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1. Cell cycle plasticity underlies fractional resistance to palbociclib in ER+/HER2− breast tumor cells

   https://doi.org/10.1073/pnas.2309261121  

   Zikry, Tarek M.; Wolff, Samuel C.; Ranek, Jolene S.; Davis, Harris M.; Naugle, Ander; Luthra, Namit; Whitman, Austin A.; Kedziora, Katarzyna M.; Stallaert, Wayne; Kosorok, Michael R.; et al (February 2024, Proceedings of the National Academy of Sciences)

   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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2. Fibroblasts Promote Proliferation and Matrix Invasion of Breast Cancer Cells in Co‐Culture Models

   https://doi.org/10.1002/adtp.201900121  

   Plaster, Madison; Singh, Sunil; Tavana, Hossein (September 2019, Advanced Therapeutics)

   Abstract Fibroblasts are an abundant cell type in tumor microenvironments. Activated fibroblasts, known as carcinoma‐associated fibroblasts (CAFs), interact with cancer cells through biochemical signaling and render cancer cells proliferative, invasive, and resistant to therapeutics. Targeting CAFs–cancer cells interactions offers a strategy to block cancer progression. 2D and 3D co‐cultures of human mammary fibroblasts and triple negative breast cancer (TNBC) cells are used to investigate the impact of heterotypic cellular interactions on the proliferation of matrix invasion of TNBC cells. The results show that fibroblasts secreting a chemokine, CXCL12, significantly enhance proliferation of TNBC cells expressing the chemokine receptor, CXCR4. Disrupting this interaction with a receptor antagonist normalizes cancer cell proliferation to that of a co‐culture model lacking this signaling. When co‐culture spheroids are embedded in collagen, fibroblasts producing CXCL12 promote collagen invasion of TNBC cells. Although co‐cultures containing normal fibroblasts also lead to TNBC cell spreading into the matrix, a morphological analysis of cells and inhibition of chemokine‐receptor signaling shows that this spreading is due to the incompatibility of fibroblasts and cancer cells leading to the segregation of the two cell types from the spheroid. 

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3. Targeted Polymeric Nanoparticles for Drug Delivery to Hypoxic, Triple-Negative Breast Tumors

   https://doi.org/10.1021/acsabm.0c01336  

   Mamnoon, Babak; Loganathan, Jagadish; Confeld, Matthew I.; De Fonseka, Nimesha; Feng, Li; Froberg, Jamie; Choi, Yongki; Tuvin, Daniel M.; Sathish, Venkatachalem; Mallik, Sanku (December 2020, ACS Applied Bio Materials)

   null (Ed.)

   High recurrence and metastasis to vital organs are the major characteristics of triple-negative breast cancer (TNBC). Low vascular oxygen tension promotes resistance to chemo- and radiation therapy. Neuropilin-1 (NRP-1) receptor is highly expressed on TNBC cells. The tumor-penetrating iRGD peptide interacts with the NRP-1 receptor, triggers endocytosis and transcytosis, and facilitates penetration. Herein, we synthesized a hypoxia-responsive diblock PLA–diazobenzene–PEG copolymer and prepared self-assembled hypoxia-responsive polymersomes (Ps) in an aqueous buffer. The iRGD peptide was incorporated into the polymersome structure to make hypoxia-responsive iRGD-conjugated polymersomes (iPs). Doxorubicin (DOX) was encapsulated in the polymersomes to prepare both targeted and nontargeted hypoxia-responsive polymersomes (DOX-iPs and DOX-Ps, respectively). The polymeric nanoparticles released less than 30% of their encapsulated DOX within 12 h under normoxic conditions (21% oxygen), whereas under hypoxia (2% oxygen) doxorubicin release remarkably increased to over 95%. The targeted polymersomes significantly decreased TNBC cells’ viability in monolayer and spheroid cultures under hypoxia compared to normoxia. Animal studies displayed that targeted polymersomes significantly diminished tumor growth in xenograft nude mice. Overall, the targeted polymersomes exhibited potent antitumor activity in monolayer, spheroid, and animal models of TNBC. With further developments, the targeted nanocarriers discussed here might have the translational potential as drug carriers for the treatment of TNBC. 

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4. Cell shape, and not 2D migration, predicts extracellular matrix-driven 3D cell invasion in breast cancer

   https://doi.org/10.1063/1.5143779  

   Baskaran, Janani_P; Weldy, Anna; Guarin, Justinne; Munoz, Gabrielle; Shpilker, Polina_H; Kotlik, Michael; Subbiah, Nandita; Wishart, Andrew; Peng, Yifan; Miller, Miles_A; et al (May 2020, APL Bioengineering)

   Metastasis, the leading cause of death in cancer patients, requires the invasion of tumor cells through the stroma in response to migratory cues, in part provided by the extracellular matrix (ECM). Recent advances in proteomics have led to the identification of hundreds of ECM proteins, which are more abundant in tumors relative to healthy tissue. Our goal was to develop a pipeline to easily predict which ECM proteins are more likely to have an effect on cancer invasion and metastasis. We evaluated the effect of four ECM proteins upregulated in breast tumor tissue in multiple human breast cancer cell lines in three assays. There was no linear relationship between cell adhesion to ECM proteins and ECM-driven 2D cell migration speed, persistence, or 3D invasion. We then used classifiers and partial-least squares regression analysis to identify which metrics best predicted ECM-driven 2D migration and 3D invasion responses. We find that ECM-driven 2D cell migration speed or persistence did not predict 3D invasion in response to the same cue. However, cell adhesion, and in particular cell elongation and shape irregularity, accurately predicted the magnitude of ECM-driven 2D migration and 3D invasion. Our models successfully predicted the effect of novel ECM proteins in a cell-line specific manner. Overall, our studies identify the cell morphological features that determine 3D invasion responses to individual ECM proteins. This platform will help provide insight into the functional role of ECM proteins abundant in tumor tissue and help prioritize strategies for targeting tumor-ECM interactions to treat metastasis. 

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5. Three‐dimensional culture models to study drug resistance in breast cancer

   https://doi.org/10.1002/bit.27356  

   Fisher, Madeline_F; Rao, Shreyas_S (April 2020, Biotechnology and Bioengineering)

   Abstract Despite recent advances in breast cancer treatment, drug resistance frequently presents as a challenge, contributing to a higher risk of relapse and decreased overall survival rate. It is now generally recognized that the extracellular matrix and cellular heterogeneity of the tumor microenvironment influences the cancer cells' ultimate fate. Therefore, strategies employed to examine mechanisms of drug resistance must take microenvironmental influences, as well as genetic mutations, into account. This review discusses three‐dimensional (3D) in vitro model systems which incorporate microenvironmental influences to study mechanisms of drug resistance in breast cancer. These bioengineered models include spheroid‐based models, biomaterial‐based models such as polymeric scaffolds and hydrogels, and microfluidic chip‐based models. The advantages of these model systems over traditionally studied two‐dimensional tissue culture polystyrene are examined. Additionally, the applicability of such 3D models for studying the impact of tumor microenvironment signals on drug response and/or resistance is discussed. Finally, the potential of such models for use in the development of strategies to combat drug resistance and determine the most promising treatment regimen is explored. 

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