Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2018-2019)

Novelty, research program and short-term goal – Bi-directional epithelial-mesenchymal transitions (EMT/MET) are fundamental cellular processes essential for normal mammalian embryonic development and adult cell homeostasis and functions. While the majority of studies thus far focus on how growth factors, extracellular signals, transcriptional factors, and intracellular signaling pathways regulate EMT/MET, a fundamental question that have been largely overlooked and yet to be answered is whether and how dynamic EMT/MET, in turn, affect their regulators to co-control embryonic development and adult cell homeostasis and functions. This will be the long-term goal of our research program ; the short-term goal of this proposed project (and hypothesis ) will determine whether and how EMT/MET states differentially affect Wnt, Akt and Yap signaling activities and adult cell functions (Fig 1).

Our recent progress related to this proposed research project – The trainees in my lab have recently observed that high level of E-cadherin expression (a cell membrane protein demarcating epithelial state) in adult cells markedly upregulates Wnt and Akt activity while suppressing Yap pathway; β-catenin knockdown (i.e. Wnt inhibition) significantly upregulates Yap in mesenchymal but not in epithelial state in adult cells (preliminary data).

Short term objectives – Adult cells, gain- and loss-of-function and multidisciplinary approaches commonly shared by academic and biotech researchers will be used in the following three aims. In Aim 1 , group 1 trainees will determine whether complete and partial epithelial-mesenchymal transitions affect Yap, β-catenin, Akt signaling activities and cell functions (proliferation, apoptosis, migration and cell cycle). In Aim 2 , group 1 trainees will further determine which cytoplasmic partner(s) of E-cadherin (α-catenin, β-catenin, and p120) is critical to the alternations of Wnt, Yap and Akt signaling activities and cell functions during mesenchymal-epithelial transition using different E-cadherin constructs. In Aim 3 , group 2 trainees will determine whether and the extent by which inhibition and activation of one pathway will differentially affect other two pathways and cell functions in an EMT/MET-dependent manner; they will also determine which cytoplasmic partner(s) of E-cadherin in the MET state is important to these alternations.

Significance – As part of the aforementioned research program, knowledge gained from this proposed project will provide new insights into the currently unknown roles of EMT/MET in regulating Wnt, Yap and Akt signaling and adult cell functions. It will also offer an excellent platform for trainees to prepare their careers for academia or biotechnology companies.