This paper describes mammary organoids with a basal‐in phenotype where the basement membrane is located on the interior surface of the organoid. A key materials consideration to induce this basal‐in phenotype is the use of a minimal gel scaffold that the epithelial cells self‐assemble around and encapsulate. When MDA‐MB‐231 breast cancer cells are co‐cultured with epithelial cells from day 0 under these conditions, cells self‐organize into patterns with distinct cancer cell populations both inside and at the periphery of the epithelial organoid. In another type of experiment, the robust formation of the basement membrane on the epithelial organoid interior enables convenient studies of MDA‐MB‐231 invasion in a tumor progression‐relevant direction relative to epithelial cell‐basement membrane positioning. That is, the study of cancer invasion through the epithelium first, followed by the basement membrane to the basal side, is realized in an experimentally convenient manner where the cancer cells are simply seeded on the outside of preformed organoids, and their invasion into the organoid is monitored. Interestingly, invasion is more prominent when tumor cells are added to day 7 organoids with less developed basement membranes compared to day 16 organoids with more defined ones.
In epithelial cancers, cells must invade through basement membranes (BMs) to metastasize. The BM, a thin layer of extracellular matrix underlying epithelial and endothelial tissues, is primarily composed of laminin and collagen IV and serves as a structural barrier to cancer cell invasion, intravasation, and extravasation. BM invasion has been thought to require protease degradation since cells, which are typically on the order of 10 µm in size, are too large to squeeze through the nanometer-scale pores of the BM. However, recent studies point toward a more complex picture, with physical forces generated by cancer cells facilitating protease-independent BM invasion. Moreover, collective cell interactions, proliferation, cancer-associated fibroblasts, myoepithelial cells, and immune cells are all implicated in regulating BM invasion through physical forces. A comprehensive understanding of BM structure and mechanics and diverse modes of BM invasion may yield new strategies for blocking cancer progression and metastasis.
more » « less- NSF-PAR ID:
- 10126981
- Publisher / Repository:
- DOI PREFIX: 10.1083
- Date Published:
- Journal Name:
- The Journal of Cell Biology
- Volume:
- 218
- Issue:
- 8
- ISSN:
- 0021-9525
- Page Range / eLocation ID:
- p. 2456-2469
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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