The phospholipid transporter PITPNC1 links KRAS to MYC to prevent autophagy in lung and pancreatic cancer

Molecular Cancer

Research

Elizabeth Guruceaga¹  Nils Halberg²  Pietro Scaparone³  Chiara Ambrogio³  Sandra Vietti Michelina³  Xabier Morales⁴  Ivan Cortes-Dominguez⁵  Ainhoa Goñi-Salaverri⁶  David Lara-Astiaso⁷  Haritz Moreno⁸  Laura Vera⁸  Oihane Erice⁸  Rodrigo Entrialgo-Cadierno⁸  Adrian Vallejo⁸  Irati Macaya⁸  Cristina Cueto-Ureña⁸  Iker Feliu⁸  Ines Lopez⁸  Connor Welch⁹  Fernando Lecanda^1,10  Silve Vicent^1,10  Elodie Darbo^1,11 

[1] Bioinformatics Platform, University of Navarra, CIMA, Pamplona, Spain;IdiSNA, Navarra Institute for Health Research, Pamplona, Spain;Department of Biomedicine, University of Bergen, Bergen, Norway;Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Centre, University of Torino, Turin, Italy;Imaging Unit and Cancer Imaging Laboratory, University of Navarra, CIMA, Pamplona, Spain;Imaging Unit and Cancer Imaging Laboratory, University of Navarra, CIMA, Pamplona, Spain;Bioinformatics Platform, University of Navarra, CIMA, Pamplona, Spain;Molecular Therapies Program, University of Navarra, CIMA, Pamplona, Spain;Molecular Therapies Program, University of Navarra, CIMA, Pamplona, Spain;Wellcome - MRC Cambridge Stem Cell Institute (CSCI), Cambridge, UK;Program in Solid Tumours, University of Navarra, Centre of Applied Medical Research (CIMA), 55 Pio XII Avenue, 31008, Pamplona, Spain;Program in Solid Tumours, University of Navarra, Centre of Applied Medical Research (CIMA), 55 Pio XII Avenue, 31008, Pamplona, Spain;Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain;Program in Solid Tumours, University of Navarra, Centre of Applied Medical Research (CIMA), 55 Pio XII Avenue, 31008, Pamplona, Spain;Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain;IdiSNA, Navarra Institute for Health Research, Pamplona, Spain;Department of Pathology, Anatomy and Physiology, University of Navarra, Pamplona, Spain;University of Bordeaux, INSERM, BRIC, U 1312, F-33000, Bordeaux, France;

关键词: PITPNC1;    KRAS;    LUAD;    PDAC;    MYC;    mTOR;    Therapy;   

DOI  :  10.1186/s12943-023-01788-w

 received in 2022-10-18, accepted in 2023-05-11,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundThe discovery of functionally relevant KRAS effectors in lung and pancreatic ductal adenocarcinoma (LUAD and PDAC) may yield novel molecular targets or mechanisms amenable to inhibition strategies. Phospholipids availability has been appreciated as a mechanism to modulate KRAS oncogenic potential. Thus, phospholipid transporters may play a functional role in KRAS-driven oncogenesis. Here, we identified and systematically studied the phospholipid transporter PITPNC1 and its controlled network in LUAD and PDAC.MethodsGenetic modulation of KRAS expression as well as pharmacological inhibition of canonical effectors was completed. PITPNC1 genetic depletion was performed in in vitro and in vivo LUAD and PDAC models. PITPNC1-deficient cells were RNA sequenced, and Gene Ontology and enrichment analyses were applied to the output data. Protein-based biochemical and subcellular localization assays were run to investigate PITPNC1-regulated pathways. A drug repurposing approach was used to predict surrogate PITPNC1 inhibitors that were tested in combination with KRASG12C inhibitors in 2D, 3D, and in vivo models.ResultsPITPNC1 was increased in human LUAD and PDAC, and associated with poor patients’ survival. PITPNC1 was regulated by KRAS through MEK1/2 and JNK1/2. Functional experiments showed PITPNC1 requirement for cell proliferation, cell cycle progression and tumour growth. Furthermore, PITPNC1 overexpression enhanced lung colonization and liver metastasis. PITPNC1 regulated a transcriptional signature which highly overlapped with that of KRAS, and controlled mTOR localization via enhanced MYC protein stability to prevent autophagy. JAK2 inhibitors were predicted as putative PITPNC1 inhibitors with antiproliferative effect and their combination with KRASG12C inhibitors elicited a substantial anti-tumour effect in LUAD and PDAC.ConclusionsOur data highlight the functional and clinical relevance of PITPNC1 in LUAD and PDAC. Moreover, PITPNC1 constitutes a new mechanism linking KRAS to MYC, and controls a druggable transcriptional network for combinatorial treatments.

【 授权许可】

CC BY   
© The Author(s) 2023

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