Many genes in the human body have the ability to code for more than one protein, giving cells a large degree of flexibility to adapt to changing conditions. When this happens in cancer cells, it gives them the ability to morph in response to external cues, in order to metastasize or even escape toxic chemotherapy.

This inherent plasticity of cancer cells is one reason cancer is so difficult to eradicate. But now a scientist at Baylor College of Medicine, Dr. Chongui Cheng, M.D., Ph.D., is studying this process, called RNA splicing, in an effort to find ways to inhibit cancer’s flexibility. Dr. Cheng was recruited in 2016 from Northwestern University School of Medicine with the help of a Rising Star Award from CPRIT.

Alternative splicing is a way that human cells can make many different proteins from one gene. It’s an ability that 95% of human cells have, but organisms like yeast – which have a similar number of genes – lack.

DNA in a gene is transcribed to a pre-messenger-RNA, which is then spliced to create messenger RNA—the genetic material that ultimately codes for proteins. Splicing factors dictate which portions of the pre-mRNA are cut out or included to code for the desired protein. The resulting proteins can have very different functions within a cell, even though they are originally encoded by the same gene.

In a cancer cell, alternative splicing of a gene called CD44 is the key to its ability to change into a cell that can escape from the primary tumor site and undergo metastasis. “If we are able to understand the regulation of alternative splicing, we could develop new therapeutic strategies to stop the spread of tumors,” Dr. Cheng says.

In breast cancer, Dr. Cheng found that one spliced form of the protein encoded by the gene CD44 is closely coupled with a cancer cell’s survival mechanism, metastasis, and chemotherapy resistance.

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Many genes in the human body have the ability to code for more than one protein, giving cells a large degree of flexibility to adapt to changing conditions. When this happens in cancer cells, it gives them the ability to morph in response to external cues, in order to metastasize or even escape toxic chemotherapy.

This inherent plasticity of cancer cells is one reason cancer is so difficult to eradicate. But now a scientist at Baylor College of Medicine, Dr. Chongui Cheng, M.D., Ph.D., is studying this process, called RNA splicing, in an effort to find ways to inhibit cancer’s flexibility. Dr. Cheng was recruited in 2016 from Northwestern University School of Medicine with the help of a Rising Star Award from CPRIT.

Alternative splicing is a way that human cells can make many different proteins from one gene. It’s an ability that 95% of human cells have, but organisms like yeast – which have a similar number of genes – lack.

DNA in a gene is transcribed to a pre-messenger-RNA, which is then spliced to create messenger RNA—the genetic material that ultimately codes for proteins. Splicing factors dictate which portions of the pre-mRNA are cut out or included to code for the desired protein. The resulting proteins can have very different functions within a cell, even though they are originally encoded by the same gene.

In a cancer cell, alternative splicing of a gene called CD44 is the key to its ability to change into a cell that can escape from the primary tumor site and undergo metastasis. “If we are able to understand the regulation of alternative splicing, we could develop new therapeutic strategies to stop the spread of tumors,” Dr. Cheng says.

In breast cancer, Dr. Cheng found that one spliced form of the protein encoded by the gene CD44 is closely coupled with a cancer cell’s survival mechanism, metastasis, and chemotherapy resistance.

In an often-deadly type of brain cancer called glioblastoma, Dr. Cheng found that the same spliced form of the protein, called CD44s, gives cancer cells a survival advantage during treatment with the drug erlotinib. Dr. Cheng would like to find a way to inhibit the formation of CD44s, which would allow erlotinib to be more effective in eradicating a patient’s glioblastoma.

Dr. Cheng says her work suggests that physicians might choose a treatment for cancer based on what makes a particular patient’s cancer grow and survive, regardless of the type of cancer it is or where it’s located.

Dr. Cheng collaborates closely with other CPRIT Scholars at Baylor, especially Dr. Matthew Ellis and Bing Zhang. Dr. Ellis is a breast cancer clinician, whose patient data gives Dr. Cheng the ability to correlate breast cancer diagnosis and disease progression with RNA regulation. And Zhang’s expertise in large data mining allows her to gain a bioinformatic understanding of RNA regulation in many different types of cancer.

“The financial support from CPRIT also allows us to recruit outstanding scientists to join us to really address fundamental questions in the field that we are interested in,”Dr. Cheng says.

Dr. Cheng received her M.D. from Peking University in China, and her master’s in biochemistry from the University of Notre Dame. She received a Ph.D. in biochemistry and structural biology from Sloan-Kettering Institute/Weill Cornell Graduate School of Medical Sciences, and was a postdoctoral fellow at the Massachusetts Institute of Technology prior to joining the faculty at Northwestern in 2007.

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