Hippo-YAP pathway as a mediator of extracellular matrix signals in non-malignant and malignant epithelial cells of the mammary gland

• Grant number: 14/25832-1
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): September 01, 2015
• Effective date (End): January 31, 2020
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Alexandre Bruni Cardoso
• Grantee: Ana Paula Zen Petisco Fiore
• Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 14/10492-0 - Hippo-YAP as a converging pathway for biochemical and mechanical signals from the extracellular matrix during mammary gland morphogenesis and breast cancer progression, AP.JP
• Associated scholarship(s): 17/18641-3 - MST2 proteolysis as a mechanism to modulate HIPPO-YAP activity in breast epithelial cells, BE.EP.PD

Abstract

The composition and organization of the extracellular matrix (ECM) and tissue architecture are crucial microenvironment components that produce biochemical and mechanical signals that can initiate and sustain asymmetrical patterns of proliferation an invasion in several tissues, including mammary gland epithelia. However, it remains uncertain which intracellular pathways/molecules connect cues from the microenvironment to the cell nucleus, triggering changes in gene expression programs that regulate cell behavior. In the FAPESP Young Investigator grant, which the present project is associated, we explore the hypothesis that Hippo-YAP, a pathway that regulates organ growth and size and acts as a relay to mechanical signals, may play a key role in ECM to nucleus communication during mammary gland morphogenesis and malignant transformation. YAP is a transcription co-activator that promotes cell proliferation and survival. The kinase cascade Hippo has been implicated as major regulator of YAP activity. Yet, the role of Hippo during changes in ECM composition in mammary gland non-malignant and malignant cells remains unclear. Our preliminary data from bioinformatics analysis indicate that YAP-regulated genes are differentially expressed during mammary gland morphogenesis and tumor progression. We observed also that the basement membrane (BM) modulates YAP localization in non-malignant mammary cells. By contrast, malignant cells do not respond to MB signals. In this project, we aim to study whether alterations in ECM composition contribute to Hippo-YAP regulation in the acquisition of malignant phenotypes. We will use bioinformatics and biochemistry and cellular assays and tools. The conclusion of this study will bring relevant information to understanding molecular processes that mediate the communication between cells and ECM in the regulation of cell proliferation and quiescence in normal and malignant cells of the mammary gland.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GOMES, LUCIANA RODRIGUES; REILY ROCHA, CLARISSA RIBEIRO; MARTINS, DAVI JARDIM; PETISCO FIORE, ANA PAULA ZEN; KINKER, GABRIELA SARTI; BRUNI-CARDOSO, ALEXANDRE; MARTINS MENCK, CARLOS FREDERICO. ATR mediates cisplatin resistance in 3D-cultured breast cancer cells via translesion DNA synthesis modulation. CELL DEATH & DISEASE, v. 10, JUN 12 2019. Web of Science Citations: 4.

ZEN PETISCO FIORE, ANA PAULA; RIBEIRO, PEDRO DE FREITAS; BRUNI-CARDOSO, ALEXANDRE. Sleeping Beauty and the Microenvironment Enchantment: Microenvironmental Regulation of the Proliferation-Quiescence Decision in Normal Tissues and in Cancer Development. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 6, JUN 7 2018. Web of Science Citations: 5.

FIORE, ANA PAULA ZEN PETISCO; SPENCER, VIRGINIA A.; MORI, HIDETOSHI; CARVALHO, HERNANDES F.; BISSELL, MINA J.; BRUNI-CARDOSO, ALEXANDRE. Laminin-111 and the Level of Nuclear Actin Regulate Epithelial Quiescence via Exportin-6. CELL REPORTS, v. 19, n. 10, p. 2102-2115, JUN 6 2017. Web of Science Citations: 14.