Change in Protein's Location May Cause Aggressive Cancers

Change in Protein's Location May Cause Aggressive Cancers

Mutations in the tumor suppressor gene INI1/SMARCB1—which codes for the nuclear protein IN1/SMARCB1—occur in many cancers. The inability to detect, through staining, the presence of IN1/SMARCB1 in the nuclei of cancer cells is a hallmark of rhabdoid tumors: aggressive pediatric cancers that occur in the brain, kidney, and other parts of the body and can’t be effectively treated.

In a study of 104 rhabdoid brain tumor specimens published online on May 18 in Acta Neuropathologica, a team led by Ganjam V. Kalpana, Ph.D., and Martin Hasselblatt, M.D., of University Hospital Münster (Münster, Germany) found that, for the majority of specimens, the protein IN1/SMARCB1 was indeed absent in the tumor cells, as expected. But in 18% of the tumor specimens, IN1/SMARCB1 was present—but in the cytoplasm rather than the nucleus. Dr. Kalpana had earlier proposed that “mis-localization” of the INI1/SMARCB1 protein in the cytoplasm can lead to cancer, based on laboratory findings in cells. Steffen Albrecht, M.D., a neuropathologist of McGill University (Montreal, Canada), realized her theory might be valid when he saw a human rhabdoid tumor with INI1/SMARCB1 mis-localization.

In the Acta Neuropathologica paper, the researchers conducted a series of experiments involving rhabdoid cancer cells and confirmed that translocation of IN1/SMARCB1 from the nucleus to the cytoplasm actually caused the cancers; and they found that the FDA-approved drug Selinexor inhibited the export of IN1/SMARCB1 into the cytoplasm—halting the growth of rhabdoid cells and potentially providing a novel therapy for this subset of rhabdoid tumors.

Dr. Kalpana is professor of genetics and of microbiology & immunology and is the Mark Trauner Faculty Scholar in Neuro-oncology at Einstein. The study’s co-first author is Rajiv Pathak, who is an associate of genetics at Einstein.

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