A new study led by researchers at Penn State has uncovered how a cancerous tumor initiates and invades the body. The study sheds light on a potential therapeutic target to block invasion and may provide a prognostic marker to help clinicians select the best treatment option.

The findings are published in The Proceedings of the National Academy of Sciences in an article titled, “Long noncoding RNA MALAT1 is dynamically regulated in leader cells during collective cancer invasion.”

“Cancer cells collectively invade using a leader–follower organization, but the regulation of leader cells during this dynamic process is poorly understood,” wrote the researchers. “Using a dual double-stranded locked nucleic acid (LNA) nanobiosensor that tracks long noncoding RNA (lncRNA) dynamics in live single cells, we monitored the spatiotemporal distribution of lncRNA during collective cancer invasion. We show that the lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) is dynamically regulated in the invading fronts of cancer cells and patient-derived spheroids.”

“Cancer cells don’t randomly detach from the primary tumor and disseminate everywhere —they often exhibit coordination and collaboration,” explained corresponding author Pak Kin Wong, PhD, professor of biomedical engineering, of mechanical engineering and of surgery at Penn State. “A leader cell may emerge to coordinate the invasion, thereby enhancing the efficiency of cancer cell dissemination. In this study, we found a molecular marker for leader cells that enables us to predict the invasiveness of the tumor and how they invade.”

The researchers designed a nanobiosensor to track long noncoding RNA (lncRNA) in cancer cells derived from human patients with muscle invasive bladder cancer.

“lncRNA are often referred to as the dark matter of the cell,” Wong said. “While many RNA are involved in protein expression, lncRNA do not encode proteins. Their functions and how they regulate cell processes are still poorly understood. We developed this sensor to study lncRNA and their potential contribution to cancer progression.”

Using the sensor, the researchers monitored how much and where lncRNA was distributed in the cells during collective cancer invasion. They found that MALAT1, a gene associated with metastasis in lung, bladder, and other cancers, was highly present in leader cells.

“We also found that reducing the expression of MALAT1 in cells prevents the formation of leader cells and abolishes the invasion of cancer cells,” Wong said. “Overall, our single-cell analysis suggests that MALAT1 plays an essential role in regulating leader cells during collective cancer invasion.”

The researchers will continue to study the mechanistic underpinnings of MALAT1 in leader cells.

“If we can comprehend the crucial characteristics and functions of leader cells, we might be able to help clinicians identify aggressive disease and predict the behavior,” Wong said. “We hope this study will lead to the development of novel prognostics and therapeutic approaches targeting bladder and other cancer. For example, if applied clinically, determining the presence of leader cells and aggressive disease could enhance a physician’s understanding of an individual patient’s prognosis and inform the most suitable treatment strategy.”

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