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Updated: Nov 14, 2025
A Novel Stromal Fibroblast-Modulated 3D Tumor Spheroid Model for Studying Tumor-Stroma Interaction and Drug Discovery
Published on: February 28, 2020
Converting melanoma-associated fibroblasts into a tumor-suppressive phenotype by increasing intracellular Notch1
Hongwei Shao1, Mecker Moller1, Long Cai1
1Department of Surgery, University of Miami School of Medicine, Miami, Florida, United States of America.
Abstract:
Cancer-associated fibroblasts (CAFs) play a crucial role in cancer progression, drug resistance and tumor recurrence. We have recently shown that the Notch pathway determines the tumor-regulatory role of experimentally created 'CAFs'. Here, we examined the status of Notch signaling in human melanoma-associated fibroblasts (MAFs) versus their normal counterparts and tested whether manipulation of the Notch pathway activity in MAFs alters their tumor-regulatory function. Using tissue microarrays, we found that MAFs exhibit decreased Notch pathway activity compared with normal fibroblasts in adjacent and non-adjacent skin. Consistently, MAFs isolated from human metastatic melanoma exhibited lower Notch activity than did normal human fibroblasts, demonstrating that Notch pathway activity is low in MAFs. We then investigated the effect of increasing Notch pathway activity in MAF on melanoma growth in co-cultures and in a mouse co-graft model. We found that activation of the Notch pathway in MAFs significantly restricted melanoma cell growth in vitro and suppressed melanoma skin growth and tumor angiogenesis in vivo. Our study demonstrates that the Notch signaling is inhibited in MAFs. Increase of Notch pathway activity can confer tumor-suppressive function on MAFs. Thus, targeting melanoma by activating Notch signaling in MAF may represent a novel therapeutic approach.
Insights
Melanoma-associated fibroblasts (MAFs) show reduced Notch signaling. Activating this pathway in MAFs inhibits melanoma growth and tumor angiogenesis, offering a potential new therapy.
Area of Science:
- Oncology
- Cell Biology
- Cancer Research
Background:
- Cancer-associated fibroblasts (CAFs) influence tumor progression, drug resistance, and recurrence.
- The Notch pathway's role in CAFs' tumor-regulatory function has been previously established.
- Melanoma-associated fibroblasts (MAFs) are a specific subtype of CAFs found in melanoma.
Purpose of the Study:
- To investigate Notch signaling status in human MAFs compared to normal fibroblasts.
- To determine if manipulating Notch pathway activity in MAFs affects their tumor-regulatory function.
- To explore the therapeutic potential of targeting Notch signaling in MAFs for melanoma treatment.
Main Methods:
- Analysis of Notch pathway activity in MAFs and normal fibroblasts using tissue microarrays.
- Isolation and co-culture of MAFs and melanoma cells in vitro.
- In vivo studies using a mouse co-graft model to assess melanoma growth and angiogenesis.
Main Results:
- MAFs exhibit significantly decreased Notch pathway activity compared to normal fibroblasts.
- Activation of the Notch pathway in MAFs suppressed melanoma cell growth in vitro.
- In vivo, Notch pathway activation in MAFs restricted melanoma skin growth and reduced tumor angiogenesis.
Conclusions:
- Notch signaling is demonstrably inhibited in MAFs.
- Enhancing Notch pathway activity in MAFs can induce tumor-suppressive functions.
- Targeting Notch signaling in MAFs presents a novel therapeutic strategy for melanoma.
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