Investigating the Proliferation-Quiescence Decision in Tissues and in Cancer Cells

Abstract

Tight regulation of cell division is important for proper development and homeostasis in all multicellular organisms. While most cells in an adult metazoan exit cell cycle and exist in a non-dividing or quiescent state, a subset of cells retain the ability to re-enter cell cycle in response to external stimuli to replace lost cells. A cell needs to receive, interpret, and integrate various stimuli with its internal cell cycle control machinery to maintain the proper balance between proliferation and quiescence. When dysregulation of the proliferation-quiescence decision happens, it can give rise to diseases such as cancer and developmental disorders. Hence, understanding the factors that influence the proliferation-quiescence decision will be important for improving our understanding of developmental biology as well as cancer. In this thesis, I investigate two contexts of regulation for the proliferation-quiescence decision. In chapter 2, I examine prostate cancer cells in cell culture, which make spontaneous and heterogeneous proliferation-quiescence decisions in the ex-vivo cell culture context, which is often used to study cancer cells. I show that these cancer cells often make asynchronous proliferation-quiescence decisions, even in pairs of daughter cells born from the same mitosis. Furthermore, I show that signals associated with cancer dormancy in-vivo, increase the frequency of cancer cells entering spontaneous quiescence, which may help cancer cells evade chemotherapy and contribute to cancer recurrence. In chapter 3, I complement this in-vitro work with an in-vivo epithelial tissue model, the Drosophila wing, to examine how the loss of the Nucleoporins Nup98 and Nup96 can affect the proliferation-quiescence decision in cells. Nup 98 and 96 are commonly mutated in a number of cancers through silencing or chromosomal translocations, but how their loss contributes to the overproliferation in cancer remains unclear. I show that a reduction in Nup98 and 96 function leads to nuclear sequestration of a ribosomal subunit, causing defects in ribosome biogenesis and protein synthesis. This leads to cellular stress signaling via activation of the JNK signaling pathway and bypass of cellular quiescence, which leads to increased cell death. However, when cell death is blocked by additional mutations, as often happens in cancer, the JNK-stress signaling instead leads to overproliferation and tissue overgrowth. This work suggests that defects in protein synthesis may underlie the overproliferation in cancers with Nup98 and 96 mutations and suggests an unexpected route for therapeutic intervention to increase protein synthesis in these cancers. Altogether, this thesis pushes forward the boundary of our understanding of the factors affecting proliferation or quiescence in cancer.