Favour Akinjiyan
Program: Molecular Genetics and Genomics
Current advisor: Gregory D. Longmore, MD
Undergraduate university: New York Institute of Technology
Research summary
Ovarian cancer has poor survival outcomes particularly for advanced stage, metastatic disease. Metastasis is promoted by interactions of stromal cells, such as cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), with tumor cells. CAFs play a key role in tumor progression by remodeling the TME and extracellular matrix (ECM) to result in a more permissive environment for tumor progression. It has been shown that fibroblasts, in particular myofibroblasts, utilize metabolism to support ECM remodeling. However, the intricate mechanisms by which CAFs support collagen production and tumor progression are poorly understood.
In this study, we show that the fibrillar collagen receptor, Discoidin Domain Receptor 2 (DDR2), promotes collagen production in human and mouse omental CAFs through arginase activity. CAFs with high DDR2 or arginase promote tumor colonization in the omentum. In addition, DDR2-depleted CAFs had decreased ornithine levels leading to decreased collagen production and polyamine levels compared to WT control CAFs. Tumor cell invasion was decreased in the presence CAF conditioned media (CM) depleted of DDR2 or arginase-1, and this invasion defect was rescued in the presence of CM from DDR2-depleted CAFs that constitutively overexpressed arginase-1. Similarly, the addition of exogenous polyamines to CM from DDR2-depleted CAFs led to increased tumor cell invasion. We detected SNAI1 protein at the promoter region of the arginase-1 gene, and DDR2-depleted CAFs had decreased levels of SNAI1 protein at the arginase-1 promoter region. Furthermore, high stromal arginase-1 expression correlated with poor survival in ovarian cancer patients. These findings highlight how
DDR2 regulates collagen production by CAFs in the tumor microenvironment by controlling the transcription of arginase 1, and CAFs are a major source of arginase activity and L-arginine metabolites in ovarian cancer models.
Graduate publications
Akinjiyan FA, Ibitoye Z, Zhao P, Shriver LP, Patti GJ, Longmore GD, Fuh KC. 2024 DDR2-regulated arginase activity in ovarian cancer-associated fibroblasts promotes collagen production and tumor progression. Oncogene, 43(3):189-201.
Akinjiyan FA, Nassief G, Phillipps J, Adeyelu T, Elliott A, Abdulla F, Zhou AY, Souroullas G, Kim KB, Vanderwalde A, Park SJ, Ansstas G. 2024 ARID2 mutations may relay a distinct subset of cutaneous melanoma patients with different outcomes. Sci Rep, 14(1):3444.
Akinjiyan FA, Morecroft R, Phillipps J, Adeyelu T, Elliott A, Park SJ, Butt OH, Zhou AY, Ansstas G. 2023 Homologous Recombination Deficiency (HRD) in Cutaneous Oncology. Int J Mol Sci, 24(13):10771.
Akinjiyan FA, Dave RM, Alpert E, Longmore GD, Fuh KC. 2022 DDR2 Expression in Cancer-Associated Fibroblasts Promotes Ovarian Cancer Tumor Invasion and Metastasis through Periostin-ITGB1. Cancers (Basel), 14(14):3482.
Akinjiyan FA, Adams A, Xu S, Wang M, Toriola AT. 2022 Plasma Growth Factor Gene Expression and Mammographic Breast Density in Postmenopausal Women. Cancer Prev Res (Phila), 15(6):391-98.
Akinjiyan FA, Han Y, Luo J, Toriola AT.. 2021 Does circulating progesterone mediate the associations of single nucleotide polymorphisms in progesterone receptor (PGR)-related genes with mammographic breast density in premenopausal women?. Discov Oncol, 12(1):47.