Robert A. WEINBERG Director, Ludwig Center for Molecular Oncology MIT, Cambridge, MA
Robert A. Weinberg
The salient properties of individual cancer cells have been defined by many in terms to the somatic mutations that they have sustained during the process of multi-step tumor progression. In fact, epigenetic mechanisms appear to be equally important if not more important in dictating the biological behavior of these cells. Included here are differentiation programs inherited from normal cells-of-origin and changes in cell phenotype induced by contextual signals that carcinoma receive from their microenvironment. Prominent among these latter changes are those associated with the cell-biological program termed the epithelial-mesenchymal transition (EMT), which is able to drive carcinoma cells from highly epithelial phenotypic states to states in which an array of mesenchymal cell-biological traits are exhibited. Among these are traits crucial to invasiveness, dissemination, the founding of new tumor colonies at distant sites, and the ability to resist elimination by various clinical therapies. In addition to conferring resistance to chemotherapeutic treatments, the EMT program can also enable more mesenchymal carcinoma cells to resist elimination by various components of the immune system, including those mobilized by checkpoint immunotherapies. The mechanisms of acquired therapeutic resistance will be described along with attempts to elucidate the molecular mechanisms enabling EMT-facilitated entrance into the stem cell state and the ability of carcinoma cells to transition with great plasticity between multiple phenotypic states lying as intermediates between the highly epithelial and highly mesenchymal states.