How a rare childhood cancer affecting muscle cells is reversed back to muscle cells

Good news! Cancer is history (soon)! Seems to be a very clever approach!

"... Rhabdomyosarcoma, also called RMS, is a rare childhood cancer that forms in muscle tissue. RMS cells start off as ordinary myoblasts—undifferentiated cells that eventually give rise to skeletal muscle. But if the differentiation process goes awry, these myoblasts never transform into full-fledged muscle cells capable of contracting and relaxing. Instead, they multiply out of control, creating devastating tumors. 

Molecular biologists wanted to see if they could reverse this process, hopefully converting cancerous cells back into normal tissue. Using a new genetic screening technique, they identify a protein called NF-Y, which plays a key role in the biology of RMS cells. And when the researchers used CRISPR gene editing to inactivate NF-Y, something astonishing happened: The cells stopped multiplying, lost their cancerous attributes, and began differentiating into regular muscle cells. ...

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"... This newfound relationship between NF-Y and RMS may set off the chain reaction needed to bring differentiation therapy to patients. And the mission doesn’t stop at RMS. The technology could be applicable to other cancer types. If so, scientists may someday work out how to turn other tumors into healthy cells. ...
Previously, ... team succeeded in transforming Ewing sarcoma cells into healthy tissue cells. ..."

From the significance and abstract:

"Significance

Rhabdomyosarcoma is a lethal pediatric cancer for which new therapies are needed. In this study, we developed a high-throughput genetic screening method to identify genes that cause rhabdomyosarcoma cells to differentiate into normal muscle. We used this platform to discover the protein NF-Y as an important molecule that contributes to rhabdomyosarcoma biology. CRISPR-based genetic targeting of NF-Y converts rhabdomyosarcoma cells into differentiated muscle, and we reveal the mechanism by which this occurs. Since many forms of human sarcoma exhibit a defect in cell differentiation, the methodology described here might have broad relevance for the investigation of these tumors. In addition, our findings suggest that NF-Y could serve as a molecular target for the development of differentiation therapy in rhabdomyosarcoma.

Abstract

Recurrent chromosomal rearrangements found in rhabdomyosarcoma (RMS) produce the PAX3–FOXO1 fusion protein, which is an oncogenic driver and a dependency in this disease. One important function of PAX3–FOXO1 is to arrest myogenic differentiation, which is linked to the ability of RMS cells to gain an unlimited proliferation potential. Here, we developed a phenotypic screening strategy for identifying factors that collaborate with PAX3–FOXO1 to block myo-differentiation in RMS. Unlike most genes evaluated in our screen, we found that loss of any of the three subunits of the Nuclear Factor Y (NF-Y) complex leads to a myo-differentiation phenotype that resembles the effect of inactivating PAX3–FOXO1. While the transcriptomes of NF-Y- and PAX3–FOXO1-deficient RMS cells bear remarkable similarity to one another, we found that these two transcription factors occupy nonoverlapping sites along the genome: NF-Y preferentially occupies promoters, whereas PAX3–FOXO1 primarily binds to distal enhancers. By integrating multiple functional approaches, we map the PAX3 promoter as the point of intersection between these two regulators. We show that NF-Y occupies CCAAT motifs present upstream of PAX3 to function as a transcriptional activator of PAX3–FOXO1 expression in RMS. These findings reveal a critical upstream role of NF-Y in the oncogenic PAX3–FOXO1 pathway, highlighting how a broadly essential transcription factor can perform tumor-specific roles in governing cellular state."

Once rhabdomyosarcoma, now muscle | Cold Spring Harbor Laboratory

Myo-differentiation reporter screen reveals NF-Y as an activator of PAX3–FOXO1 in rhabdomyosarcoma (no public access)

The cartoon model above illustrates RMS cells’ transformation to healthy muscle cells. When NF-Y is depleted from the cells, the cancer stops multiplying and starts to take on typical muscle features and functions. The microscopy images on the bottom row capture real cells before and after this transformation.