[Seminar] Mechanobiology of the Nuclear Membrane and Its Potential Application in Antitumor Treatment by Prof. Zhaocai Zhou

Title: Mechanobiology of the Nuclear Membrane and Its Potential Application in Antitumor Treatment
Speaker: Dr. Zhaocai (Joe) Zhou, Professor, Principal Investigator
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science,
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences

Date: November 30, Thursday
Time:  10:30 - 11:30
Venue: C700, Level C, Lab 3

Abstract:
As key regulators of immunity, development and tissue homeostasis, macrophages are plastic in function and can be polarized in response to environmental cues to generate proinflammatory (M1) or prohealing (M2) phenotypes. Repolarizing tumor-associated macrophages to obtain the M1-like activity is of wide clinical interest in cancer immunotherapy. Here we discovered that M1-polarizing signals induced significant shrinkage and softening of the nucleus with widened nuclear envelope spacing and an out-of-center repositioning. In response to an M1 polarization signal, the expression of the nuclear envelope proteins SUN1/2 changed in a CK2-bTrCP-dependent manner to alter the micromechanics and positioning of the nucleus, which in turn affected the morphology of the cytoskeleton and of the entire cell. Depletion or overexpression of SUN1/2 significantly alters the mechanical properties of the nuclear envelope, inducing conformational changes of chromatins and epigenetic reprogramming. As a result, the protein levels of SUN1/2 strongly correlated with phenotype transition of macrophages between M1-like and M2-like profiles in terms of TLR signaling, phagocytosis, gene transcription and metabolism. Consistent with these observations, knockout of SUN1/2 in mice exacerbated inflammatory damage during LPS-induced septic shock. Silencing of SUN1/2 in mouse macrophages dramatically enhanced antitumor immunity of the mice by inhibiting M2-like polarization of tumor-associated macrophages. Overall, these findings indicate that SUN1/2 can actively “translate” polarization signals into a physical remodeling of the nucleus, and that SUN1/2-mediated micromechanical properties of the nucleus act as a key determinant of the functional plasticity of macrophage that relays polarization signals to the specification or functional reprogramming of the cell.

EXPLANATION OF SIGNIFICANCE FOR THE ABSTRACT
Macrophages can be polarized as the M1 type with a killing ability (to induce an inflammatory response and remove pathogens or tumor cells) or the M2 type with a healing ability (to resolve inflammation and help tissue repair). Repolarizing tumor-associated macrophages to obtain the M1-like activity is of great clinical interest in cancer immunotherapy. Yet it is unclear how the plasticity of the macrophage is controlled and how a specific type of polarization is reached. Here, we demonstrated that nuclear remodeling is a critical event for macrophage plasticity. Particularly, we identified the nuclear envelope proteins SUN1/2 as molecular modulators that respond to polarization signals to alter the size, mechanics and positioning of the macrophage nucleus. The SUN proteins not only bridge the nuclear remodeling to cytoskeleton, cellular morphology, and chromosome for optimal phagocytosis and tissue penetration, but also connect TLR signaling to YAP signaling for gene transcription and metabolic reprogramming. Strikingly, silencing SUN1/2 is sufficient to reprogram the function of macrophages by both promoting M1- and inhibiting M2- and TAM-polarization. Given that SUN1/2-/- mice showed substantially enhanced antitumor immunity, it is promising to target nuclear membrane micromechanics in macrophages for therapeutic purpose.