Scientists in the U.S. have created genetically engineered mesenchymal stem cells (MSCs) that can recognize and target “stiff” metastatic tumor tissue and deliver cancer-killing drugs directly to the tumor site. Tests in mouse models of metastatic breast cancer confirmed that the mechanoresponsive cell system (MRCS) can selectively target and destroy cancer cells and shrink tumors, without harming normal tissue either around the tumor or in other organs. The University of California, Irvine team, led by Weian Zhao, Ph.D., associate professor of pharmaceutical sciences, hopes that stiffness-targeting MSCs, and potentially other engineered cell types including chimeric antigen receptor (CAR) T cells, could be developed to treat or diagnose a wide range of cancers, and possibly other disorders characterized by fibrosis.

It’s a unique approach that hasn’t been attempted before, Dr. Zhao told GEN. “Cancer, including metastatic tissues and their extracellular matrix, become stiff due to abnormal collagen deposition and crosslinking, which is caused by cancer cells and in turn promotes cancer progression and metastasis. The biophysical properties of the cancer tissue have not been targeted before, making our study innovative.”

The treatment also only targets metastatic tissue, which could avoid some of the unwanted side effects of  conventional chemotherapy, suggests Dr.  Zhao, who is a member of the Chao Family Comprehensive Cancer Center and the Sue & Bill Gross Stem Cell Research Center at UC Irvine.

The rationale behind the therapeutic concept was inspired both by the discovery that the tumor microenvironment has this unique, abnormal biophysical property and also by another recent finding, “that the fate of stem cells is regulated by biophysical properties of the environment where they reside,” Dr. Zhao added. “We also use stem cells because they can preferentially migrate to tumor sites when they are transplanted. Our idea was to engineer stem cells so when they are transplanted into the body, they can sense and respond to the unique stiffness at cancer microenvironment to activate antitumor therapeutics to kill cancer cells.”

Dr. Zhao’s team engineered bone marrow MSCs to home in on and respond to the stiffness of tumor tissue by producing the prodrug-activating enzyme cytosine deaminase (CD), which converts the inactive prodrug 5-fluorocytosine (5-FC) into its active cancer cell-killing form 5-fluorouracil (5-FU). “Stem cells are engineered with a mechanosensitive promoter that is coupled with downstream therapeutics (or cancer diagnostic reporters),” Dr. Zhao explained to GEN. “These stem cells, when transplanted, will naturally migrate to the metastatic sites—just like how our white blood cells migrate to site of infection. There, they will sense and respond to stiff tissue and release drug to kill cancer cells.”

The researchers first validated the MRCS concept in vitro, using hydrogels of various stiffness. They then confirmed that the stiffness-activated MRCS engineered to release CD could migrate to and kill cultured breast cancer cells exposed to 5-FC. Encouragingly, when the team then tested the engineered MSCs in a mouse model of metastatic breast cancer, the treatment shrank tumors and prolonged survival, without harming healthy brain, lung, liver, or bone marrow. In contrast, MSCs that weren’t engineered to respond specifically to tissue stiffness did cause off-target toxicity.

“Our study demonstrates that the MRCS, which is engineered to be inducible by biophysical and mechanical cues, specifically responds to matrix stiffness in vitro and can selectively target and kill cancer metastases with minimal side effects in vivo,” the researchers write in their published paper in Science Translational Medicine (“Mechanoresponsive Stem Cells to Target Cancer Metastases through Biological Cues“). “Our MRCS can serve as a platform for future diagnostics and therapies targeting aberrant tissue stiffness in conditions such as cancer and fibrotic diseases, and it should help to elucidate mechanobiology and reveal what cells “feel” in the microenvironment in vivo.

Although the published research is focused on breast cancer metastases in the lungs, the UC Irvine technology will be applicable to other metastases, because a number of different solid tumor types exhibit the same biophysical characteristic of being stiffer than normal tissue, Zhao suggested. “This is why our system is innovative and powerful, as we don't have to spend the time to identify and develop a new genetic or protein marker for every kind of cancer.”

The technique could therefore address common challenges associated with existing tumor-targeting approaches, he commented to GEN. “Previous effort of cancer treatment has been focused on targeting cancer cell biochemical factors (e.g., genes, proteins, etc). However, it is difficult to identify biochemical factors that are unique to particular cancer because they are heterogeneous. Cancer also can easily develop resistance to treatments that target cancer biochemical factors. These are the challenges that we hope our approach of targeting biophysical cues of tissue can help to address.”

The team hopes to broaden the basic concept of targeting biophysical stiffness to other disease types. “Basically, this platform technology can target any diseases that possess abnormal stiffness,” Dr. Zhao added. “In the case of fibrosis, for example, we use cells to deliver matrix metalloproteinases to eradicate fibrotic tissue (in contrast to antitumor drugs to kill cancer cells), using other engineered cell types.”

Dr. Zhao also stressed the potential to apply the stiffness-sensing tumor-targeting technology to therapeutic cell types other than MSCs. “Expanding the approach of targeting cancer biophysical cues to CAR T cells is something ongoing and we are extremely excited about,” he indicated to GEN. “In this way, we can leverage T cell's natural tumor killing ability, together with our specific target and activation, only at the tumor site but not healthy tissue site [so] we can improve both killing efficacy and reduce side effects. …We are keen to move this technology, especially the engineered mechanosensing CAR-T treatment for solid tumor, to the clinic. We are excited to look for partnership to rapidly translate the technology.”


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