Golgi-based signalling pathways initiated by the ERp44-KDEL Receptors axis link oxidative protein folding to cancer cell invasion in response to hypoxia.

PIANO NAZIONALE DI RIPRESA E RESILIENZA (PNRR)

Missione 4 - Componente 2 - Investimento 1.1

“Fondo per il Programma Nazionale della Ricerca (PNR) e Progetti di Ricerca di Rilevante Interesse Nazionale (PRIN)” - Finanziato dall’Unione europea – NextGenerationEU

Bando PRIN 2022

D.D. n. 104 del 02.02.2022

Progetto “Golgi-based signalling pathways initiated by the ERp44-KDEL Receptors axis link oxidative protein folding to cancer cell invasion in response to hypoxia”

Codice Identificativo Progetto: 2022MZJR9X- CUP: D53D23007940006

Several research lines converge towards the unravelling of a new mechanism of adaptation/ response to hypoxia in tumours. Low oxygen levels are common in malignant tumours and drive enhanced resistance to treatments and poor prognosis. Research in our and other laboratories indicates that a specific mechanism exists that integrates oxidative folding, cyclic transport between ER and Golgi, and intracellular signalling processes to generate an adaptive control system acting as a sensor of hypoxia and as initiator of survival and escape responses in tumour and normal cells.

This project aims to dissect this adaptive mechanism starting from the following working model: ER chaperones and enzymes of the redox folding machinery (e.g. ERP44, ERP46, and the enzymes PRDX4 and ERO1- in brief, collectively, redox chaperones) form transient complexes that bind through their C-terminal KDEL motif, or variants thereof, to the KDELR, a protein that cycles between the ER and the Golgi. The KDELR, upon binding these chaperones, drives both their retrograde trafficking to the ER and several G protein-based signalling pathways. This signalling elicits multiple cellular responses including cytoskeleton reorganization, matrix degradation, cell motility/ invasion and proliferation, energy consumption. In tumours, hypoxia enhances the levels of KDELRs and of the redox chaperones, resulting in enhanced matrix degradation and proliferation, helping the survival/ escape of tumour cells.

We plan to use advanced imaging, omics and computational techniques to analyse A) the main elements of this model under both control and hypoxic conditions including the dynamics of ER- and Golgi-based molecular system that integrates the functions of redox folding (ERO1, PRDX4, ERP44, ERP46) trafficking (KDELRs) and signalling (G proteins) components and B) the mechanisms by which this system helps the tumour to sense and react to hypoxia.

The project has an important application potential in three main areas: one is the field of cancer treatment. A deep understanding of the KDELR / redox cycle and of its functional consequences can create new opportunities for the discovery of treatments targeting hypoxic tumour cells. The second concerns the basic knowledge of how cells coordinate the activity of different molecular modules to optimize their performances under varying conditions. The third is technological. RU2 (IEOS-CNR) is member of the pan European imaging infrastructure Eurobioimaging. The project will stimulate the development of new imaging technologies such as FRET and super resolution imaging applied to KDELR signalling as well as computational analyses of imaging and omics data.

In conclusion, the proposed research, by dissecting the KDELR / redox cycle and the related signalling pathways underlying the tumour reactions to hypoxia, and by developing innovative technologies, has the potential to contribute to cancer research and treatment.