Unwinding Lymphoma – How Researchers Better Understand Key Pathways

For Francisco Vega, M.D., Ph.D., Director of Hematopathology at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, sorting out cancer cell biology has been a years-long endeavor. Vega is particularly focused on the molecular signals that drive lymphoma. Several years ago, he showed that a protein called Hedgehog helps cancer cells survive in diffuse large B-cell lymphoma.

Individual cancer cells are like a tangled ball of rarely used cords hidden away in a junk drawer. At first glance, it’s hard to discern where one wire stops and another begins or how the mess is even put together. But slowly, with patience, we can unwind the ball and get at the cord we need.

To understand cancer, researchers have to tease out the molecular pathways that drive the disease. Which proteins are talking to each other and what are the results? By slowly unwinding this tangled web, scientists can figure out how specific proteins contribute to cancer and develop therapies to target them.

“We found this pathway is active in lymphoma and by inhibiting it we could sensitize the cells to better respond to chemotherapy, decreasing their viability,” said Vega. But Hedgehog wasn’t acting alone; it was communicating with other proteins. To fully understand lymphoma, Vega needed to reconstruct this pathway.

Now, in a new paper published in the journal Blood, Vega and colleagues have unwound the complex Hedgehog pathway a little more, illuminating the important relationships between three other proteins driving lymphoma — GLI1, IKKbeta and TNFalpha.

GLI1 plays a role in embryonic development, but it is not normally found in mature cells. Cancer is a different story. GLI1 has been implicated in lymphoma, glioblastomas, neuroblastomas and other malignancies.

GLI1 is common in lymphoma cells, and Vega’s new research helps explain why. First, the cancer turns on the GLI1 gene, making more of the protein. Normally, when there’s too much of a protein, cells tag it for destruction. However, with an assist from TNFalpha, IKKbeta partners with GLI1to protect it from this critical process.

“IKKbeta blocks GLI1 degradation in lymphoma cells,” said Vega. “As a result, GLI1 is more active.”

Increased GLI1 is trouble because it’s a transcription factor. In other words, it turns on genes that support cancer progression and survival. GLI1 activates AKT, which drives cell growth, and ABCG2, which helps cancers resist chemotherapy.

“ABCG2 is a transporter protein that actually carries chemotherapy out of the cell,” he said. “More GLI1 translates into more ABCG2, which increases chemo resistance.”

Understanding how these proteins interact could lead to new cancer treatments. In their research, Vega’s team showed that by inhibiting both GLI1 and IKKbeta, they could suppress lymphoma. Though it’s unclear whether current GLI1 and IKKbeta inhibitors will work in patients, this research provides a clear target for future research.

“This is significant because we understand a step further how this oncogenic pathway is regulated,” Vega said. “We now have the opportunity to investigate ways to interfere with that pathway, not just in lymphoma but also, quite possibly, in other tumors.”

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