Abstract
The normal mammary microenvironment can suppress tumorigenesis and redirect cancer cells to adopt a normal mammary epithelial cell fate in vivo. Understanding of this phenomenon offers great promise for novel treatment and detection strategies in cancer, but current model systems make mechanistic insights into the process difficult. We have recently described a low-cost bioprinting platform designed to be accessible for basic cell biology laboratories. Here we report the use of this system for the study of tumorigenesis and microenvironmental redirection of breast cancer cells. We show our bioprinter significantly increases tumoroid formation in 3D collagen gels and allows for precise generation of tumoroid arrays. We also demonstrate that we can mimic published in vivo findings by co-printing cancer cells along with normal mammary epithelial cells to generate chimeric organoids. These chimeric organoids contain cancer cells that take part in normal luminal formation. Furthermore, we show for the first time that cancer cells within chimeric structures have a significant increase in 5-hydroxymethylcytosine levels as compared to bioprinted tumoroids. These results demonstrate the capacity of our 3D bioprinting platform to study tumorigenesis and microenvironmental control of breast cancer and highlight a novel mechanistic insight into the process of microenvironmental control of cancer.
Highlights
Understanding the capacity of the local microenvironment to control the fate of cells is of vital importance to developmental biology, cancer biology, and regenerative medicine[1,2,3,4]
We demonstrate that both MCF-7 and MDA-MB-468 human breast cancer cells incorporate into bioprinted organoids
We show that MCF-7 cells incorporated and contributed to luminal structure formation and undergo epigenetic alterations evidenced by significant increases in 5-hydroxymethylcytosine (5-hmC) levels
Summary
Understanding the capacity of the local microenvironment (niche) to control the fate of cells is of vital importance to developmental biology, cancer biology, and regenerative medicine[1,2,3,4]. The redirected cells displayed normal MEC morphology and function and could self-renew and contribute to second generation outgrowths demonstrating they had not been terminally differentiated These results were interpreted to mean that the non-mammary/cancer cells would be incorporated into niches as they were reformed by the dispersed MECs during transplantation. Www.nature.com/scientificreports do not have the 3D architectures necessary to elicit the functional organization and cellular relationships of the in vivo environment[17] For these reasons, 3D in vitro and ex vivo cell culture systems represent an indispensable tool to investigate the processes related to tissue and tumor formation. We describe the adaptation of our mammary epithelial organoid printing protocol for the generation of 3D tumoroids and chimeric organoids We demonstrate that both MCF-7 and MDA-MB-468 human breast cancer cells incorporate into bioprinted organoids. This system offers a significant improvement over traditional culture techniques and establishes a platform for future study into the microenvironmental control of cancer
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