Bone is the third most frequent site of metastasis, behind lung and liver.[1] In breast and prostate cancer, bone marrow is a preferential site of metastasis, responsible for the majority of skeletal metastases. These skeletal or bone metastases are often indications of a short-term prognosis for the cancer patient. In advanced stages, cancer spread to the bones can rarely be cured, but in many cases, it can still be treated to slow tumor growth.[2]

A new study by researchers at the University of Arizona Health Sciences found that cancer cells become more aggressive when exposed to tissue stiffening and that these changes persist over time.[3]

Ghassan (Gus) Mouneimne, Ph.D. associate professor of cellular and molecular medicine and cancer biology in the University of Arizona College of Medicine in Tucson, AZ.

The study, published in the journal Cell Reports, confirms that tumor stiffening, which develops as diseased breast tissue becomes fibrotic, plays a major role in how breast cancer cells spread throughout the body. The authors of the study found that the stiffness of the breast tumor microenvironment can cause changes to cancer cells that make them more aggressively spread to the bone. The resulting changes are maintained as “mechanical memory,” which instructs the cancer cells to send signals that lead to the breakdown of bone. Once this happens, patients often suffer debilitating complications like spontaneous fractures.

“Unfortunately, bone metastasis is normally not identified until an advanced state when it’s not reversible,” said senior author Ghassan Mouneimne, Ph.D., associate professor of cellular and molecular medicine and cancer biology in the University of Arizona College of Medicine in Tucson, AZ.

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“What’s really exciting is one day being able to take a sample from the patient’s primary tumor and predict who is at high risk for bone metastasis. Then we could intervene with a prevention strategy that we are now validating in the lab,” Mouneimne added.

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Mechanical memory
The study is the first to demonstrate the concept of mechanical memory during cancer metastasis, developed a novel mechanical conditioning, or “MeCo,” score, to quantify the cellular changes. Eventually, researchers hope the MeCo score can be used to help identify breast cancer patients who might benefit from repurposed antifibrotic treatments to prevent bone metastasis.

“The higher the patient’s breast tumor MeCo score, the higher the likelihood they would go on to have bone metastasis and poorer outcomes,” said Casey Romanoski, Ph.D., assistant professor of cellular and molecular medicine and a member of the BIO5 Institute and University Arizona Cancer Center.

“This stiffness signature could have incredible clinical utility,” she added.

Casey Romanoski, Ph.D., assistant professor of cellular and molecular medicine and a member of the BIO5 Institute and University Arizona Cancer Center, is one of the researchers who helped develop the MeCo score.

Clinical application
To further explore the clinical application, Mouneimne and Adam Watson, Ph.D., a former graduate student and postdoctoral fellow at the University of Arizona Cancer Center, worked with Tech Launch Arizona, the office of the university that commercializes inventions stemming from research, to launch a startup called MeCo Diagnostics.

The company is working toward maturing the technology and bringing it to the marketplace where it can impact the lives of breast cancer patients everywhere.

It was previously known that tumor stiffness induces cellular changes that lead to a more aggressive cancer, but according to Watson, lead author on the paper, the concept of “stiffness” was misleading.

“Most early-stage breast tumors are stiffer than surrounding tissue, yet most don’t spread to the bone,” he explained.

“It’s not about tumor stiffness but rather stiffness responsiveness of the cancer cells, which we call mechanical conditioning.”

To study this phenomenon, the team created a laboratory environment that mimicked the stiff or soft tumor environments encountered in the body and assessed how breast cancer cells responded. They found that cells grown in a stiff environment had a “mechanoresponse” characterized by cell spreading, invasion, and turning on genes linked with both bone development and disease. And these gene changes endured even after the cells were moved to a soft environment.

Next, researchers looked at what genes were turned on and off in breast cancer cells in response to the stiff environments. Based on these gene expression changes, they developed the MeCo score, which was validated and refined using data from thousands of patients with breast cancer.

“This is the culmination of a lot of work by researchers from many different fields,” Dr. Mouneimne said. “It highlights the environment we have at the University of Arizona Health Sciences, and how working together can make progress in this challenging area of breast cancer metastasis.”

Future investigations could focus on how cancer cells maintain the gene expression changes that drive metastasis, based on additional findings that identified a transcription factor called RUNX2 that was activated by fibrotic-like stiffness. RUNX2 stays attached to the DNA as the cell divides and “bookmarks” which genes remain turned on, which includes the genes that drive bone metastasis and the breakdown of bone.

Reference
[1] Macedo F, Ladeira K, Pinho F, Saraiva N, Bonito N, Pinto L, Goncalves F. Bone Metastases: An Overview. Oncol Rev. 2017 May 9;11(1):321. doi: 10.4081/oncol.2017.321. PMID: 28584570; PMCID: PMC5444408.
[2] Cecchini M, Wetterwald A, Pluijm G, Thalmann G. Molecular and biological mechanisms of bone metastasis. EAU Update Series 2005;3:214-26
[3] Watson AW, Grant AD, Parker SS, Hill S, Whalen MB, Chakrabarti J, Harman MW, Roman MR, Forte BL, Gowan CC, Castro-Portuguez R, Stolze LK, Franck C, Cusanovich DA, Zavros Y, Padi M, Romanoski CE, Mouneimne G. Breast tumor stiffness instructs bone metastasis via maintenance of mechanical conditioning. Cell Rep. 2021 Jun 29;35(13):109293. doi: 10.1016/j.celrep.2021.109293. PMID: 34192535.

Featured image: Watching a mammogram-the result of x-ray examination of the mammary glands for the prevention of breast cancer. Photo Courtesy: © 2016 – 2021 Fotolia/Adobe/Evgeniy Kalinovskiy.

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