Cancer Cells May Be Limited to Just a Few Stable States, Researcher Says

Andrea Califano, a physicist by training who is now a cancer researcher at Columbia University, argues that despite the immense genetic diversity of cancer, tumor cells may be confined to only a handful of stable, recurring states. Califano compares this to the way electrons in an atom are restricted to specific quantized energy levels, an idea he says is not literal but reflects a real, observed pattern: cancer cells occupy one of a small number of stable states, or move rapidly between them, and these states appear to be conserved across virtually all patients with a given type of cancer.

Traditional chemotherapy and radiation attack a defining feature of many tumors, rapid cell division, largely by inflicting DNA damage, but this can also harm healthy fast-growing tissue. Targeted therapies are more selective; the drug Herceptin, for example, blocks abnormal HER2 signaling that can drive cancer cells to multiply, an approach that helped establish personalized medicine, in which treatment is matched to a tumor's specific mutations. But tumors can carry many genetic alterations, different patients with the same cancer may have very different combinations of them, and cancer cells can evolve under treatment, letting resistant populations survive.

Califano says a mutation-focused approach captures only part of the disease. His laboratory instead studies what a cell's mutations ultimately make it become, using molecular data from living cancer cells to identify master regulators, the proteins that work together to maintain a malignant state. Earlier work from his lab found this number to be unexpectedly small: an analysis of more than 10,000 samples across over 20 cancer types identified only 112 distinct states, and later single-cell studies found one cancer with just a single state, with none examined so far showing more than seven.

In a paper published August 26 in Nature Genetics, Pasquale Laise, Mikko Turunen and Alvaro Curiel Garcia analyzed cells from pancreatic tumors and identified only six distinct states among all the tumors examined. A separate analysis found a similarly limited number of states in diffuse midline gliomas. Califano says that even when two tumors carry different mutations, they may still depend on the same master regulators if their cells occupy the same state, meaning a combination of therapies targeting a handful of detectable states could potentially work across many patients rather than requiring a different strategy for every tumor.