Mechanical load as an endogenous tumor suppressor: Nesprin-2-mediated mechanotransduction reshapes the cancer epigenome

Abstract

In a recent study published in Science , Ciucci et al. show that physiological mechanical loading suppresses cancer cell proliferation in the heart through Nesprin-2-dependent nuclear mechanotransduction and epigenetic remodeling. 1 These fi ndings identify cardiac mechanics as an endogenous barrier to cancer and suggest new mechanically and epigenetically informed therapeutic strategies.Whydoes a highly vascularized organ that is continuously exposed to circulating tumor cells so rarely develop primary tumors or myocardial metastases? This paradox has usually been framed through the “ seed-and-soil ” concept, emphasizing the myocardium ’ s metabolic, cellular, and extracellular peculiarities. Cancer mechanobiology, meanwhile, has largely focused on tumor-promoting matrix stiffness and mechanosensitive signaling. 2 Yet, force is not a unitary stimulus, because its biological consequences depend on its magnitude, direction, periodicity, and the surrounding tissue architecture, while compressive stress can also restrain proliferation. 3 The study ’ s strength lies in triangulation across several experimental models. In mice with inducible KRAS G12D activation and p53 loss, oncogenic recombination produced tumors in several tissues but not in the heart.