Cancer Cell CD44 Mediates Macrophage/Monocyte-Driven Regulation of Head and Neck Cancer Stem Cells

Abstract

Tumor-associated macrophages (TAM) in the tumor microenvironment (TME) cooperate with cancer stem cells (CSC) to maintain stemness. We recently identified cluster of differentiation 44 (CD44) as a surface marker defining head and neck squamous cell carcinoma (HNSCC) CSC. PI3K-4EBP1-SOX2 activation and signaling regulate CSC properties, yet the upstream molecular control of this pathway and the mechanisms underlying crosstalk between TAM and CSC in HNSCC remain largely unknown. Because CD44 is a molecular mediator in the TME, we propose here that TAM-influenced CD44 signaling could mediate stemness via the PI3K-4EBP1-SOX2 pathway, possibly by modulating availability of hyaluronic acid (HA), the main CD44 ligand. HNSCC IHC was used to identify TAM/CSC relationships, and in vitro coculture spheroid models and in vivo mouse models were used to identify the influence of TAMs on CSC function via CD44. Patient HNSCCderived TAMs were positively and negatively associated with CSC marker expression at noninvasive and invasive edge regions, respec-tively. TAMs increased availability of HA and increased cancer cell invasion. HA binding to CD44 increased PI3K-4EBP1-SOX2 signaling and the CSC fraction, whereas CD44-VCAM-1 binding promoted invasive signaling by ezrin/PI3K. In vivo, targeting CD44 decreased PI3K-4EBP1-SOX2 signaling, tumor growth, and CSC. TAM depletion in syngeneic and humanized mouse models also diminished growth and CSC numbers. Finally, a CD44 isoform switch regulated epithelial-to-mesenchymal plasticity as standard form of CD44 and CD44v8-10 determined invasive and tumorigenic phenotypes, respectively. We have established a mechanistic link between TAMs and CSCs in HNSCC that is mediated by CD44 intracellular signaling in response to extracellular signals.Significance: These findings establish a mechanistic link between tumor cell CD44, TAM, and CSC properties at the tumor-stroma interface that can serve as a vital area of focus for target and drug discovery.

The Macrophage-Osteoclast Axis in Osteoimmunity and Osteo-Related Diseases

“…CD9 and CD81 belong to the superfamily of membrane proteins and negatively regulate the process of macrophages fusion into osteoclasts (50,(55)(56)(57). Another cell surface adhesion molecule, CD44, has been shown to be involved in regulating the adhesion and fusion of macrophages (49,58,59). The activity of osteoclasts is significantly inhibited through the NF-kB/ NFATc1 signaling pathway after CD44 is knocked out (60).…”

Macrophages and cancer stem cells: a malevolent alliance

“…PI3K–4EBP1–SOX2). Thus, a reciprocal feed forward loop has been identified which includes the enzyme HAS2, the matrix component hyaluronan and signaling events from the CD44 receptor on CSCs and TAMs (Gomez et al 2020 ; Skandalis et al 2019 ) (Fig. 2 ).…”

Further Understanding of the Immune Microenvironment in Head and Neck Squamous Cell Carcinoma: Implications for Prognosis

“…They established a mechanistic link between TAMs and CSCs in response to extracellular signals. 17 Targeting the reprogramming of TAMs toward M1-like macrophages has been investigated as a strategy to reverse the immunosuppressive TME. 18…”