Abstract
Cancer-associated fibroblasts (CAF) play a crucial role in regulating cancer progression, yet the molecular determinant that governs the tumor regulatory role of CAF remains unknown. Using a mouse melanoma model in which exogenous melanoma cells were grafted on the skin of two lines of mice where the genetic activation or inactivation of Notch1 signaling specifically occurs in natural host stromal fibroblasts, we demonstrated that Notch1 pathway activity could determine the tumor-promoting or tumor-suppressing phenotype in CAF. CAF carrying elevated Notch1 activity significantly inhibited melanoma growth and invasion, while those with a null Notch1 promoted melanoma invasion. These findings identify the Notch1 pathway as a molecular determinant that controls the regulatory role of CAF in melanoma skin growth and invasion, unveiling Notch1 signaling as a potential therapeutic target for melanoma and potentially other solid tumors.
Highlights
Cancer-associated fibroblasts (CAF) are stromal fibroblasts residing within and in the vicinity of the tumor mass
To examine the role of CAF with high Notch1 activity in regulating melanoma growth, 5 x 105 Luciferase 2 (Luc2)+/B16-F10 cells were inoculated onto skin of GOFNotch1 vs. GOFctrl mice
There are numerous options for activation of Notch1 pathway in CAF, such as using gene therapy approach or novel genome editing method, CRISPR/Cas9 or CRISPR/Cpf1, to introduce N1IC, or applying Notch pathway activating compound, which can be identified through a similar high-throughput screening method [20], activating Notch1 signaling in CAF, while not simultaneously increasing the Notch activity in melanoma cells, pose a therapeutic challenge, as the biological function of Notch signaling is cell contextdependent [21], and high Notch activity is oncogenic to melanoma [13]
Summary
CAF are stromal fibroblasts residing within and in the vicinity of the tumor mass They are primarily derived from activated local quiescent fibroblasts and recruited circulating bone marrow mesenchymal stem cells (MSC) [1,2]. CAF are involved in regulating tumor progression by eliciting soluble factors, extracellular matrix (ECM) [3] and exosomes [4]. Their contribution to primary and secondary malignancies [5,6] as well as taking part in drug resistance and tumor recurrence [7,8] make CAF potential targets for therapeutic interventions on the tumor microenvironment (TME). Loss of Notch in mouse embryonic fibroblasts (MEF) resulted in faster cell growth and motility rate, whereas
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