Neural Networks Recapitulation by Cancer Cells Promotes Disease Progression: A Novel Role of p73 Isoforms in Cancer-Neuronal Crosstalk

SIMPLE SUMMARY: Cancer is initiated by alterations in specific genes. However, at late stages, cancer cells become metastatic not necessarily through continuous accumulation of additional mutations, but by hijacking programs of normal embryonic development and reactivating them in an unusual place, at the wrong time. Here, we applied computational and experimental approaches to show that these malignant reactivations include genes that are crucial for the development and function of the nervous system. We use the paradigm of melanoma transition from less invasive to highly aggressive stages in order to show that major players of metastasis, such as TP73 gene products, are implicated in this process. This work provides evidence for interactions between cancer cells and the neuronal system, which may have important future implications for metastasis prevention and cancer management. ABSTRACT: Mechanisms governing tumor progression differ from those of initiation. One enigmatic prometastatic process is the recapitulation of pathways of neural plasticity in aggressive stages. Cancer and neuronal cells develop reciprocal interactions via mutual production and secretion of neuronal growth factors, neurothrophins and/or axon guidance molecules in the tumor microenvironment. Understanding cancer types where this process is active, as well as the drivers, markers and underlying mechanisms, has great significance for blocking tumor progression and improving patient survival. By applying computational and systemic approaches, in combination with experimental validations, we provide compelling evidence that genes involved in neuronal development, differentiation and function are reactivated in tumors and predict poor patient outcomes across various cancers. Across cancers, they co-opt genes essential for the development of distinct anatomical parts of the nervous system, with a frequent preference for cerebral cortex and neural crest-derived enteric nerves. Additionally, we show that p73, a transcription factor with a dual role in neuronal development and cancer, simultaneously induces neurodifferentiation and stemness markers during melanoma progression. Our data yield the basis for elucidating driving forces of the nerve–tumor cell crosstalk and highlight p73 as a promising regulator of cancer neurobiology.