, Ph.D., Karanvir Prakash, M.D., Hope Richard, M.D., Ph.D., Arjun Rijal, M.S., Sadia Sayeed, M.D., Kumari Shree, Vignesh Vudatha, M.D., Kyoung Jae Won and Dongyu Zhang, M.D., of the VCU School of Medicine.

Written by: Blake Belden