September 2022 is a month Ekrem Emrah Er won’t soon forget.
Er, PhD, assistant professor of physiology and biophysics at the UIC College of Medicine and member of the University of Illinois Cancer Center’s Cancer Biology program, received two new grants – one federally funded by the National Cancer Institute (NCI) – and served as corresponding author on a review paper that has been published in the journal Cancer Research, all within the month. Er’s research focuses on the most deadly form of breast cancer, metastatic breast cancer.
“The lives of tens of thousands of women each year are affected by metastatic breast cancer,” Er said. “The majority of treatment options, unfortunately, do not cure the disease. Current treatment strategies often target the genetic and biomechanical abnormalities of the cancer cells, but the cells also undergo profound changes in their biophysical properties, such as cellular stiffness.
“Targeting biophysical properties offers exciting new therapeutic avenues, but we’re still trying to learn more about the relationship between cancer cell stiffness and how the disease is spread.”
In an effort to identify additional defects in cancer cells that can be targeted for treatments, Er and his laboratory discovered that a body’s immune system could sense and destroy cancer cells based on their altered biophysical stiffness. This is due in part, Er said, to the fact that when cancer cells are attacked by immune cells, softer cancer cells bend but do not break, whereas stiffer cells shatter.
“Based on the mechanical nature of this mode of immune surveillance, we termed it ‘mechanosurveillance’ and demonstrated that it cooperates with the FDA-approved immune checkpoint blockade therapies in preclinical settings,” Er said. “We also identified Myocardin Related Transcription Factor A expression as a vulnerability to mechanosurveillance.”
A protein coding gene, MRTFA factors heavily in Er’s latest project, as he will use patient derived organoids, breast cancer tissues and mouse models of experimental metastasis to determine how it and the subsequent cellular calcium update stiffen the cancer cells and render them more vulnerable to mechanosurveillance.
“Our goal is to identify novel nodes of therapeutic intervention to facilitate mechanosurveillance and guide its deployment alongside cutting-edge immunotherapies in the fight against metastatic breast cancer,” Er said.
NCI will fund the grant (1R37CA269370-01A1) for five years at more than $1.8 million. It is a MERIT Award (The Method to Extend Research in Time) that can be extended for another two years of funding support based on expedited review by NCI.
Er was also the recipient of a new grant from Concern Foundation, a Los Angeles-based organization that “funds promising cancer research scientists in the early stage of discovery within the laboratory to understand the fundamental principles of tumor immunology. The knowledge gained from these young research scientists will lead to future treatments and early diagnosis, and eventually stop this insidious disease,” according to the not-for-profit’s website.
Er will expand on his research with mechanosurveillance to identify ways cytotoxic lymphocytes can be used to safely target metastatic cancer.
“The immune system’s cytotoxic lymphocytes are the ultimate defenders of vital secondary organs as they effectively target metastatic cancer cells,” Er said. “We’ve discovered that increasing the physical stiffness of cancer cells mechanically activated near cytotoxic lymphocytes is a method to successfully treat the disease.”
The two-year grant is funded at $60,000 per year.
In a review paper published in Cancer Research, a journal of the American Association of Cancer Research (AACR), Er and his colleagues discussed the mechanical changes cancer cells undergo during metastasis, how the changes affect immune and stromal responses, and the implications of the new insights for therapeutic intervention.
“Epithelial transformation and carcinogenesis are characterized by profound alterations in cell mechanics that significantly affect multiple steps of the metastatic cascade,” Er said. “The ability of cancer cells to grow in the primary tumor, to locally invade through the confining extracellular matrix, to survive in circulation, and to extravasate into distant vital organs all depend on specific mechanical characteristics.
“Most importantly, recent studies have shown that the mechanical properties of cancer cells also influence their interactions with immune and stromal cells.”
Prior research has concluded that biophysical forces regulate multiple stages of the metastatic cascade (where the aggressive cells leave the tumor, travel through the bloodstream and reach other organs) and that the alteration involved more than just bi-directional interplay between the extracellular matrix and cancer cells. The understanding of the phenomenon is “still rudimentary,” Er said.
“The molecular and cellular complexity of tumors is recapitulated in their mechanobiology. A basic understanding of the mechanobiology driving the growth and suppression of metastasis offers valuable insights into how the metastatic cascade is regulated and reveals nodes of therapeutic intervention,” he said.