Mutations in Adenomatous Polyposis Coli, Their Role in Cytoskeletal Dynamics and Cancer Onset

Abstract

Perturbations of the cellular cytoskeleton in cancer are typically associated with oncogenic mutations that result in changes in cell shape, migration, and division control. However, studies of monoallelic mutations in the tumor suppressor adenomatous polyposis coli (APC) reveal that disruption of cytoskeletal dynamics precedes cancer cell transformation and potentially alters a remarkable number of pathways that can independently contribute to disease progression. In this chapter, we lay out the evidence that monoallelic mutations in APC, found in human colorectal cancers, act dominantly to inhibit microtubule dynamics. We discuss evidence that inhibition of microtubule dynamics affects intestinal crypt cells where cancer originates. We will review the evidence that inhibition of microtubule dynamics results in a wide array of cellular defects including: mitotic errors and changes in chromosome ploidy; changes in spindle orientation that can alter cell fate; chronic perturbations in cytoskeletal dynamics that affect cell polarity and cell homeostasis. In addition, we will discuss how each of these pathways fits into current models that implicate genomic instability and changes in cellular programming in cancer onset. Finally, we propose a model whereby APC mutations and the resulting changes in cytoskeletal dynamics lead to a “permissive” state of heightened cellular adaptation that allows for cell proliferation in the presence of oncogenic mutations, thus promoting cancer onset and progression.