Domestication of overactive mTOR in renal cell carcinoma

In a new study from the Johns Hopkins University Kimmel Cancer Center, researchers describe a novel mechanism
of kidney cancer tumor formation driven by overexpression of mechanistic targets of the rapamycin complex 1 (mTORC1) signaling pathway leading to deletion of tumor suppressor genes in the tuberous sclerosis complex (TSC).
Their findings point to potential therapeutic targets for some of the most aggressive renal cell carcinoma
.

Non-counter-signaling through mTOR – overactivity – 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).

The findings were published Nov.
10 in the journal Nature Communications
.

Dr.
Tamara Lotan, a genitourinary cancer specialist and research leader, has studied embryonic development and mTOR signaling in cancer for more than a decade
.
While mTOR has been the focus of many cancer studies for its role in regulating cell division and growth, its cancer-promoting mechanisms are not fully understood, Lotan said
.

"For many years, it was thought that mTOR signaling directly inhibited the activity of the transcription factors TFEB and TFE3 associated with microphthalmia, keeping them away from the nucleus and unable to activate transcription
," Lotan said.
Paradoxically, however, we found that TFEB and TFE3 are actually activated downstream of an unusually continuous mTOR signal
.
”

mTOR proteins are important in cancer cell phosphorylation, or activate proteins involved in the cell cycle, including cell death, DNA repair, and more
.
Continuously activated mTOR signaling is common in kidneys and other types of tumors that are prone to losing the tumor suppressor genes TSC1 or TSC2
.

"A better understanding of these mechanisms makes this work particularly interesting," said Kaushal Asrani, a research assistant
in Lotan's lab.
"We've known for some time that there are subsets of kidney and soft tissue tumors that may be caused by overactive mTOR signaling or other genetic alterations that directly activate TFEB and TFE3, but how these molecular events are linked is a mystery
.
" This work shows that in all cases, the unifying mechanism is TFEB and TFE3 activation
.
”

These transcription factors are often 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 was actually inhibited in TSC-deficient kidney tumor cells, causing them to become overactive
.
The combined loss of TFEB and TFE3 is sufficient to reduce tumor growth
under the sustained mTOR signaling pathway.

Lotan said the new findings inform renal cell carcinoma research while also raising awareness about other cancers, including pancreatic cancer and melanoma skin cancer
.

She hopes the findings may lead to new targeted therapies for kidney cancer with overactive mTORs, which will be the focus of
ongoing research.