Diverse cancer subtypes can originate from a single progenitor cell

How do different cancer subtypes arise? Do they originate from distinct cells, or from a single multipotent cell capable of differentiating into multiple cell types? This question, debated for decades in cancer biology, is now gaining new insight thanks to the work of the Laboratory of Experimental Pathology at the University of Liège, in collaboration with researchers from Université Paris Cité and Sorbonne University.

The scientists focused on adenosquamous carcinomas of the cervix, rare but particularly informative tumors. These tumors combine two types of cancer cells, glandular and squamous, within the same lesion, in a shared context of human papillomavirus (HPV) infection. This makes them an ideal model for understanding how multiple tumor identities can develop and coexist.

By combining advanced histopathological, virological, and genomic analyses, the researchers were able to separately compare these two tumor components within the same samples. Their conclusion is unequivocal: glandular and squamous cancer cells share a common origin. In particular, they exhibit identical viral features (the same HPV variants and identical integration sites in human DNA), as well as some shared genetic alterations.

However, this initial similarity does not last. Very early in tumor development, the two malignant cell populations diverge and evolve independently, each following its own trajectory. Notably, only a small fraction of genetic alterations is shared between the two components, indicating that divergence occurs early in cancer development, before most mutations accumulate.

"This study provides robust and direct evidence in humans that distinct tumor phenotypes can emerge from a single initiating event through early clonal divergence," explains Michael Herfs. "The project, supported by an Audacious Medical Grant from the FNRS, was based on an innovative hypothesis whose outcome remained uncertain; the publication validating our initial premise is therefore a particularly rewarding achievement."

These findings challenge the traditional view that each cancer subtype originates from a specific cell of origin. Instead, they support a model in which a progenitor cell, potentially multipotent, can give rise to phenotypically distinct tumor cells.

Beyond cervical cancer, this discovery opens new avenues for understanding tumor heterogeneity, a major issue in oncology, particularly in explaining certain forms of treatment resistance. It suggests that the diversity observed within cancers may, in many cases, result from early divergence stemming from a single initial event.

By providing a clear answer to a long-standing controversy, this work establishes a new framework for understanding tumor plasticity and, ultimately, for better guiding treatment choices.