Solid tumors often contain genetically different populations of cancer cells, stromal cells, various structural and soluble proteins, and other soluble signaling molecules. The American Cancer society estimated 1,958,310 new cancer cases and 609,820 cancer deaths in the United States in 2023. A major barrier against successful treatment of cancer patients is drug resistance. Gain of stem cell-like states by cancer cells under drug pressure or due to interactions with the tumor microenvironment is a major mechanism that renders therapies ineffective. Identifying approaches to target cancer stem cells is expected to improve treatment outcomes for patients. Most of our understanding of drug resistance and the role of cancer stemness is from monolayer cell cultures. Recent advances in cell culture technologies have enabled developing sophisticated three-dimensional tumor models that facilitate mechanistic studies of cancer drug resistance. This review summarizes the role of cancer stemness in drug resistance and highlights the various tumor models that are used to discover the underlying mechanisms and test potentially novel therapeutics.
Engineered three-dimensional (3D) cell culture models can accelerate drug discovery, and lead to new fundamental insights in cell–cell, cell–extracellular matrix (ECM), and cell–biomolecule interactions. Existing hydrogel or scaffold-based approaches for generating 3D tumor models do not possess significant tunability and possess limited scalability for high throughput drug screening. We have developed a new library of hydrogels, called Amikagels, which are derived from the crosslinking of amikacin hydrate (AH) and poly(ethylene glycol) diglycidyl ether (PEGDE). Here we describe the use of Amikagels for generating 3D tumor microenvironments (3DTMs) of breast cancer cells. Biological characteristics of these breast cancer 3DTMs, such as drug resistance and hypoxia were evaluated and compared to those of two-dimensional (2D) monolayer cultures. Estrogen receptor (ER) positive breast cancer 3DTMs formed on Amikagels were more dormant compared to their respective 2D monolayer cultures. Relative to their respective 2D cultures, breast cancer 3DTMs were resistant to cell death induced by mitoxantrone and doxorubicin, which are commonly used chemotherapeutic drugs in cancer, including breast cancer. The drug resistance seen in 3DTMs was correlated with hypoxia seen in these cultures but not in 2D monolayer cultures. Inhibition of Mucin 1 (MUC1), which is overexpressed in response to hypoxia, resulted in nearly complete cell death of 2D monolayer and 3DTMs of breast cancer. Combination of an ER stress inducer and MUC1 inhibition further enhanced cell death in 2D monolayer and 3DTMs. Taken together, this study shows that the Amikagel platform represents a novel technology for the generation of physiologically relevant 3DTMs in vitro and can serve as a platform to discover novel treatments for drug-resistant breast cancer.
more » « less- Award ID(s):
- 1706268
- PAR ID:
- 10488428
- Publisher / Repository:
- WSPC
- Date Published:
- Journal Name:
- Nano LIFE
- Volume:
- 12
- Issue:
- 04
- ISSN:
- 1793-9844
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Cell cycle plasticity underlies fractional resistance to palbociclib in ER+/HER2− breast tumor cellsmore » « less
The CDK4/6 inhibitor palbociclib blocks cell cycle progression in Estrogen receptor–positive, human epidermal growth factor 2 receptor–negative (ER+/HER2−) breast tumor cells. Despite the drug’s success in improving patient outcomes, a small percentage of tumor cells continues to divide in the presence of palbociclib—a phenomenon we refer to as fractional resistance. It is critical to understand the cellular mechanisms underlying fractional resistance because the precise percentage of resistant cells in patient tissue is a strong predictor of clinical outcomes. Here, we hypothesize that fractional resistance arises from cell-to-cell differences in core cell cycle regulators that allow a subset of cells to escape CDK4/6 inhibitor therapy. We used multiplex, single-cell imaging to identify fractionally resistant cells in both cultured and primary breast tumor samples resected from patients. Resistant cells showed premature accumulation of multiple G1 regulators including E2F1, retinoblastoma protein, and CDK2, as well as enhanced sensitivity to pharmacological inhibition of CDK2 activity. Using trajectory inference approaches, we show how plasticity among cell cycle regulators gives rise to alternate cell cycle “paths” that allow individual tumor cells to escape palbociclib treatment. Understanding drivers of cell cycle plasticity, and how to eliminate resistant cell cycle paths, could lead to improved cancer therapies targeting fractionally resistant cells to improve patient outcomes.
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1142/S1793984422500118
