Rosalind and Morris
Goodman Cancer
Institute Principal
Investigators
Prof. Armin Pause's lab focuses on:
- The molecular and cellular biology of the tumour suppressor folliculin (FLCN) and TFE3, its function and regulation in breast cancer progression.
- The mechanism of FLCN inhibition with respect to AMPK sensing activity as well as the effect of FLCN loss and AMPK activation in malignant cells.
Dr. Pause’s research interests focus on the molecular biology of energy-sensing pathways that are involved in the oncogenic transformation of normal cells.
The Birt-Hogg-Dubé (BHD) syndrome is a hereditary human cancer syndrome that predisposes affected individuals to develop renal carcinoma of nearly all subtypes, as well as benign fibrofolliculomas, pulmonary, colon and renal cysts, caused by loss of-function mutations in the FLCN gene. FLCN was identified as an AMPK binding partner and his group has demonstrated that FLCN is an evolutionarily conserved negative regulator of AMPK.
Loss of FLCN constitutively activates AMPK, resulting in PGC-1α-mediated mitochondrial biogenesis, increased ROS production, which induces HIF transcriptional activity and triggers Warburg metabolic reprogramming. This reprogramming stimulates cellular bioenergetics and conferres a HIF-dependent tumorigenic advantage in FLCN-negative cancer cells.
Loss of FLCN results in constitutive AMPK-dependent induction of autophagy, inhibition of apoptosis, enhanced cellular bioenergetics, and resistance to energy-depleting stresses including oxidative stress, heat, anoxia, and serum deprivation. We further showed that AMPK activation conferred by FLCN loss is independent of the cellular energy state suggesting that FLCN controls the AMPK energy sensing ability. Together, our data suggest that FLCN is an evolutionarily conserved regulator of AMPK signaling that acts as a tumour suppressor by negatively regulating AMPK function. Their current work is now aimed at studying the mechanism of FLCN inhibition with respect to AMPK sensing activity as well as the effect of FLCN loss and AMPK activation in tumour progression in various human cancer.
What we are
currently
working on
Our research group is highly interested in exploring the transcriptional regulation of stress-response transcription factors like TFE3 and TFEB, given their crucial involvement in the progression of cancer. These factors are frequently dysregulated in various cancer types, contributing to tumour initiation, progression, and drug resistance. By delving into the mechanisms that govern the expression and activity of TFE3 and TFEB, we aim to decipher the intricate molecular details that underlie these dysregulations.
Such a comprehensive understanding could shed light on the broader biology of diverse cancer types, elucidating common pathways of importance, to help uncover novel targets that play crucial roles in cancer progression and drug resistance. Ultimately, deciphering the transcriptional control of stress transcription factors not only advances our fundamental understanding of cancer biology but also has the potential to revolutionize treatment strategies by identifying innovative avenues for precision medicine approaches.
Our lab focuses on the study of different aspects of the above-mentioned avenues. This includes integrating molecular biology techniques as well as mouse models that have proven invaluable for understanding the fundamental features of cancer.
- Interaction entre l'AMPK, le FLCN (folliculine) et TFE3/TFEB et sa régulation sous différentes contraintes cellulaires L'AMPK médie la phosphorylation de TFEB et TFE3 sur trois résidus de sérine, entraînant l'activité transcriptionnelle de TFEB et TFE3 lors de privation de nutriments, de déplétion de FLCN et de manipulation pharmacologique de MTORC1 ou d'AMPK. De manière intéressante, notre laboratoire a montré que la chimiorésistance est médiée par l'activation dépendante de l'AMPK de TFEB, ce qui est annulé par l'inhibition pharmacologique de l'AMPK. L'AMPK joue un rôle clé dans l'activité transcriptionnelle de TFEB et TFE3, et nous validons l'AMPK comme une cible prometteuse pour la thérapie du cancer. Cette interaction fascinante sera étudiée dans le contexte de différentes contraintes cellulaires et de cellules malignes à l'avenir. Interplay between AMPK, FLCN (folliculin) and TFE3/TFEB and its regulation under different cellular stresses AMPK mediates phosphorylation of TFEB and TFE3 on three serine residues, leading to TFEB and TFE3 transcriptional activity upon nutrient starvation, FLCN depletion and pharmacological manipulation of MTORC1 or AMPK. Interestingly, our lab showed that chemoresistance is mediated by AMPK-dependent activation of TFEB which is abolished by pharmacological inhibition of AMPK. AMPK plays a key role in TFEB and TFE3 transcriptional activity, and we validate AMPK as a promising target for cancer therapy. This fascinating interplay will be studied in the context of different cellular stresses and malignant cells in the future.
- Rôle de FLCN et du facteur de transcription TFE3 dans la tumorigenèse et la progression du cancer La perte de FLCN dans le cancer du sein luminal favorise la croissance tumorale par le biais de l'activation de TFE3 et l'induction subséquente de plusieurs voies, dont l'autophagie, la biogenèse lysosomale, la glycolyse aérobie et l'angiogenèse. Cependant, la surexpression de FLCN dans des modèles de cancer du sein basal invasif atténue la localisation nucléaire de TFE3, l'activité transcriptionnelle dépendante de TFE3 et la croissance tumorale. Ces découvertes soutiennent un rôle général d'une voie de suppresseur de tumeur FLCN/TFE3 dérégulée dans les cancers humains. Étant donné que les voies mentionnées ci-dessus ont également été décrites comme étant dérégulées pendant le processus d'EMT et dans les métastases, nous cherchons à étudier comment FLCN/TFE3 modulent les métastases. Role of FLCN and transcription factor TFE3 in tumorigenesis and cancer progression FLCN loss in luminal breast cancer promotes tumour growth through TFE3 activation and subsequent induction of several pathways, including autophagy, lysosomal biogenesis, aerobic glycolysis, and angiogenesis. Conversely, FLCN overexpression in invasive basal-like breast cancer models attenuates TFE3 nuclear localization, TFE3-dependent transcriptional activity, and tumour growth. These findings support a general role of a deregulated FLCN/TFE3 tumour suppressor pathway in human cancers. Considering the above-mentioned pathways having been described to also be dysregulated during the EMT process and metastasis, we seek to investigate how FLCN/TFE3 modulate metastasis.
Our team
Ariadna Pollato Assistant.e de recherche Research Assistant 
Hyeonju Jeong Assistant.e de recherche Research Assistant 
Josue Ramirez Étudiant.e au doctorat PhD Student
Major discoveries
- 2021 AMPK-dependent phosphorylation is required for transcriptional activation of TFEB and TFE3.
- 2021 Loss of hepatic Flcn protects against fibrosis and inflammation by activating autophagy pathways.
- 2021 Folliculin impairs breast tumor growth by repressing TFE3-dependent induction of the Warburg effect and angiogenesis.
Research Partners
Get in touch
3655 Promenade Sir William Osler
Montreal, Quebec H4A 3J1
Office: 707
Lab: 706
T. 514 398 1521
T. 514 398 1577
F. 514-398-3380
arnim.pause@mcgill.ca
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