New cancer target, let-7, unifies theories on neuroblastoma’s origins

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Striking the nerve tissue, neuroblastoma is the most common cancer in infants and toddlers. Great strides have been made in its treatment, but advanced cases still are often fatal, and children who survive often face life-long physical and intellectual challenges related to their treatment.

A study published online by Nature last week, led by researchers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, finds that a microRNA called let-7 is central in curbing neuroblastoma. The study unifies several theories about neuroblastoma and could bring focus to efforts to find a targeted, nontoxic alternative to chemotherapy.

The findings also have implications for other solid tumors in which let-7 is lost, such as Wilms tumor, lung, breast, ovarian and cervical cancers, says first author John Powers, PhD, of the Division of Pediatric Hematology/Oncology at Boston Children’s Hospital.

neuroblastoma let-7
A typical neuroblastoma. (Maria Tsokos, National Cancer Institute)

The let-7 family of microRNAs (bits of genetic code that regulate genes) is known to be involved in both stem-cell differentiation and tumor suppression. Recent research implicated LIN28B, a protein that inhibits let-7 maturation, in neuroblastoma. That made sense: If a cell’s let-7 can’t mature, it can’t differentiate. Instead, it remains stem-like and can potentially become cancerous.

But through work on neuroblastoma cells and analysis of patient data, Powers and colleagues found that LIN28B is only one player among several cancer mechanisms, all involving let-7 suppression.

“We’re showing that let-7 inhibition is central to the development of this disease,” Powers says. “So critical in fact that neuroblastoma uses at least three distinct ways of eliminating it.”

A unifying theory

MYCN amplification (courtesy Tom Look, DFCI)
MYCN amplification (courtesy Tom Look, DFCI)

People had noticed, for example, that in some cases of neuroblastoma, the oncogene MYCN is hugely amplified — allowing production of many thousands of copies of its mRNA.

“Children with a MYCN-amplification event, which occurs in about 25 percent of cases, have the poorest prognosis,” says Powers, a senior scientist in the laboratory of George Q. Daley, MD, PhD, director of the Stem Cell Transplantation Program at Dana-Farber/Boston Children’s. “A big question in neuroblastoma research has been, ‘why does the cancer need so much MYCN mRNA?’”

Powers and colleagues found an answer. They demonstrated that genetic MYCN amplification enables neuroblastomas to sequester let-7, taking it out of circulation.

MYCN mRNA is expressed at such high levels that it is able to sponge up otherwise functional let-7, and still function as an oncogene,” says Powers.

Similarly, certain chromosome deletions — in the 11q and 3p regions — had been known to be associated with neuroblastoma. Powers and colleagues showed that these lost chunks of DNA are home to multiple let-7 family members.

They also demonstrated that genetic loss of let-7 also tracks with poor outcomes — as shown in these survival curves for 202 patients with neuroblastoma. Patients with chromosomal let-7 loss (tracked in red) had markedly reduced survival in both MYCN-amplified and non-MYCN-amplified neuroblastoma compared to those with no let-7 loss:

Neuroblastoma survival MYCN and let-7

“Genetic loss of let-7 was not widely appreciated in neuroblastoma,” says Powers. “People knew about chromosomal losses and were looking for a tumor suppressor, but they were mainly looking at the protein-coding genes, not microRNAs.”

A pragmatic cancer

Interestingly, in the patient sample, chromosomal loss of let-7 rarely occurred in patients with MYCN amplification. The two cancer-promoting events, both suppressing let-7, were nearly mutually exclusive, meaning most neuroblastomas involved either one or the other — as shown in this Venn diagram.

Venn diagram neuroblastoma let-7 MYCN

The researchers believe this mutual exclusivity indicates that once a cancer comes up with one weapon, it’s no longer under selective pressure to find another, since to do so would be redundant.

“From the cancer’s point of view, you have to deal with let-7,” says Powers. “If MYCN is not amplified, the tumor instead just loses it genetically. In either case, let-7 is mitigated.”

Likewise, if let-7 is eliminated through chromosomal loss, MYCN amplification becomes unnecessary for the cancer to spread. “Once a tumor has disrupted let-7 genetically, it doesn’t need to sponge let-7, so it doesn’t need to amplify MYCN.”

Precision medicine for neuroblastoma?

The team’s findings, if replicated in a larger number of patient samples, could help establish genetic typing of neuroblastomas, predicting disease severity based on LIN28B levels, genetic loss of let-7 and MYCN amplification. This could potentially guide a precision medicine approach, as with medulloblastoma.

As for treatment strategies, Powers believes that restoring let-7 could provide a low-toxicity approach to neuroblastoma and other cancers in which let-7 is lost. Let-7 itself could potentially be a drug, if the challenges of delivery — common to all RNA therapeutics — can be overcome.

Powers wants to work on this challenge. “If we can master let-7, then we could have a less toxic way to treat the disease,” he says. “Then we have the chance to really help those kids.”

The study was supported by the National Institutes of Health (R01GM107536), Alex’s Lemonade Stand Foundation, the Ellison Medical Foundation, the Howard Hughes Medical Institute and the National Institute of General Medical Sciences (T32GM007753).