TARGETING INHERITED CANCER SYNDROMES

Introduction

Transcription factors EB and E3 (TFEB and TFE3), members of the MiT-TFE family, are master controllers of lysosomal biogenesis and autophagy. The activity of TFEB and TFE3 is regulated by mechanistic Target Of Rapamycin Complex 1 (mTORC1), a central hub of cell metabolism, which inhibits their cytoplasm-to-nucleus translocation.

Discovery of NC-mTORC1 Mechanism

We recently discovered that mTORC1 phosphorylates TFEB and TFE3 via a non-canonical TORC1 (NC-mTORC1) signaling mechanism. This provides the first evidence that mTORC1 can produce specific responses to different environmental cues by differential substrate phosphorylation.

Dysregulation and Cancer Syndromes

We and others recently discovered that dysregulation of NC-mTORC1, leading to constitutive activation of TFEB/TFE3, is the main driver of the renal cystic and tumorigenic phenotype of inherited cancer syndromes:

1. Birt-Hogg-Dube' (BHD)
2. Tuberous Sclerosis Complex (TSC)

Remarkably, deletion of TFEB completely rescued renal cystogenesis and tumorigenesis in BHD and TSC mouse models. Furthermore, additional types of cancer have been associated with the induction of TFEB/TFE3, suggesting that this may be an emerging mechanism of tumorigenesis.

Research Goals in INCANTAR

In INCANTAR (INherited CANcer TARgeting), we aim to identify novel regulators of TFEB/TFE3 factors by:

• CRISPR screening
• Protein interactome analyses

These approaches may reveal new therapeutic targets.

Characterization of Pathogenic Roles

We also plan to thoroughly characterize the pathogenic role of TFEB and TFE3 in TSC and BHD using:

• Transgenic mice
• Kidney and brain organoids

Exploration of Therapeutic Strategies

Finally, we will explore novel therapeutic strategies for TFEB/TFE3 driven diseases, such as:

• Selective ablation of cells expressing GPNMB, a sensitive transcriptional target of MiT-TFE factors
• Drug screening for MiT-TFE inhibitors using a newly developed MiT-TFE transcriptional reporter

These studies will shed new light on the mechanisms underlying the pathogenic role of MiT-TFE factors and are likely to generate novel therapeutic tools for several cancer-associated conditions.