Restrictions on Phenotypic Plasticity Have Been Unlocked To Progress As Cancer

Restrictions on Phenotypic Plasticity Have Been Unlocked To Progress As Cancer ...

Cancer has been dubbed a complex adaptive system1, and it can be seen through many lenses, including cancer epigenetics (e.g., DNA methylation, histone modifications, and microRNA,2), cancer metabolism (e.g., how nutrient availability affects tumorigenesis3 and tumor immunology (e.g., the involvement of different immune cells at different stages of tumor progression).4

In the original Hallmarks of Cancer publication, Hanahan and Weinberg predicted that research scientists would practice a drastically different science than it was in the last quarter of the nineteenth century, and that cancer might become understandable in terms of a limited number of underlying beliefs. The 2022 review builds on the original principles and proposes new hallmarks and enabling characteristics, including those under the umbrella of promoting phenotypic plasticity.

What is phenotypic plasticity, and how is it beneficial to cancer cell biology?

Cells are generally limited in the extent to which they can differentiate.7 This restriction allows them to remain organized and functional inside their respective tissue. In cancer, however, cells undergo molecular and phenotypic changes that allow them to adopt different identities along a cellular plasticity spectrum.8

Changes in the cell phenotype are crucial to cancer progression because these changes may aid tumor initiation and metastasis, immune invasion, chemoresistance, and other aspects of tumor development.8 Hanahan (2022) describes three types of phenotypic plasticity that can be unlocked during cancer:7

Mesenchymal-to-epithelial transitions are well-known examples of developmental regulatory activities that resemble transdifferentiation.9 During EMT, cells lose apicobasal polarity and gain motility, aiding cancer cells'' invasive growth capacity.7,10

phenotypic plasticity is crucial because it allows cells to take on a form that assists them in their invasive and metastatic abilities. As demonstrated by the successful development of a differentiation therapy for acute promyelocytic leukemia (APL), knowledge of this phenotypic plasticity may be clinically beneficial.11,12APL can be successfully treated by a combination of therapeutics which enable a blocked differentiation pathway to resume.13

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Diversity in cells is evident in cellular, with potential implications for medicine''s recovery

Cancer''s morphology and the dynamic nature are a challenge for human breast cancer therapies, as cells have different attachments to treatment.14 In addition, cancer''s morphology has been well-established in terms of genomics and single-cell sequencing. However, tumor evolution may also be non-genomic, according to a recent and thorough study conducted by Carlos Caldas, a leading researcher in cancer medicine at the Cambridge Institute.15Caldas and his colleagues investigated phenotypic diversity in a biobank of

According to Caldas, the group measured protein expression profiles in over 400,000 individuals. In the context of in vitro drug screening, the landscape of cell phenotypes and activation states was mapped and later integrated with genomic data. However, the phenotypic diversity as a result of cellular plasticity is vital for drug-tolerant states.

The Phenotypic states were mainly defined by lineage, particularly a spectrum spanning luminal versus basal-like states, and the epithelial-to-mesenchymal state transition described earlier. Cancer cells try to imitate the tissue from which they are derived, and triple-negative breast cancers are mostly luminal-like. In the normal breast epithelium, there are two layers of epithelial cells, which are myoepithelial and abut the basement membrane

According to Caldas, the field now believes that basal cells and luminal cells originate from different progenitors. In many instances, basal-like breast cancers in some instances originate from a luminal progenitor, rather than from the basal cells in the epithelium.

Because there is growing evidence to suggest that pretreatment cellular phenotypic composition is a factor in treatment effectiveness. This was the conclusion from Caldas'' experiments, and in some instances, cell phenotypes even outperformed genomic markers in determining treatment response.

Understanding the effect of bone microenvironment on breast cancer cells

Given that cancer can resurface following a period of dormancy, there is need to understand how certain cells escape therapy and identify therapies that can eradicate those cells. This is the focus of the Xiang (Shawn) Zhang laboratory of the Baylor College of Medicine; recently, the group identified a method in which the bone microenvironment drove metastasized ER+ breast cancer cells in bone toward a basal and stem-like state.16 In this study, we found that the heterotypic interaction

Luminal breast cancer in bone. A luminal (ER+/PR+/Her-) breast cancer technique was developed to produce a bone metastasis with intra-iliac artery injection (IIA) technique. The green, blue, and grey represent the expression of E-cadherin, cytokeratin 8, and nucleus, respectively. Image credit: Xiang Zhang laboratory

According to Zhang, the group identified a link between the inhibition of luminal markers and the EMT, indicating that bone as a tumor microenvironment can reprogram cancer cells into more aggressive cells. However, these changes may be reversed as metastases grow and some cancer cells are pushed away from osteoblasts, resulting in further support for continuing EZH2.

EZH2 is part of a complex that is crucial for heterochromatin formation, according to Bado. Exposing cancer cells to bone leads to increased heterochromatin formation, and the bone effect is altered by the ER, and the acquired endocrine resistance. EZH2 is therefore a potential partner in the development of long-term survival efforts by reducing secondary metastasis and therapeutic resistance to anti-estrogen medications.

The presence of diverse cell phenotypes has significant clinical implications.

phenotypic plasticity has been established as an important feature of cancer cells and serves as a reference to cell signaling. Alternatively, an array of molecules may be found in different regions, such as the clone of origin, and these factors may be incorporated in the cells. Moreover, this method may be used to determine tumor cell appearance.

Without the right analytical methods, phenotypic plasticity will be difficult to comprehend. However, advances in technology will continue to open doors to future research in this field. I believe that phenotypic plasticity will require single-cell DNA analysis (sequence and methylation), RNA and protein levels. There are currently several techniques that demonstrate this, but these are still not widely available and are expensive.

A phenotypic plasticity has been proposed as a discrete hallmark capability, which has significant implications for preclinical drug screening and the development of combination therapies.7,15


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17-year-old Duan R, Du W, Guo W. EZH2: a novel strategy for cancer treatment. J. Hematol. Oncol. 2020;13(1). doi:10.1186/s13045-020-00937-8

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