Cancer development can be defined as a process of cellular and tissular microevolution ultimately leading to malignancy. Strikingly, though this concept has prevailed in the field for more than a century, the precise mechanisms underlying evolutionary processes occurring within tumours remain largely uncharacterized and rather cryptic. Nevertheless, although our current knowledge is fragmentary, data collected to date suggest that most tumours display features compatible with a diverse array of evolutionary paths, suggesting that most of the existing macro-evolutionary models find their avatar in cancer biology. Herein, we discuss an up-to-date view of the fundamental genetic and non-genetic mechanisms underlying tumour evolution with the aim of concurring into an integrated view of the evolutionary forces at play throughout the emergence and progression of the disease and into the acquisition of resistance to diverse therapeutic paradigms. Our ultimate goal is to delve into the intricacies of genetic and non-genetic networks underlying tumour evolution to build a framework where both core concepts are considered non-negligible and equally fundamental.

We have previously shown that c-Fos activates phospholipid synthesis through a mechanism independent of its genomic AP-1 activity. Herein, using PC12 cells induced to differentiate by nerve growth factor, the genomic effect of c-Fos in initiating neurite outgrowth is shown as distinct from its nongenomic effect of activating phospholipid synthesis and sustaining neurite elongation. Blocking c-Fos expression inhibited differentiation, phospholipid synthesis activation, and neuritogenesis. In cells primed to grow, blocking c-Fos expression determined neurite retraction. However, transfected cells expressing c-Fos or c-Fos deletion mutants with capacity to activate phospholipid synthesis sustain neurite outgrowth and elongation in the absence of nerve growth factor. Results disclose a dual function of c-Fos: it first releases the genomic program for differentiation and then associates to the endoplasmic reticulum and activates phospholipid synthesis. Because phospholipids are key membrane components, we hypothesize this latter phenomenon as crucial to support membrane genesis demands required for cell growth and neurite elongation.

During the last decade, and mainly primed by major developments in high-throughput sequencing technologies, the catalogue of RNA molecules harbouring regulatory functions has increased at a steady pace. Current evidence indicates that hundreds of mammalian RNAs have regulatory roles at several levels, including transcription, translation/post-translation, chromatin structure, and nuclear architecture, thus suggesting that RNA molecules are indeed mighty controllers in the flow of biological information. Therefore, it is logical to suggest that there must exist a series of molecular systems that safeguard the faithful inheritance of RNA content throughout cell division and that those mechanisms must be tightly controlled to ensure the successful segregation of key molecules to the progeny. Interestingly, whilst a handful of integral components of mammalian cells seem to follow a general pattern of asymmetric inheritance throughout division, the fate of RNA molecules largely remains a mystery. Herein, we will discuss current concepts of asymmetric inheritance in a wide range of systems, including prions, proteins, and finally RNA molecules, to assess overall the biological impact of RNA inheritance in cellular plasticity and evolutionary fitness.