The human body is a crowded place. This crowding is even more acute when the regulation of cell growth and proliferation fails during the formation of a tumor. Dealing with the lack of space in crowded environments presents cells with a challenge. This is especially true for immune cells, whose task is to patrol tissues, causing them to experience both acute and sustained deformation as they move. Although changes in tissue crowding and associated cell shape alterations have been known by pathologists to be key diagnostic traits of late-stage tumors since the 19th century, the impact of these changes on the biology of cancer and immune cells remains unclear. Moreover, it is not known whether cells can detect and adaptively respond to deformations in densely packed spaces.

To test the hypothesis that cells possess an ability to detect and respond to environmentally induced changes in their shape, we fabricated artificial microenvironments that mimic the conditions experienced by tumor and immune cells in a crowded tissue. By combining dynamic confinement, force measurements, and live cell imaging, we were able to quantify cell responses to precisely controlled physical perturbations of their shape.

Our results show that, although cells are surprisingly resistant to compressive forces, they monitor their own shape and develop an active contractile response when deformed below a specific height. Notably, we find that this is achieved by cells monitoring the deformation of their largest internal compartment: the nucleus. We establish that the nucleus provides cells with a precise measure of the extent of their deformation. Once cell compression exceeds the size of the nucleus, it causes the bounding nuclear envelope (NE) to unfold and stretch. The onset of the contractile response occurs when the NE reaches a fully unfolded state. This transition in the mechanical state of the NE and its membranes permits calcium release from internal membrane stores and activates the calcium-dependent phospholipase cPLA2, an enzyme known to operate as a molecular sensor of nuclear membrane tension and a critical regulator of signaling and metabolism. Activated cPLA2 catalyzes the formation of arachidonic acid, an omega-6 fatty acid that, among other processes, potentiates the adenosine triphosphatase activity of myosin II. This induces contractility of the actomyosin cortex, which produces pushing forces to resist physical compression and to rapidly squeeze the cell out of its compressive microenvironment in an “evasion reflex” mechanism.

Although the nucleus has traditionally been considered a passive storehouse for genetic material, our work identifies it as an active compartment that rapidly convers mechanical inputs into signaling outputs, with a critical role of its envelope in this sensing function. The nucleus is able to detect environmentally imposed compression and respond to it by generating a signal that is used to change cell behaviors. This phenomenon plays a critical role in ensuring that cells, such as the immune cells within a tumor, can adapt, survive, and efficiently move through a crowded and mechanically heterogeneous microenvironment. Characterizing the full spectrum of signals triggered by nuclear compression has the potential to elucidate mechanisms underlying signaling, epigenetic, and metabolic adaptations of cells to their mechanoenvironment and is thus an exciting avenue for future research.

(1) Cell confinement below resting nucleus size, leading to nuclear deformation and to unfolding, and …