Lack of NKX2-1 gene activity in the animals was associated with higher grade tumors and metastasis.

Researchers have used a mouse model of lung cancer to identify a transcription factor that they say is implicated in the metastasis of lung cancer. They found that lack of NKX2-1 gene activity in the animals was associated with higher grade tumors and metastasis. Subsequent analysis of the genetic profiles of human lung tumors confirmed that lack of NKX2-1 was associated with higher death rates.

The Massachusetts Institute of Technology (MIT) researchers and their colleagues subsequently showed that NKX2-1 essentially represses HMGA2 in adult tissues. HMGA2 is highly expressed in embryonic lung tissue but is not normally expressed in any adult lung tissues. The new research found that when the transcription factor gene is switched off, HMGA2 essentially becomes active and increases the ability of lung cancer to seed metastases.

This suggestion was supported by the observation that transplanted tumor cells in which HMGA2 was knocked out were far less aggressive than those in which HMGA2 was active. The MIT team, led by Tyler Jacks, Ph.D., director of the David H. Koch Institute for Integrative Cancer Research, reports its findings in Nature in a paper titled “Suppression of lung adenocarcinoma progression by Nkx2-1.”

Despite the high prevalence and poor outcome of patients with metastatic lung cancer, the mechanisms of tumor progression and metastasis remain largely uncharacterized, the authors note. To investigate the potential mechanisms further, the researchers studied a mouse model engineered with a deleted p53 tumor suppressor gene and a mutant Kras gene. They found that while all the mice developed tumors, only some of the cancers metastasized. It was the absence of NKX2-1 activity that was the striking difference between the two types of tumor, claims Monte Winslow, Ph.D., co-researcher at the Koch Institute.  

The subsequent discovery that NKX2-1 normally acts to repress HMGA2 provides a potential new therapeutic target for preventing lung cancer metastasis, the researchers suggest. Developing drugs that switch genes off, in this case HMGA2, is a relatively more feasible prospect than developing candidates capable of turning the NKX2-1 gene back on.

In the meantime, analysing patients’ tumors to see whether NKX2-1 is active could give some indication of disease prognosis. “the sad reality is that if you could tell a patient whether their cancer has turned down this gene, you would know they will have a worse outcome, but it wouldn’t change the treatment,” Dr. Winslow admits.

The MIT team is now investigating other types of cancer to see if NKX2-1 or HMGA2 have the same role in metastasis. “It’s great to find something that’s important in lung cancer metastasis, but it would be even better if it controlled metastasis in even a subset of other cancer types,” Dr Winslow notes.

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