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Keeping tumors in check

Feb 3, 2015

Gene-blocking clusters of microRNAs disrupt tumor cell migration and could be used to improve diagnosis and treatment

February 3, 2015, New York, NY -  Researchers led by Ludwig Chicago’s Ralph Weichselbaum have identified a key biological mechanism that underlies oligometastasis, an intermediate and potentially curable stage between localized cancer and the full-blown metastasis that causes the vast majority of cancer-related deaths. Their study is published in the February 2015 issue of the journal Oncotarget.

“Our findings open the door to developing new methods to identifying patients with oligometastases and perhaps even devising new ways to treat them,” said Weichselbaum, co-director of the Ludwig Center at the University of Chicago.

Weichselbaum and co-author Samuel Hellman, Ludwig Board member former dean of the University of Chicago’s Division of the Biological Sciences, first described and named oligometastasis two decades ago as a stage of cancer in which a primary tumor has spawned only a few localized secondary tumors, typically no more than five. The two researchers, authorities on radiotherapy, subsequently proved that oligometastatic tumors could often be cured with targeted local treatment such as surgery or focused radiation.

In this study, Weichselbaum and his colleagues gathered genetic information from tumor samples culled from their own clinical trials, the only known datasets of patients with oligometastases. They used this information to identify small clusters of gene-blocking microRNAs expressed only by oligometastatic cells.

MicroRNAs regulate gene expression and are the products of DNA sequences that are transcribed but not translated into proteins. Weichselbaum and his team show in their study how certain microRNAs can bind to the transcripts (messenger RNAs) of specific genes, preventing their translation into proteins.

The researchers found that 14 of these microRNAs are encoded by DNA in a small chromosomal region known as 14q32. This region is known to be important for early embryonic development: its mutation is linked to severe developmental disorders.

When the researchers studied the genes that these microRNAs suppressed, they found that many of them were involved in pathways that enable cells to adhere to other types of cells, invade tissues and migrate to distant sites—all of which are essential to metastasis.

“We call this the AIM phenotype,” Weichselbaum said. Tumor cells that express certain microRNAs from 14q32 lack the ability to adhere, invade or migrate (hence, AIM). “Instead they give rise to a small number of less aggressive tumors, many of which are curable with local therapy.”

The researchers suggest these microRNAs could provide a personalized biomarker, permitting physicians to predict how aggressively a tumor might spread. “We could use that knowledge to guide treatment,” Weichselbaum said.

His team identified four microRNAs from the 14q32 cluster that correlated with a good prognosis. Overexpression of these four microRNAs was associated with a prolonged recurrence-free interval after surgical removal of secondary tumors. Sixty percent of 24 patients with elevated levels of these microRNAs had no metastatic recurrence after five years of follow-up. Conversely, 70 percent of 24 patients with low microRNA expression had a recurrence, usually within the first year.

Additional tests, using an animal model of human breast cancer that measures tumor spread to the lungs, confirmed the initial results. Three of the four microRNAs (miR-127-5p, miR-544a and miR-655-3p) suppressed the rapid growth of new lung tumors in immunocompromised mice injected through the tail with breast cancer cells.

The researchers were able to trace some of the benefits to inhibition of specific genes. Blocking a gene called TGFBR2 suppressed cellular adhesion and invasion and reduced the number of lung metastases. Inhibiting a gene called ROCK2 suppressed invasion and also lowered metastases.

The research was supported by Ludwig Cancer Research, the Lung Cancer Foundation, the Prostate Cancer Foundation, and the Foglia family.

Adapted with permission from the University of Chicago School of Medicine.

About Ludwig Cancer Research

Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for more than 40 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested more than $2.5 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers.