Publications

Authors:

De Santis, Maria Chiara; Gozzelino, Luca; Margaria, Jean Piero; Costamagna, Andrea; Ratto, Edoardo; Gulluni, Federico; Di Gregorio, Enza; Mina, Erica; Lorito, Nicla; Bacci, Marina; Lattanzio, Rossano; Sala, Gianluca; Cappello, Paola; Novelli, Francesco; Giovannetti, Elisa; Vicentini, Caterina; Andreani, Silvia; Delfino, Pietro; Corbo, Vincenzo; Scarpa, Aldo; Porporato, Paolo Ettore; Morandi, Andrea; Hirsch, Emilio; Martini, Miriam

Title:

Lysosomal lipid switch sensitises to nutrient deprivation and mTOR targeting in pancreatic cancer

Year:

2023

Type of item:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Language:

Inglese

Format:

Elettronico

Referee:

No

Name of journal:

Gut

ISSN of journal:

0017-5749

N° Volume:

72

Number or Folder:

2

Page numbers:

360-371

Keyword:

AMINO ACIDS; CELL BIOLOGY; LIPID METABOLISM; PANCREATIC CANCER; SIGNAL TRANSDUCTION

Short description of contents:

Objective: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited therapeutic options. However, metabolic adaptation to the harsh PDAC environment can expose liabilities useful for therapy. Targeting the key metabolic regulator mechanistic target of rapamycin complex 1 (mTORC1) and its downstream pathway shows efficacy only in subsets of patients but gene modifiers maximising response remain to be identified. Design: Three independent cohorts of PDAC patients were studied to correlate PI3K-C2γ protein abundance with disease outcome. Mechanisms were then studied in mouse (KPC mice) and cellular models of PDAC, in presence or absence of PI3K-C2γ (WT or KO). PI3K-C2γ-dependent metabolic rewiring and its impact on mTORC1 regulation were assessed in conditions of limiting glutamine availability. Finally, effects of a combination therapy targeting mTORC1 and glutamine metabolism were studied in WT and KO PDAC cells and preclinical models. Results: PI3K-C2γ expression was reduced in about 30% of PDAC cases and was associated with an aggressive phenotype. Similarly, loss of PI3K-C2γ in KPC mice enhanced tumour development and progression. The increased aggressiveness of tumours lacking PI3K-C2γ correlated with hyperactivation of mTORC1 pathway and glutamine metabolism rewiring to support lipid synthesis. PI3K-C2γ-KO tumours failed to adapt to metabolic stress induced by glutamine depletion, resulting in cell death. Conclusion: Loss of PI3K-C2γ prevents mTOR inactivation and triggers tumour vulnerability to RAD001 (mTOR inhibitor) and BPTES/CB-839 (glutaminase inhibitors). Therefore, these results might open the way to personalised treatments in PDAC with PI3K-C2γ loss.

Note:

Epub 2022 May 27 Supplemental material pp. 13-48

Product ID:

127103

Handle IRIS:

11562/1066314

Last Modified:

February 23, 2023

Bibliographic citation:

De Santis, Maria Chiara; Gozzelino, Luca; Margaria, Jean Piero; Costamagna, Andrea; Ratto, Edoardo; Gulluni, Federico; Di Gregorio, Enza; Mina, Erica; Lorito, Nicla; Bacci, Marina; Lattanzio, Rossano; Sala, Gianluca; Cappello, Paola; Novelli, Francesco; Giovannetti, Elisa; Vicentini, Caterina; Andreani, Silvia; Delfino, Pietro; Corbo, Vincenzo; Scarpa, Aldo; Porporato, Paolo Ettore; Morandi, Andrea; Hirsch, Emilio; Martini, Miriam, Lysosomal lipid switch sensitises to nutrient deprivation and mTOR targeting in pancreatic cancer «Gut» , vol. 72 , n. 2 , 2023 , pp. 360-371

Consulta la scheda completa presente nel repository istituzionale della Ricerca di Ateneo