SPINT2 Suppresses Hippo Effector YAP and Limits Cellular Tolerance for Aneuploidy

Abstract

Oncogenic transformation is often accompanied by chromosome instability, an increased rate of chromosome missegregation. The consequent gain or loss of chromosomes—termed aneuploidy—hinders the growth of most non-cancerous tissues, but is prevalent in tumors. During tumorigenesis, aneuploidy contributes to cellular heterogeneity and may promote downstream mutations, including chromosome rearrangements and oncogene amplification. Cellular mechanisms that safeguard against aneuploidy remain unclear. The Hippo pathway is a tumor-suppressor mechanism with essential roles in regulating tissue homeostasis. YAP, the downstream effector inhibited by the Hippo pathway, is an oncogenic transcriptional cofactor that promotes proliferation and is frequently amplified in cancers. Upstream regulators of the Hippo pathway and YAP are partially understood. SPINT2 is a transmembrane protein with extracellular serine protease inhibitor domains and is a negative regulator of various proteases including activators of growth factors. Epigenetic silencing of SPINT2 by promoter hypermethylation is observed in cancers such as medulloblastoma, renal cell carcinoma, and acute myeloid leukemia. Notably, recent findings demonstrate that SPINT2 loss enables cells to tolerate multiple types of stress, including cytokinesis failure and DNA damage. Considering the distinct cellular machineries that respond to these stresses, it is conceivable that SPINT2 may regulate multiple signaling pathways. In the present dissertation, I delineate SPINT2’s role as a negative regulator of YAP. I demonstrate that SPINT2 limits YAP activity via protease-activated receptors. In addition, using models of chromosome missegregation and aneuploidy, I establish that loss of SPINT2 confers heightened cellular tolerance for aneuploidy. My findings highlight two intriguing hypotheses regarding cellular processes of cancer development. First, broad-spectrum membrane-anchored protease modulators such as SPINT2 may serve as “convergence points” where a multitude of extracellular signals are regulated for discrete downstream signaling events inside the cell. Second, the tolerance for aneuploidy may be a “built-in” component of oncogenic signaling such as YAP activation, as opposed to requiring separate cellular mechanisms. The aneuploid state of tumors, therefore, may be an integral output of intra- and extra-cellular oncogenic signaling, and may serve as a feedforward process that enhances further genomic instability during tumorigenesis.