If a row of dominos started to fall, and you were intent on keeping as many dominos standing as possible, you would likely remove a domino as near the start of the row as possible. And so it is with a disease pathway, a sequence of molecular events that may culminate in illness if it is not interrupted, preferably near the start, before a cascade gathers force and becomes irresistible.
One such disease pathway has been identified in metastatic breast cancer. This particular molecular cascade is launched, in part, by a protein called heterogeneous nuclear ribonucleoprotein M, or hnRNPM. Once hnRNPM starts the molecular dominos tumbling, the results become increasingly dire: breast cancer cells break away from the original tumor, penetrate the blood stream, invade another part of the body, and form a new nodule of that tumor.
In experiments with human cells, researchers at Northwestern Medicine identified hnRNPM’s role in controlling the processes linked to tumor metastasis. The researchers, led by Chonghui Cheng, M.D., looked at breast cancer tumor specimens from patients and levels of hnRNPM in those samples. They found aggressive breast tumors, including those that show metastatic traits, expressed higher levels of hnRNPM. Then they removed the protein in a mouse model of breast cancer and discovered the cancer’s ability to spread was significantly reduced.
The scientists published their results June 1 in the journal Genes & Development, in an article entitled “Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing.” The article details how the scientists uncovered a splicing-mediated pathway that is essential for breast cancer metastasis.
“We show that hnRNPM promotes breast cancer metastasis by activating the switch of alternative splicing that occurs during epithelial–mesenchymal transition (EMT),” the authors explained. “Genome-wide deep sequencing analysis suggests that hnRNPM potentiates TGFβ signaling and identifies CD44 as a key downstream target of hnRNPM.”
The scientists reported that they not only showed that hnRNPM ablation prevents TGFβ-induced EMT and inhibits breast cancer metastasis in mice, they also demonstrated that enforced expression of the specific CD44 standard (CD44s) splice isoform overrides the loss of hnRNPM and permits EMT and metastasis
The authors also noted that hnRNPM is associated with aggressive breast cancer and correlates with increased CD44s in patient specimens. “This confirmed hnRNPM’s role in the metastasis of human breast cancer,” Dr. Cheng said. “Now we’re investigating how the protein works in order to be able to develop a drug that could prevent tumor metastasis.”
According to the investigators, the ubiquitously expressed hnRNPM acts in a mesenchymal-specific manner to precisely control CD44 splice isoform switching during EMT. “This restricted cell-type activity of hnRNPM is achieved by competition with ESRP1,” the authors continued, “an epithelial splicing regulator that binds to the same cis-regulatory RNA elements as hnRNPM and is repressed during EMT.”
“Our research suggests that hnRNPM could be an effective target to stop cancer cells from spreading,” reflected Dr. Cheng. “So far there isn't a really good target that can cure breast cancer. The more we understand of cancer metastasis and the pathways that control it, the better we will be able to stop breast cancer from spreading.”