Breast-Tumour Stiffness Directs Bone Metastasis Through Mechanical Conditioning Maintenance

Saptaparna Dasgupta, Bennett University

The intermediate and transitory reaction of breast-tumour stiffness to pathological rigidity has been carefully investigated in their native microwave environment. However, it remains unclear how the main phenotypes of stiffness caused by the cancer cell are stained in vivo over a while. Certain mechanisms are associated based on how fibrotic-like matrix rigidity assists metastatic phenotypes in the oncogenic cells. These phenotypes, after they transition to a softer microenvironment like bone marrow, are preserved for long terms. A multigenic score of mechanical conditioning (MeCo) using differential gene expression analysis of stiffness-responsive breast carcinoma cells was created. Respectively, the association of it with bone metastases in individuals with breast cancer was studied.

Mechanism of Metastasis Induction

The previous studies on breast cancer indicate that breast-tumour stiffness is a ubiquitous feature for the progression of breast cancer. Mechanotransduction thus occurs as the resultant signalling stimuli, after the cells get adhered to a stiff matrix. This stimulus promotes metastasis and directs the tumour behaviour within the primary tumours. Soft microenvironments such as the bone marrow, which comprises the primary site for the outgrowth of tumours in the bone marrow. Runt-related transcription factor 2 (RUNX2) is used as a tool to characterize some of the dynamical variations in chromatin accessibility that are a function of mechanical conditioning maintenance. RUNX2 gets activated by the fibrotic-like stiffness, it stays adhered to the DNA during the time of cell division and it is known for tagging the cells which help in the induction of metastasis.

Devastating effects of breast-tumour metastasis

Tumour stiffening develops while the breast tissue with the oncogene turns fibrotic, this thus plays a crucial role in the metastasis and invasion of breast cancer. The resultant conversion put up in the body in the form of mechanical memory, induces the signals leading to the destruction of the osteocytes (Fig 1). This further causes complications like spontaneous fractures in the patients. Considering the danger that bone metastasis is non-detectable until it attains an advanced stage where it turns irreversible.

Fig1. Effects of breast-tumors and the journey of metastasis of tumors followed by invasion of the bone marrow, wherein, they lead to the destruction of osteocytes.

MeCo score

Demonstration of the aspects of mechanical memory has turned to a novel concept of mechanical conditioning (MeCo) score. This score helps in the quantification of cellular changes. Also, it is used to identify the breast cancer patients to whom repurposed antifibrotic treatments could benefit and prevent tumour metastasis to bones. It was inferred that the higher the MeCo score of the breast tumour, the higher shall be the chance for the tumours to metastasize to bones and result in unsatisfactory outcomes. Thus, MeCo can be used as the analytical medium for assessing the breast-tumour stiffness response. This property stands to be favourable as most of the invasive breast tumours are stiffer as compared to the tissues surrounding them, out of which only a portion is responsible for the osteolytic metastasis.

Fibrotic-like stiffness

For the identification of genes that are actively involved in the MeCo score and bone metastasis, linear regression was used. It was observed that the subset of MeCo genes was constantly influenced either by upregulation or downregulation within the primary tumours. Fibrotic-like stiffness was determined in vivo, which revealed that the cells under a softer microenvironment grew faster, which further induced the reduction of the cortical bone volume. Thus, mechanical conditioning (MeCo) is proven to promote metastasis of breast tumours to bones in breast cancer patients.

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References:

1. Watson, A. W., Grant, A. D., Parker, S. S., Hill, S., Whalen, M. B., Chakrabarti, J., Harman, M. W., Roman, M. R., Forte, B. L., Gowan, C. C., Castro-Portuguez, R., Stolze, L. K., Franck, C., Cusanovich, D. A., Zavros, Y., Padi, M., Romanoski, C. E., & Mouneimne, G. (2021). Breast tumor stiffness instructs bone metastasis via maintenance of mechanical conditioning. Cell Reports, 35(13), 109293. https://doi.org/10.1016/j.celrep.2021.109293
2. Breast cancer’s response to tumour stiffness might help predict bone metastasis. (n.d.). ANI News. Retrieved July 5, 2021, from https://www.aninews.in/news/science/breast-cancers-response-to-tumour-stiffness-might-help-predict-bone-metastasis20210703224042/

About author:

Saptaparna Dasgupta, currently a B. Tech 3^rd year student, pursuing Biotechnology, is a diligent student and determined in terms of her career goals. Being a budding biotechnologist, she is open to all research fields of her course and passionate about knowledge. She is focused and constantly tries to improve her writing skills, also a project enthusiast and is fond of gaining hands-on experience in laboratories. She believes that all hard work and efforts pays off eventually and follows this as the motto of her life. Check out some of her works at:

• Dasgupta, S. (2021, June 22). Etheno Adducts of Nucleic Acids and their Carcinogenic Aspects – BioXone. https://bioxone.in/news/worldnews/etheno-adducts-of-nucleic-acids-and-their-carcinogenic-aspects/
• Dasgupta, S. (2021, June 28). The Venomous Doratifera vulnerans as the Savior of Life – BioXone. https://bioxone.in/news/worldnews/the-venomous-doratifera-vulnerans-as-the-savior-of-life/
• Dasgupta, S. (2021, June 30). Pfizer and Moderna: Long-Lasting Protection Against COVID-19 – BioXone. https://bioxone.in/news/worldnews/pfizer-and-moderna-long-lasting-protection-against-covid-19/

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