Lili Wang, MD, PhD: From Fundamental Immunology to the Frontiers of Blood Cancer
Lili Wang, MD, PhD did not set out to study cancer. In fact, when Wang began her training, she was on a different path, training to become a practicing physician. But during her hospital rotations, her curiosity shifted.
“I realized I’m more interested in the underlying mechanism behind the disease,” Wang says. “If you do not understand the molecular pathways or mechanisms critical for a disease, it will be very difficult to treat.”
That instinct to dive into the details has guided her scientific journey for more than two decades. Now a new member of the Herbert Irving Comprehensive Cancer Center (HICCC), Wang brings a deep background in immunology and cancer genomics, with a particular focus on chronic lymphocytic leukemia (CLL) and RNA splicing.
Choosing Mechanism Over Medicine
After completing her medical training, Wang gravitated toward immunology, which was an emerging and rapidly expanding field. She earned her PhD at Tokai University in Japan, studying T cell development and fundamental questions about how the immune system forms and functions.
Her first postdoctoral fellowship at the University of Illinois at Chicago focused on B cell biology, specifically the mechanisms by which B cells generate different types of antibodies. That work laid the foundation for her next pivot: a second postdoctoral position at Dana-Farber Cancer Institute.
“There, I changed totally from very fundamental B cell biology to B cell lymphoma,” she says. “Now, I’ve been studying it for the past 20 years.”
Her timing coincided with a scientific inflection point. Large-scale cancer genome sequencing projects were just beginning to take shape, opening unprecedented opportunities to understand the genetic underpinnings of blood cancers.
Working with leading cancer genomicist Catherine Wu, Wang began sequencing primary CLL patient samples alongside their germline DNA. In doing so, she identified the RNA splicing factor as one of the most frequently mutated genes in CLL. Around the same time, it was also discovered that the same gene was mutated in myelodysplastic syndromes (MDS), acute myeloid leukemia, uveal melanoma, breast cancer, and other types of solid cancers.
Splicing allows cells to create multiple proteins from a single gene, a critical mechanism for biological diversity. But when mutations disrupt that process, the consequences can be profound.
“You can think of RNA splicing like a puzzle,” Wang describes. “You put different pieces together to generate one protein, and another combination generates a different protein. They may share some pieces, but they are not exactly the same.”
At the time, however, it was unclear whether splicing factor mutations were true drivers of cancer or merely passengers.
Cracking the “Unclonable” Gene
Determined to understand the function of these mutations, Wang sought out experts in the field. One of the first challenges she encountered was technical.
“When we first discovered this gene mutation, we went to the person who had cloned it,” she recalls. “She told us that part of the sequence was ‘nonclonable’ because there were so many repeats. Basically, people just didn’t study that part of the gene.”
For Wang, that was not a deterrent—it was an invitation.
Over the years, her lab has helped clarify how splicing factor mutations alter RNA processing and contribute to genomic instability—findings that have reshaped understanding of how these mutations promote CLL development.
What began as a genomic observation has evolved into a sustained effort to map the functional consequences of splicing mutations in blood cancers, with implications for diagnosis, prognosis, and potentially therapy.
Solving Problems Through Team Science
After two decades at Dana-Farber and City of Hope, Wang was drawn to Columbia by what she describes as a uniquely collaborative scientific culture. At the HICCC, she has found the close integration between basic scientists and physician-scientists to be an essential ingredient for translating discovery into impact.
“Here, when I reach out with questions, clinicians are ready to answer. They’re willing to spend time with basic researchers.”
She attends weekly clinical meetings and participates in joint research conferences that bring laboratory and clinical perspectives together. Columbia’s Hematologic Malignancies Initiative and cancer center research programs, she notes, actively encourage cross-program partnerships.
“I have never talked to so many people,” she says with a laugh.
One recent example began in an elevator. Wang struck up a conversation with physician-scientist Ben Izar. By the time they reached her floor, they had agreed to continue the discussion, which had turned to findings from his perturbation screen that hinted at a splicing-related phenotype.
“It turns out we have a publication suggesting that splicing factors are involved in the chromosomal instability phenotype they are seeing,” she says. “Elevator conversations turn into real collaborations.”
For Wang, the move to Columbia represents not just a change in institution, but an expansion of possibility.
“With this teamwork,” she says, “I hope we’ll be able to solve a lot of problems in CLL.”
In a scientific environment she describes as “rich” and energized by collaboration, Wang is continuing to follow the questions at Columbia that first drew her away from the hospital and into the laboratory.
