Evidence for the atavistic reversal to a unicellular-like state as a central hallmark of cancer

Abstract

The International Journal of Cancer (IJC) published at its web site the article “‘Cell dedifferentiation’ versus ‘evolutionary reversal’ theories of cancer: the direct contest of transcriptomic features” by Alexander Vinogradov and Olga Anatskaya. The publication presents a very relevant study on cells' genetic signatures, describing a detailed comparison between stem and differentiated cells, and also between cancer and normal cells. The results are exciting, concluding, in a statistically compelling way, that cancer cells present an atavistic reversal to a unicellular-like state,^{1, 2} the consequences of which can explain some of the accepted cancer hallmarks.³

Cell dedifferentiation is widely recognized as a key hallmark of cancer, but the “atavistic” theory, the concept of cancer as a reversion to a unicellular-like state behavior, to an earlier stable state in the evolutionary history, is less commonly accepted. The researchers searched for evidence for both theories by conducting a meta-analysis of human single-cell transcriptomes, comparing gene signatures between stem and differentiated cells, and between cancerous and normal cells. In this last comparison, the unicellular gene signature did not overlap with the ontogenetic signature, favoring the atavistic theory. This finding positions the unicellular-like state as a central hallmark of cancer, supported by an evolutionary mechanism capable of generating other hallmarks, as the behavior associated with unicellular organisms is less controlled or determined by the presence of other cells or from environmental clues.

If the stress level introduced by tumorigenic events, as ionizing radiation or carcinogenic chemicals, surpasses a certain limit, it can drive a change of epigenetic state to an evolutionarily earlier one, not necessarily associated with genetic mutations, implying a loss of control mechanisms and reduction in the system's resilience to perturbation. In this work, it is not yet clear if this reversal is a single event, a jump from a multicellular epigenetic stable state of a differentiated cell to a unicellular stable state, as in the Waddington's epigenetic landscape metaphor,⁴ or if this is an accumulation of reversals, moving across this landscape through intermediate states. It also not yet evident if this is a reversal involving a single cell or if it is a collective event, involving many cells in a tissue, which requires further research.

The results obtained by the team suggest a paradigm shift in understanding oncogenesis, offering a different and unified framework for further cancer research. In oncologic practice, the predominance of unicellular signatures over ontogenetic ones could serve as a biomarker for tumorigenicity, aiding early diagnosis and in plausible applications to new focused therapies. A promising therapeutic approach across diverse cancer types can be targeting the unicellular-centric networks within cancer cells, moving away from the standard somatic mutation theory by embracing this alternative view.

The research question in this work, oncogenesis, is still very much relevant and is, in no way, a settled question. This work has the potential to change the perspective on cancer initiation and diagnosis, and, less likely, its therapy. The results presented put genetic expression associated with a unicellular-like state, predominant in early stages of life evolution, as a central hallmark of cancer. This state, with the absence of the sophisticated and complex control mechanisms present in multicellular tissues, can drive the manifestation of other cancer hallmarks. The upregulation of the unicellular signature indicates potential tumorigenicity, which can be used in early diagnostics. For therapy, the results suggest that a unicellular stable attractor can exist in the epigenetic landscape, which can be a universal target for various cancer types.