A team of scientists has harnessed CRISPR technology to identify a protein that helps cancers spread to bone tissue, opening the door for potential therapies to prevent the common and painful disease progression.
Mice with increased levels of acyl–coenzyme A binding protein (ACBP) had a greater chance of their lung or breast cancer metastasizing to their bones, and an analysis of genetic data from human lung and breast cancers found that higher ACBP was correlated with bone metastasis and poorer survival outcomes.
When mice implanted with metastasis-prone human cancer cells were treated with compounds that targeted ACBP’s activity, none of the rodents’ cancer spread to their bones. These compounds were imidazole ketone erastin (IKE) and etomoxir.
The research, published in Science Translational Medicine on May 21, was led by oncologist Li Ma, Ph.D., of the University of Texas MD Anderson Cancer Center, in collaboration with scientists from Rice University in Houston and Shanghai Jiao Tong University in China.
A key feature of cancer is its ability to metastasize, migrating from its place of origin and colonizing other organs in the body. The bones are a common destination for metastasizing cancers, along with the lymph nodes, liver and lungs. Bone metastases can produce a near-constant ache of pain and increase the risk of bone fractures.
Treating secondary bone cancer usually entails managing symptoms, administering bone-strengthening medicines called bisphosphonates and continuing to treat the primary cancer at its source.
“Current therapeutic interventions remain largely palliative in patients with bone metastases,” the researchers wrote in their paper. “Understanding and targeting the molecular underpinnings of bone metastasis represent one of the most pressing challenges in cancer therapy.”
To identify ACBP as a bone metastasis promoter, the researchers used a CRISPR activation screen. They built a library of 2,302 guide RNA molecules targeting different genes and attached those RNAs to protein machinery, derived from proteins used in CRISPR gene editing, that boosts the expression of targeted genes. The team could then insert this machinery into cancer cells and see which activated genes made the cells more metastatic.
Once ACBP was fingered as a culprit, further tests revealed that the protein helped cancer cells generate energy through fatty acid oxidation (FAO) and avoid a programmed cell death process called ferroptosis. The compounds Ma and colleagues tested—etomoxir and IKE—interfere with FAO and promote ferroptosis, respectively.
“We found that FAO blockade or treatment with a ferroptosis inducer inhibited bone metastasis in mouse models, suggesting translational potential,” the scientists wrote.
General interest in bone metastasis spiked after the May 18 announcement that former President Joe Biden was diagnosed with an aggressive form of prostate cancer that has spread to his bones. Despite this, Biden’s cancer is expected to be manageable, according to his office’s statement.