How two cellular pathways team up to drive kidney cysts and tumors

Kidney cysts and tumors are hallmarks of several inherited disorders, but exactly how the cellular changes that drive these diseases work together has remained unclear. New research from scientists at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children's Hospital, Baylor College of Medicine (Baylor), and international collaborators has uncovered how two major cellular signaling pathways cooperate to fuel kidney cyst formation and tumor development.

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Led by Dr. Andrea Ballabio, principal investigator at the Duncan NRI, Professor in the department of Molecular and Human Genetics at Baylor and former Director of the Telethon Institute of Genetics and Medicine (TIGEM), the study, published in Cell Death & Differentiation, focused on two inherited disorders, Birt-Hogg-Dubé (BHD) syndrome and Tuberous Sclerosis Complex (TSC). Both conditions increase the risk of kidney cysts and tumors and are caused by mutations in genes that regulate cellular growth and metabolism.
Previous work from Dr. Ballabio revealed that two transcription factors, TFEB and TFE3, are major drivers of kidney disease in these disorders. These proteins act as master regulators for cellular recycling, metabolism, and stress response. Researchers also knew that TFEB and TFE3 can promote activation of mTORC1, a protein complex widely recognized as a key regulator of cell growth and a contributor to cancer development. What remained unknown was whether TFEB and TFE3 cause disease primarily through mTORC1 activation or through additional, independent mechanisms.

To answer this question, the investigators developed a series of genetically engineered mouse models that allowed them to separate the activities of TFEB/TFE3 and mTORC1. By selectively turning these pathways on or off in kidney tissue, the team could determine each pathway's individual contribution to disease progression.

• Their experiments revealed several key findings. Elevated mTORC1 activity promoted kidney cyst formation and tumor development. When TFEB and TFE3 were activated, kidney disease progressed more rapidly and became even more severe. Rather than acting in a single linear pathway, mTORC1 and TFEB and TFE3 work together. mTORC1 provides a strong tumor-promoting signal, while TFEB and TFE3 activate broadly helping cells adapt their metabolism and respond to stress, creating an environment that supports cyst and tumor growth.

Together, these findings define a previously unrecognized mechanism of kidney tumorigenesis in which both mTORC1 and TFEB and TFE3 become hyperactive and cooperate to drive disease. The study also helps explain why inherited disorders such as BHD and TSC can produce aggressive kidney abnormalities despite arising from mutations in different genes.

The implications extend beyond rare genetic syndromes. Many cancers show alterations in pathways controlled by mTORC1, TFEB, or TFE3. Understanding how these molecular networks interact could guide the development of therapeutic strategies that target both arms of the disease process rather than focusing on a single pathway. This work provides important insight into the biology of kidney cysts and tumors and identifies new avenues for future treatments aimed at preventing or slowing disease progression.
 

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Other contributors to this work include Marco Ferniani, Irene Sambri, Tuong Huynh, Rossella Pennella, Gennaro Tufano, Niculin J. Herz, Barbara Rossi, Antonella Iannaccone, Francesco Trepiccione, and Alessia Calcagnì. The authors are affiliated with one or more of the following organizations: Baylor College of Medicine, Duncan NRI, TIGEM, CNR, Biogem, the University of Campania, and Federico II University.

This work was supported by the National Institutes of Health (R01CA260205), the Italian Telethon Foundation, the Associazione Italiana per la Ricerca sul Cancro (AIRC), the European Research Council, the U.S. Army Medical Research Acquisition Activity, and the Italian Ministry of Health.