Research

Regulation of Nuclear Size in Xenopus Embryos and Cancer Cells (American Cancer Society)

PI: Levy

Background: Organelle size control is a fundamental cell biological problem. Understanding size control of the nucleus is particularly important because nuclear size is often inappropriately enlarged in cancer cells in a ploidy-independent manner, a change used by pathologists to diagnose and stage disease. Despite a tremendous amount of correlative data linking cancer and abnormal nuclear size, no studies have addressed whether changes in nuclear size are a cause or consequence of the disease state. That this major morphological hallmark of cancer has received so little attention is due to a gap in our knowledge of the mechanisms that regulate nuclear size and our ability to manipulate nuclear size in cells to test the functional significance of proper nuclear size control.

Hypothesis: We will test the hypothesis that normal physiological changes in nuclear size during embryogenesis contribute to proper timing and morphology in the developing embryo. We will also test the hypothesis that changes in nuclear size during carcinogenesis affect the functional properties of dividing cells.

Specific Aims: (1) Demonstrate how nuclear size contributes to developmental progression; (2) Identify developmental mechanisms that regulate nuclear size; (3) Demonstrate how nuclear size contributes to carcinogenesis.

Study Design: (1) The objective is to test how altering nuclear size in Xenopus embryos affects developmental timing and later development at the organismal level. The approach is to experimentally manipulate nuclear size by mRNA microinjection and observe the resulting effects on embryogenesis by microscopy. (2) The objective is to identify mechanisms and factors that control reductions in nuclear size during early Xenopus development. The working hypothesis is that nuclear size is regulated by changes in nuclear lamina dynamics, nucleocytoplasmic transport, and/or membrane structure and proteins. The approach is to compare the composition and functional capacities of early and late stage Xenopus embryo extracts and to test how nuclear size is affected by manipulating these activities. (3) The objective is to test how nuclear scaling factors identified in Xenopus control nuclear size in cultured mammalian cells and to test how cell function is modulated by nuclear size. The approach is to alter the levels of nuclear scaling factors in tissue culture cells to ascertain effects on nuclear and cell size and cell proliferation and motility.

Cancer Relevance: Little is known about the causes or effects of nuclear morphology changes in cancer. We will identify developmental mechanisms that control nuclear size and demonstrate how nuclear size impacts embryogenesis and cell transformation, informing how nuclear size contributes to carcinogenesis. Aberrant nuclear size in cancer might actually be required for cell homeostasis and viability, so therapeutic manipulation of nuclear size could provide a means to selectively target and kill only affected cells.