Targeting cancer metastasis by inhibiting curvature-induced kinase activation - PROJECT SUMMARY/ABSTRACT: The overwhelming majority of cancer-associated deaths are caused by cancer metastasis rather than primary tumors. Cancer cells can metastasize, while normal cells cannot. This is due to unique characteristics that cancer cells acquire as they progress and become more aggressive. Cancer cells undergo genetic mutations that allow them to detach from the primary tumor, migrate through surrounding tissues, and enter the bloodstream or lymphatic system. Detached cancer cells must resist anoikis - a form of programmed death that occurs when cells detach from the extracellular matrix. In the absence of cell adhesions that provide survival signals for anchored cells, metastatic cancer cells must acquire special traits that enable them to persist and survive during invasion and in circulation. In this proposal, we aim to develop an effective therapy for solid tumors by targeting a survival characteristic that is newly discovered and crucial for cancer cell survival during metastasis. Very recently, we identified nanoscale membrane curvature as such a trait that is crucial for cancer cell survival in suspension but not when cells are in contact with substrates. Membrane curvature is a physical property of the lipid bilayer, but it is now recognized as an important and active constituent of biological processes. Curved membranes create distinct microenvironments that facilitate or inhibit the recruitment of specific proteins involved in signaling pathways. The discovery that the survival of cancer cells in suspension hinges on their nanoscale membrane curvature, and that this curvature facilitates essential survival signals through curvature-induced kinase activation, opens up new therapeutic avenues. In this proposal, we seek to unravel the molecular mechanisms underlying curvature-induced kinase activation, to explore the function of curvature-induced kinase activation in cancer metastasis, and to develop new therapeutic strategies by blocking curvature-induced kinase activation. Through these studies, we hope to develop curvature-blocking approaches that selectively kill metastatic cancer cells when they are detached from their surroundings without affecting normal cell survival when they are anchored to the basement membrane and other cells. These studies could lead to new treatments for combating metastatic cancer, addressing one of the most critical and challenging aspects of cancer therapy.
