TY - JOUR
T1 - Stromal cell-laden 3D hydrogel microwell arrays as tumor microenvironment model for studying stiffness dependent stromal cell-cancer interactions
AU - Yue, Xiaoshan
AU - Nguyen, Trung Dung
AU - Zellmer, Victoria
AU - Zhang, Siyuan
AU - Zorlutuna, Pinar
N1 - Funding Information:
This work is funded by American Cancer Society IRG-14-195-01 (P.Z.), HCRI Notre Dame Day Pilot Fund (S.Z.) and Walther Cancer Foundation Cancer Cure Ventures (P.Z. and S.Z.).
Funding Information:
This work is funded by American Cancer Society IRG-14-195-01 (P.Z.), HCRI Notre Dame Day Pilot Fund (S.Z.) and Walther Cancer Foundation Cancer Cure Ventures (P.Z. and S.Z.).
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/7
Y1 - 2018/7
N2 - Tumor properties such as growth and metastasis are dramatically dependent on the tumor microenvironment (TME). However, the diversity of the TME including the stiffness and the composition of the extracellular matrix (ECM), as well as the involvement of stromal cells, makes it extremely difficult to establish proper in vitro models for studying tumor growth and metastasis. In this research, we fabricated a stromal cell-laden microwell array system with tunable stiffness ranging from 200 Pa up to 3 kPa, which covers the stiffness range of normal and cancerous mammary tissues, to study the effect of ECM stiffness on stromal-cancer interaction. Our results showed that, tumor spheroids closely interacted with the pre-adipocyte stromal cells encapsulated within the microwell array, influencing their differentiation and maturation degree in a stiffness related manner. They inhibited adipogenesis in high stiffness tissue constructs that were at breast cancer stiffness range, while the inhibition effect diminished in the low stiffness tissue constructs that were at normal human breast tissue range. Furthermore, the 3D structure of tumor spheroids was shown to be important for the inhibition of the adipogenesis, as conditioned media from monolayer culture of cancer cells did not show any significant effect. These results show, for the first time in literature, that stromal-cancer interactions are highly dependent on ECM stiffness. The biomimetic TME platform developed here is a powerful organ-specific cancer model for studying the involvement of stromal cells in early mammary tumorigenesis and metastasis, and could be powerful platform for high-throughput drug discovery.
AB - Tumor properties such as growth and metastasis are dramatically dependent on the tumor microenvironment (TME). However, the diversity of the TME including the stiffness and the composition of the extracellular matrix (ECM), as well as the involvement of stromal cells, makes it extremely difficult to establish proper in vitro models for studying tumor growth and metastasis. In this research, we fabricated a stromal cell-laden microwell array system with tunable stiffness ranging from 200 Pa up to 3 kPa, which covers the stiffness range of normal and cancerous mammary tissues, to study the effect of ECM stiffness on stromal-cancer interaction. Our results showed that, tumor spheroids closely interacted with the pre-adipocyte stromal cells encapsulated within the microwell array, influencing their differentiation and maturation degree in a stiffness related manner. They inhibited adipogenesis in high stiffness tissue constructs that were at breast cancer stiffness range, while the inhibition effect diminished in the low stiffness tissue constructs that were at normal human breast tissue range. Furthermore, the 3D structure of tumor spheroids was shown to be important for the inhibition of the adipogenesis, as conditioned media from monolayer culture of cancer cells did not show any significant effect. These results show, for the first time in literature, that stromal-cancer interactions are highly dependent on ECM stiffness. The biomimetic TME platform developed here is a powerful organ-specific cancer model for studying the involvement of stromal cells in early mammary tumorigenesis and metastasis, and could be powerful platform for high-throughput drug discovery.
KW - Adipocytes
KW - Breast cancer
KW - Methacrylated gelatin
KW - Microwell array
KW - Photocrosslinkable hydrogel
KW - Stromal cells
KW - Tumor microenvironment
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U2 - 10.1016/j.biomaterials.2018.04.001
DO - 10.1016/j.biomaterials.2018.04.001
M3 - Article
C2 - 29653286
AN - SCOPUS:85045071452
SN - 0142-9612
VL - 170
SP - 37
EP - 48
JO - Biomaterials
JF - Biomaterials
ER -