The antitumor effects of WNT5A against hematological malignancies

Author(s)

Bueno, Maura Lima Pereira ; Saad, Sara Teresinha Olalla ; Roversi, Fernanda Marconi

• Document type: Journal article
• Source: JOURNAL OF CELL COMMUNICATION AND SIGNALING; v. 17, n. 4, p. 13-pg., 2023-06-13.

Abstract

The bone marrow (BM) microenvironment (niche) is abnormally altered in acute myeloid leukemia (AML), leading to deficient secretion of proteins, soluble factors, and cytokines by mesenchymal stromal cells (MSC) that modifies the crosstalk between MSC and hematopoietic cells. We focused on a WNT gene/protein family member, WNT5A, which is downregulated in leukemia and correlated with disease progression and poor prognosis. We demonstrated that WNT5A protein upregulated the WNT non-canonical pathway only in leukemic cells, without modulating normal cell behavior. We also introduced a novel WNT5A-mimicking compound, Foxy-5. Our results showed reduction of crucial biological functions that are upregulated in leukemia cells, including ROS generation, cell proliferation, and autophagy, as well as G0/G1 cell cycle arrest. Additionally, Foxy-5 induced early-stage macrophage cell differentiation, a crucial process during leukemia development. At a molecular level, Foxy-5 led to the downregulation of two overexpressed leukemia pathways, PI3K and MAPK, which resulted in a disarrangement of actin polymerization with consequent impairment of CXCL12-induced chemotaxis. Notably, in a novel tri-dimensional bone marrow-mimicking model, Foxy-5 led to reduced leukemia cell growth and similar results were observed in a xenograft in vivo model. Overall, our findings highlight the pivotal role of WNT5A in leukemia and demonstrate that Foxy-5 acts as a specific antineoplastic agent in leukemia, counterbalancing several leukemic oncogenic processes related to the crosstalk in the bone marrow niche, and represents a promising therapeutic option for AML. [GRAPHICS] . (AU)

• FAPESP's process: 17/21801-2 - Predictors of severity and new treatments for bone marrow neoplasias
• Grantee: Sara Teresinha Olalla Saad
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/25247-5 - Study of inhibitory and antitumor activity of natural substance-associated MAPK and WNT inhibitors in in vitro models
• Grantee: Maura Lima Pereira Bueno
• Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training
• FAPESP's process: 21/05320-0 - Profile of Brazilian undergraduates who use electronic cigarettes: an epidemiological study on forbidden use
• Grantee: Gabriella dos Santos Maximino
• Support Opportunities: Scholarships in Brazil - Scientific Initiation