Taming overactive mTOR in kidney cell cancer

Taming overactive mTOR in kidney cell cancer

Reducing overactive mTOR signalling in its embryonic development could lead to new therapeutic treatments for aggressive renal cancers, new research suggests

In a new study from the Johns Hopkins Kimmel Cancer Center, researchers described a novel mechanism of tumour formation in kidney cancers driven by overexpression of the mechanistic target of rapamycin complex 1 (mTORC1) signalling pathway with loss of the tuberous sclerosis complex (TSC) tumour suppressor gene.

Their findings point to potential therapeutic targets for some of the most aggressive renal cell cancers.

Unopposed signalling – overactivity – through mTOR may lead to abnormal activation of a family of molecules that regulate cell growth and spread, also known as oncogenic transcription factors, specifically the microphthalmia transcription factor family (MITF).

Genitourinary cancer expert and study leader Tamara Lotan, M.D., professor of pathology and oncology with a joint appointment in urology, has studied mTOR signalling in embryonic development and cancer for more than a decade.

Although mTOR has been the focus of many cancer studies for its role in regulating cell division and growth, its mechanisms in promoting cancer are not fully understood.

Lotan said: “For years, the dogma has been that mTOR signalling directly suppresses the activity of the microphthalmia-related transcription factors TFEB and TFE3 by keeping them out of the nucleus and unable to activate transcription.

“However, we found that TFEB and TFE3 are actually, paradoxically, activated downstream of abnormal, continuous mTOR signalling.”

See also: Dietary change starves cancer cells

unifying mechanism

The protein mTOR is important in cancer cell phosphorylation, or the activation of proteins involved in cell cycle, including cell death, DNA repair and more; and Lotan says continuously activated mTOR signalling is common in renal and other types of tumours that are prone to losing the tumour suppressor genes TSC1 or TSC2.

Kaushal Asrani, MBBS, PhD, a research associate in the Lotan laboratory, said: “A better understanding of these mechanisms is what makes this work particularly interesting.

“We have known for some time that there are subsets of kidney and soft tissue tumours that can be caused by overactive mTOR signalling or other genetic alterations that directly activate TFEB and TFE3, but how these molecular events were all tied together was a mystery.

“This work suggests that the unifying mechanism in all cases is activation of TFEB and TFE3.”

These transcription factors are typically inactivated in response to cellular nutrients such as amino acids. In laboratory experiments, Asrani found that this amino acid-dependent regulation of TFEB and TFE3 is actually suppressed in kidney tumour cells with TSC loss, leading to their overactivity.

The combined loss of TFEB and TFE3 was enough to reduce growth of tumours with continuous mTOR signalling.

Lotan said the new findings are informing renal cell cancer research while also improving the understanding of other cancers, including pancreatic cancer and melanoma skin cancer.

She is hopeful that the findings may point to new targeted therapies for kidney cancers with overactive mTOR, which will be a focus of ongoing research.

The findings are published in Nature Communications.

Image: Murine renal tumours with Tsc2 loss have increased TFEB/TFE3 nuclear localisation. Credit: Clarence Rachel Villanueva and Adrianna A Mendes.

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