Study Finds Breast Cancer Response to Tumor Stiffness May Predict Bone Metastasis


Three-dimensional culture of human breast cancer cells, with DNA stained blue and a protein on the surface membrane of the cell stained green. Image created in 2014 by Tom Misteli, Ph.D., and Karen Meaburn, Ph.D. to NIH IRP.

In cases of breast cancer, bone metastasis (when cancer cells spread to new bone sites) causes the most damage related to breast cancer and is often incurable in advanced diseases. A new study by health sciences researchers at the University of Arizona found that cancer cells become more aggressive when exposed to tissue stiffness and that these changes persist over time.

Tumor hardening, which develops as diseased breast tissue becomes fibrotic, plays an important role in how breast cancer spread all over the body. The document, “Mama stiffness instructs bone metastasis by maintaining mechanical conditioning, ”published today in the journal Cell reports, found that the stiffness of the breast tumor microenvironment can cause changes in cancer cells that cause them to spread more aggressively to the bone. The resulting changes are maintained as “mechanical memory,” which tells cancer cells to send signals that lead to bone degradation. Once this happens, patients often experience debilitating complications such as spontaneous fractures.

“Unfortunately, bone metastasis is not normally identified until an advanced state when it is not reversible,” said lead author Ghassan Mouneimne, Ph.D., associate professor of and cancer biology at UArizona College of Medicine – Tucson. “What’s really exciting is that one day you can take a sample of the patient’s primary tumor and predict who has a high risk of bone metastasis. Then we could intervene with a prevention strategy that we’re now validating in the lab.”

The study, which is the first to demonstrate the concept of mechanical memory during cancer metastasis, developed a new mechanical conditioning, or “MeCo” score, to quantify cell changes. Finally, the researchers hope that the MeCo score can be used to help identify breast cancer patients who may benefit from reused antifibrotic treatments to prevent bone metastasis.

“The higher the MeCo score of the patient’s breast tumor, the greater the likelihood that they will have bone metastasis and worse outcomes,” said Casey Romanoski, Ph.D., assistant professor of cellular and molecular medicine and member of the BIO5 Institute and UArizona Cancer Center. “This rigidity signature could have incredible clinical utility.”

To delve deeper into the clinical application, Dr. Mouneimne and Adam Watson, Ph.D., a former graduate student and postdoctoral fellow at the UArizona Cancer Center, worked with Tech Launch Arizona, the university’s office that markets research-derived inventions, to start a startup, MeCo Diagnostics , LLC. The company is working to mature the technology and bring it to market, where it can affect the lives of breast cancer patients everywhere.

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

“Most early-stage breast tumors are more rigid than the surrounding tissues, but most do not spread to the bones,” he said. “It’s not about tumor stiffness, it’s about responding to the stiffness of cancer cells, which we call mechanical conditioning.”

To study this phenomenon, the team created a laboratory environment that mimicked the rigid or soft tumor environments found in the body and evaluated how breast cancer cells responded. They found that cells cultured in a rigid environment had a “mechanical response” characterized by the spread, invasion, and activation of cellular genes related to both bone development and disease. And these gene changes persisted even after the cells moved to a soft environment.

The researchers then examined which genes are activated and turned off in response to rigid environments. Based on these changes in gene expression, they developed the MeCo score, which was validated and refined using data from thousands of breast cancer patients.

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

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

The bone microenvironment promotes the metastatic behavior of breast cancer

More information:
Adam W. Watson et al, Breast Tumor Stiffness Instructs Bone Metastasis by Maintaining Mechanical Conditioning, Cell reports (2021). DOI: 10.1016 / j.celrep.2021.109293

Provided by Health Sciences University of Arizona

Citation: Study Finds Breast Cancer Response to Tumor Stiffness May Predict Bone Metastasis (2021, June 30) Retrieved July 1, 2021 at breast-cancer-response-tumor-stiffness.html

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