Finding by Fox Chase Researchers That YAP1 Molecule is Essential to Development of Gastruloids Using Embryonic Stem Cells May Have Implications for Cancer

PHILADELPHIA (February 17, 2022)—Researchers at Fox Chase Cancer Center have discovered that the Hippo signaling effector YAP1 is a master regulator of Nodal signaling in human embryonic stem cells (hESCs) for a process essential to human development.

“Our findings may have a wide range of implications, from understanding the process of human development to cancer progression,” said Conchi Estarás, PhD, a member of both the Cancer Epigenetics Institute and Cancer Signaling and Epigenetics research program at Fox Chase.

YAP1 is highly active in development but its activity decreases after birth. However, in adulthood, YAP1 is reactivated in many types of cancer, including liver cancer.

“Our work focuses on understanding the role of YAP in the context of normal stem cells during development. Understanding how YAP1 works in this context will provide us the knowledge necessary to generate new tools to fight against YAP1-driven cancers,” she said. Estarás is also an assistant professor in the Department of Cardiovascular Sciences and a member of the Center for Translational Medicine at the Lewis Katz School of Medicine at Temple University.

A gastruloid is a small aggregate of cells that mimics an early developmental structure called gastrula. The gastruloid is composed of three layers: ectoderm, mesoderm, and endoderm. These layers contain the founder cells of all organs in the human body, making gastrulation and the gastrula a milestone developmental stage. Errors in this process lead to embryonic death or birth defects.

In order for an embryo to develop past the gastrulation process, the appropriate dose of Nodal protein is essential. Previous research had suggested a role for YAP1 in gastrulation, but more information was needed.

In this study, Estarás and researchers at the Katz School of Medicine and other institutions used hESCs to create gastruloids in vitro and investigate the role of YAP1 in the process of gastrulation. They used 2D micropattern surfaces to make hESCs cells differentiate into mesoderm, ectoderm, and endoderm cells in the so-called gastruloid structure.

“Ethical restrictions forbid the study with human embryos, therefore recreated embryogenesis using in vitro-generated gastruloids allow us to investigate the molecular pathways involved in this essential developmental process,” Estarás said.

The analysis yielded two important findings. First, that YAP1 regulates the correct allocation of the three-germ layers in the gastruloids and that gastruloids with YAP1 deleted had a reduced ectoderm layer and an enlarged mesoderm and endoderm layers.

“The ectoderm is the germ layer that gives rise to the nervous system and the outer surface of the body, such as the skin,” Estarás said. “The right formation of the ectoderm layer is then essential for the development of the embryo.”

Second, in order for an embryo to develop past the gastrulation process, the right dose of Nodal protein is essential. Estarás and colleagues found that YAP1 is essential to dictating how much Nodal protein is produced in the gastruloid.

“Removing YAP1 in the gastruloid leads to too much Nodal protein, which in turn leads to gastrulation defects,” Estarás said. “In vivo, this mechanism would lead to developmental arrest.” 

The study, “YAP1 Regulates the Self-Organized Fate Patterning of hESCs-Derived Gastruloids,” was published in Stem Cell Reports, an open access journal from Cell Press.

Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase is also one of just 10 members of the Alliance of Dedicated Cancer Centers. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence six consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

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