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鈥淓very successful medicine has its origin story. And research like this is the soil from which new drugs are born,鈥� says LaboratoryProfessor Christopher Vakoc.

For six years, Vakoc鈥檚 lab has been on a mission to transform sarcoma cells into regularly functioning tissue cells. Sarcomas are cancers that form in connective tissues like muscle. Treatment often involves chemotherapy, surgery, and radiation鈥攑rocedures that are especially tough on kids. If doctors could transform cancer cells into healthy cells, it would offer patients a whole new treatment option鈥攐ne that could spare them and their families a great deal of pain and suffering.

A devastating and aggressive type of pediatric cancer, rhabdomyosarcoma (RMS) resembles children鈥檚 muscle cells. No one knew whether this proposed treatment method, called differentiation therapy, might ever work in RMS. It could still be decades out. But now, thanks to Vakoc鈥檚 lab, it seems like a real possibility.

To carry out their mission, Vakoc and his team created a new genetic screening technique. Using genome-editing technology, they hunted down genes that, when disrupted, would force RMS cells to become muscle cells. That鈥檚 when a protein called NF-Y emerged. With NF-Y impaired, the scientists witnessed an astonishing transformation. Vakoc recounts:

鈥淭丑别 cells literally turn into muscle. The tumor loses all cancer attributes. They鈥檙e switching from a cell that just wants to make more of itself to cells devoted to contraction. Because all its energy and resources are now devoted to contraction, it can鈥檛 go back to this multiplying state.鈥�

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鈥檛 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.

鈥淭his technology can allow you to take any cancer and go hunting for how to cause it to differentiate,鈥� Vakoc explains. 鈥淭his might be a key step toward making differentiation therapy more accessible.鈥�

Previously, Vakoc and his team succeeded in transforming Ewing sarcoma cells into healthy tissue cells. The Ewing sarcoma and RMS discoveries were supported by local families who鈥檇 lost loved ones to these cancers. 鈥淭丑别y came together and funded us to try to find, with some desperation, a new therapeutic strategy,鈥� says Vakoc.

Those families and Vakoc鈥檚 lab may now be heroes of a new origin story: a scientific breakthrough that could someday help save children鈥檚 lives and revolutionize cancer treatment as we know it.

Written by: Luis Sandoval, Communications Specialist | sandova@cshl.edu | 516-367-6826

Funding

National Cancer Institute, Pershing Square Sohn Cancer Research Alliance, National Institutes of Health, Edward and Martha Gerry Fellowship, The Miles Levin Impact Award, Christina Renna Foundation, The Mary Ruchalski Foundation, Friends of T.J. Foundation, The Michelle Paternoster Foundation, Summer鈥檚 Way Foundation, The Clark Gillies Foundation, Daniela Conte Foundation, Maddie鈥檚 Promise.

Citation

Sroka, M. et al., 鈥淢yo-differentiation reporter screen reveals NF-Y as an activator of PAX3-FOXO1 in rhabdomyosarcoma鈥�, PNAS, August 2023. DOI:

Core Facilites

鈥淭丑别 Functional Genomics Shared Resource offers services for functional screens and gene modulation using RNAi and CRISPR technologies. We also assist in the design and implementation of other screening modalities. The process of screening is designed to be a collaborative endeavor between the core and the investigator鈥檚 lab. The core offers custom RNAi/CRISPR library design and construction services.鈥� 鈥� Director Kenneth Chang, Ph.D.

鈥淭丑别 Sequencing Technologies and Analysis Shared Resource provides access to an array of high throughput Next Generation Sequencing (NGS) technologies. We offer cutting-edge technology alongside convenient in-house services for a broad range of genetic analysis.鈥� 鈥� Project Manager Sara Goodwin, Ph.D.

鈥淭丑别 Single Cell Genomics Core Facility brings cutting-edge single-cell technologies to collaborators both inside and outside of the Laboratory. We currently specialize in single-cell transcriptomics and offer assistance in a variety of gene expression workflows, including the latest in spatial gene expression profiling technologies.鈥� 鈥� Director Jon Preall, Ph.D.