Researchers at the University of Liège have solved a decades-old mystery in cancer biology: multiple distinct cancer subtypes can all emerge from a single rogue cell that splits into different evolutionary paths early in tumor development. The discovery, published in Cell Reports by scientist Michael Herfs and colleagues, reframes how scientists understand cancer's notorious diversity—and may eventually reshape how we treat it.
The breakthrough came from studying adenosquamous carcinomas of the cervix, rare tumors that contain two entirely different types of cancer cells—glandular and squamous—living side by side within the same lesion. Both types arise in the context of human papillomavirus (HPV) infection. This unusual pairing gave the research team an ideal natural laboratory. If the two cell types had separate origins, they would look genetically distinct from the start. But if they came from one source, they should share telltale fingerprints of their common ancestor.
Working in collaboration with researchers from Université Paris Cité and Sorbonne University, Herfs's team compared the glandular and squamous components within the same tumor samples using advanced histopathological, virological, and genomic analyses. What they found was striking: the two seemingly different cancer cell populations shared identical viral signatures—the same HPV variants and the exact same integration sites where the virus had inserted itself into human DNA. They also carried some shared genetic mutations, a clear mark of common ancestry.
But the story doesn't end at the point of origin. The researchers discovered that very early in tumor development, before most mutations have accumulated, these initially identical cells begin to diverge. The two malignant populations then evolve independently, each following its own genetic trajectory. Only a small fraction of their mutations are shared, indicating that this crucial split happens almost immediately after the tumor initiates.
This finding upends the traditional model that each cancer subtype arises from a specific, predetermined cell of origin. Instead, it supports a very different picture: a single progenitor cell—potentially capable of multiple developmental fates—can seed an entire tumor that later fragments into phenotypically distinct cell types. The implications ripple far beyond cervical cancer. Tumor heterogeneity, the bewildering diversity of cell types within a single cancer, is one of oncology's thorniest challenges. It helps explain why some patients develop resistance to treatment: cancers with multiple distinct cell populations are harder to kill with a single drug.
"This study provides robust and direct evidence in humans that distinct tumor phenotypes can emerge from a single initiating event through early clonal divergence," Herfs explains. The team's work establishes a new conceptual framework for understanding how cancers develop plasticity—the ability to shift between different cell identities—and why that plasticity matters so much when choosing treatment strategies.
The discovery opens new research directions for understanding how a single malignant event can bloom into a tangle of different cancer cell types, and how physicians might better anticipate and overcome treatment resistance by accounting for this early divergence from a common starting point.