Author response: Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling

Calcagnì, Alessia; Kors, Lotte; Verschuren, Eric H. J.; Cegli, Rossella De; Zampelli, Nicolina; Nusco, Edoardo; Confalonieri, Stefano; Bertalot, Giovanni; Pece, Salvatore; Settembre, Carmine; Malouf, Gabriel G.; Leemans, Jaklien C.; Heer, Emile de; Salvatore, Marco; Peters, Dorien J.M.; Fiore, Pier Paolo Di; Ballabio, Andrea

doi:10.7554/elife.17047.030

Cited by 3 publications

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“…The lack of animal models that faithfully reproduce the initiation and progression of renal carcinomas has limited progression in the field. Although both Myc and TFEB overexpression recapitulate some features of RCCs (Shroff et al, 2015;Calcagnì et al, 2016), the inactivation of tumor suppressors, such as Fh1, Vhl, and Tsc1, results in kidney cysts (Frew et al, 2008;Pollard et al, 2007;Onda et al, 1999;Wilson et al, 2005). However, recent studies have demonstrated that the combined inactivation of multiple tumor suppressors results in renal carcinogenesis (Gu et al, 2017;Harlander et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

mTORC1 Upregulation Leads to Accumulation of the Oncometabolite Fumarate in a Mouse Model of Renal Cell Carcinoma

et al. 2018

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Renal cell carcinomas (RCCs) are common cancers diagnosed in more than 350,000 people each year worldwide. Several pathways are de-regulated in RCCs, including mTORC1. However, how mTOR drives tumorigenesis in this context is unknown. The lack of faithful animal models has limited progress in understanding and targeting RCCs. Here, we generated a mouse model harboring the kidney-specific inactivation of Tsc1. These animals develop cysts that evolve into papillae, cystadenomas, and papillary carcinomas. Global profiling confirmed several metabolic derangements previously attributed to mTORC1. Notably, Tsc1 inactivation results in the accumulation of fumarate and in mTOR-dependent downregulation of the TCA cycle enzyme fumarate hydratase (FH). The re-expression of FH in cellular systems lacking Tsc1 partially rescued renal epithelial transformation. Importantly, the mTORC1-FH axis is likely conserved in human RCC specimens. We reveal a role of mTORC1 in renal tumorigenesis, which depends on the oncometabolite fumarate.

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Section: Introductionmentioning

confidence: 99%

mTORC1 Upregulation Leads to Accumulation of the Oncometabolite Fumarate in a Mouse Model of Renal Cell Carcinoma

et al. 2018

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“…Signaling events that influence the nucleocytoplasmic distribution of these transcription factors function as de facto regulators of endolysosomal biogenesis (Martina et al, 2012;Medina et al, 2015;Palmieri et al, 2017;Roczniak-Ferguson et al, 2012;Settembre et al, 2011). Several cancers are characterized by either the constitutive localization of TFEB/TFE3/MITF in cell nuclei or by amplifications that upregulate their expression (Argani, 2015;Blessing et al, 2017;Calcagnì et al, 2016;Kauffman et al, 2014;Kundu et al, 2018;Li et al, 2019;Perera et al, 2015Perera et al, , 2019Ploper et al, 2015). The attendant potentiation of endolysosomal biogenesis supports cancer cell survival, proliferation, and metastases.…”

Section: Introductionmentioning

confidence: 99%

p53 mitigates the effects of oncogenic HRAS in urothelial cells via the repression of MCOLN1

et al. 2021

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Transcription Factor EB regulates phosphatidylinositol-3-phosphate levels on endomembranes and alters lysosome positioning in the bladder cancer model

Mathur

Santos

Lachuer

et al. 2020

Preprint

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Late endosomes/lysosomes (endolysosomes) emerge as a potential regulatory hub during cancer. Here, we investigate the intracellular landscape of this organelle in a collection of bladder cancer cell lines and normal human urothelium cells under standardized culture conditions. We find that high-grade bladder cancer cells are characterized by scattered endolysosomes that are accompanied by an altered cellular pH homeostasis and major changes of mTORC1 regulation. Mechanistically, we reveal that mTORC1 substrate specificity is altered, and mTORC1 responsiveness to endolysosome positioning is lost in high-grade cancer cells compared to low-grade cells, highlighting unexpected mechanisms of mTORC1 deregulation in the bladder cancer model. Because endolysosome positioning was critical for invasion from 3D spheroids, our results indicate that changes in their cellular positioning and ability to support signaling, strongly impact cancer cell behavior. Thus, monitoring detailed changes of endolysosomes at different steps of cancer disease reveals intricate spatial and temporal dimensions of tumorigenesis.Statement of significanceOur study reveals significant changes of endolysosomes in bladder cancer progression, highlighting endolysosome dysfunction as a fundamental driving progress in malignancies. The identified alterations in endolysosome positioning and associated mTORC1 signaling regulation could help to stratify emerging therapeutic strategies targeting the endolysosomal compartment.

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Author response: Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling

Cited by 3 publications

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mTORC1 Upregulation Leads to Accumulation of the Oncometabolite Fumarate in a Mouse Model of Renal Cell Carcinoma

mTORC1 Upregulation Leads to Accumulation of the Oncometabolite Fumarate in a Mouse Model of Renal Cell Carcinoma

p53 mitigates the effects of oncogenic HRAS in urothelial cells via the repression of MCOLN1

Transcription Factor EB regulates phosphatidylinositol-3-phosphate levels on endomembranes and alters lysosome positioning in the bladder cancer model

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