Scott Lowe, PhD, identified a precancerous sign in cells that is “sort of like the first wobble as the wheels start to fall off the wagon.”
If you know the name of just one gene involved in cancer, it should be p53. Half of all cancers have a broken version of it — making it the most common of all cancer mutations.
The protein made by the gene — p53 — helps guard the body against cancer, in part by detecting and repairing damaged DNA. That’s why scientists call it the “guardian of the genome.” This tumor suppressor gene is so famous, there’s a popular science book about its discovery.
And yet, over the 30 years since p53 was first discovered, it has remained a stubborn mystery, resisting efforts to tease apart exactly how the loss of the gene’s protection leads to the development of cancer.
In August 2022, however, researchers in the Sloan Kettering Institute were able to provide some new answers in a groundbreaking study published in Nature — answers that hint at new avenues for treatment.
“Rather than promoting genetic chaos, what we see when cells lose p53 is an orderly progression of genetic changes that is actually quite predictable,” says the study’s senior author, Scott Lowe, PhD, Chair of the Cancer Biology and Genetics Program in the Sloan Kettering Institute. “That came as a complete surprise to us and suggests a new way to think about possibly treating cancer.”
It’s not surprising that such a discovery was made at the institute. It’s a research hub within Memorial Sloan Kettering Cancer Center (MSK) that brings together scientists from many disciplines to tackle foundational questions in biology. And over the 75 years since it first opened its doors, investigators there have made significant advances in the fundamental understanding of cancer, as well as helped pioneer advances in chemotherapy, radiation therapy, drugs targeting specific cancer mutations, and modern immunotherapies.
“When people ask, ‘Why is it important to support basic science research?’ — and by that I mean research aimed first and foremost at deepening our understanding of biology — I like to point to studies like this,” says leading cancer metastasis researcher Joan Massagué, PhD, Chief Scientific Officer for Memorial Sloan Kettering Cancer Center (MSK) and Director of the Sloan Kettering Institute.
Understanding p53’s Role in Cancer
For years, scientists struggled to fully understand p53’s role in cancer, in part because there are few good laboratory models that allow the study of p53 function at the earliest stages of tumor development, well before cells have acquired obvious hallmarks of cancer.
To bring those early changes into view, Dr. Lowe’s lab — including study first authors Timour Baslan, PhD; Zhen Zhao, MD, PhD; and John P. Morris IV, PhD — produced a unique mouse model of pancreatic cancer in which p53’s loss could be detected early on, just as the cells started to transition from benign to malignant.
The model’s key feature is a set of colorful fluorescent tags that can be seen under the microscope. These colorful patterns allowed the scientists to identify specific populations of cells that had lost p53 function but hadn’t yet turned into cancer.
“It’s sort of like the first wobble as the wheels start to fall off the wagon,” Dr. Lowe says.
A deeper analysis was able to pinpoint the genetic changes that occurred immediately following p53 loss and those that continued after.
Genetic Evolution of Tumors and Their Patterns
Instead of opening a Pandora’s box of genetic chaos, the researchers observed that changes caused by the loss of p53 always seemed to unfold in a consistent pattern — genetic deletions, duplication of chromosomes, more deletions, and finally, gaining additional copies of certain genes.
Knowing that there are “rules” to the genetic evolution of tumors suggests new ways to think about treating them, the scientists say.
Many existing cancer drugs target extra copies of genes that arise in tumors. But these additions happen late in a tumor’s evolution, so not all cells in the tumor will have them. This means that drugs targeting such changes leave some of the earliest-developing cancer cells unscathed.
A more effective approach to treating cancer might be to target the gene deletions that occur very early in cancer development, immediately after the loss of p53, since these changes will be found in almost all of the tumor cells — leaving far fewer of them to grow and spread.
Targeting these deletions could be tricky, Dr. Lowe notes, but the possibility is there: “If there’s order and rules to cancer development, then we might ultimately be able to understand and exploit those rules against the cancer itself,” he says.
“When or where the next major advance in cancer treatment will occur is unknown, but it often begins with basic research,” Dr. Massagué says.
This work was supported in part by the David M. Rubenstein Center for Pancreatic Cancer Research.
Dr. Massagué holds the Marie-Josée and Henry R. Kravis Chair.
Dr. Lowe holds the Geoffrey Beene Chair at MSK and is a Howard Hughes Medical Institute Investigator.
