CAFs‐derived MFAP5 promotes bladder cancer malignant behavior through NOTCH2/HEY1 signaling

Abstract

Cancer‐associated fibroblasts (CAFs) are an important component of the tumor microenvironment and contribute to tumor cell proliferation and metastasis. Microfibrillar‐associated protein 5 (MFAP5), a component of elastic microfibers and an oncogenic protein in several types of tumors, is secreted by CAFs. However, the role of MFAP5 in the bladder cancer remains unclear. Here, we report that MFAP5 is upregulated in bladder cancer and is associated with poor patient survival. Downregulation of MFAP5 in CAFs led to an impairment in proliferation and invasion of bladder cancer cells. Luciferase reporter assays and electrophoretic mobility shift assays (EMSA) showed QKI directly downregulates MFAP5 in CAFs. In addition, CAFs‐derived MFAP5 led to an activation of the NOTCH2/HEY1 signaling pathway through direct interaction with the NOTCH2 receptor, thereby stimulating the N2ICD release. RNA‐sequencing revealed that MFAP5‐mediated PI3K‐AKT signaling activated the DLL4/NOTCH2 pathway axis in bladder cancer. Moreover, downregulation of NOTCH2 by short hairpin RNA or the inactivating anti‐body NRR2Mab was able to reverse the adverse effects of MFAP5 stimulation in vitro and in vivo. Together, these results demonstrate CAFs‐derived MFAP5 promotes the bladder cancer proliferation and metastasis and provides new insight for targeting CAFs as novel diagnostic and therapeutic strategy.

Cancer: a mirrored room between tumor bulk and tumor microenvironment

“…TME of solid malignancies has crucial roles in tumor progression, invasiveness, metastasis, drug resistance [ 2 – 4 ], and even in the maintenance of the cancer stem-like phenotype [ 5 ].…”

“…Despite the huge effort made by the scientific community in the last century, the incidence of cancer is continuously increasing [ 1 ] and it remains an incurable and lethal disease in the majority of cases. It has been widely documented that the tumor microenvironment (TME) of solid malignancies plays a key role in the promotion of tumor progression, invasiveness, metastasis, drug resistance [ 2 – 4 ] and even in the maintenance of the cancer stem-like phenotype [ 5 ]. TME is composed of an extracellular matrix, an extensive vascular network, lymphatic vessels, soluble molecules, and cells: cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-endothelial cells, pericytes, tumor-associated adipocytes, B lymphocytes or T lymphocytes [ 6 ].…”

Cancer-Associated Fibroblasts: Understanding Their Heterogeneity

“…MFAP5 promotes ECs motility and the rearrangement of their cytoskeleton via Notch signaling [ 153 , 154 ]. Recent studies show a correlation between MFAP5 and ACTA2 expression in CAFs, suggesting that they may identify a new subtype of CAFs [ 79 , 155 ]. In bladder cancer and oral squamous cell carcinoma, MFAP5 secreted by CAFs activates NOTCH2/HEY1, ERK and PI3K signaling pathways directly, promoting the proliferation, migration and invasion of cancer cells [ 155 , 156 ].…”

“…Recent studies show a correlation between MFAP5 and ACTA2 expression in CAFs, suggesting that they may identify a new subtype of CAFs [ 79 , 155 ]. In bladder cancer and oral squamous cell carcinoma, MFAP5 secreted by CAFs activates NOTCH2/HEY1, ERK and PI3K signaling pathways directly, promoting the proliferation, migration and invasion of cancer cells [ 155 , 156 ]. In murine xenografted models of ovarian cancer, MFAP5 secreted by CAFs upregulates lipoma-preferred partner (LPP) in ECs via FAK/ERK signaling, which promotes paclitaxel chemoresistance and angiogenesis [ 157 ].…”

“…In murine xenografted models of ovarian cancer, MFAP5 secreted by CAFs upregulates lipoma-preferred partner (LPP) in ECs via FAK/ERK signaling, which promotes paclitaxel chemoresistance and angiogenesis [ 157 ]. In bladder and breast cancers, high expression of MFAP5 in CAFs correlated with high-grade malignancy, presence of metastasis and unfavorable clinical outcome [ 155 ]. In murine models of ovarian and PDAC cancers, inhibition of MFAP5 with monoclonal antibodies is associated with a decrease in the number of CAFs and microvessels, but also with increased sensitivity to paclitaxel [ 158 ].…”