Integrins, by acting as signalling molecules, mechanotransducers and components of cell migration
machinery, regulate cancer progression. In high-grade serous ovarian cancer (HG-SOC), integrin β1
(Intβ1) impacts intraperitoneal spread and metastatic colonization with a distinct organotropism for
the omentum. Cumulative work indicated that hundreds of proteins associate with the integrin
adhesion complex to fine-tune intracellular activation, so-called inside out, including members of
the G-protein coupled receptors (GPCRs). The scaffolding protein β-arrestins (β-arrs), key
regulators of GPCR signalling, act as a core hub for proteins involved in invasive signalling,
cytoskeleton remodelling and pericellular proteolysis mediated by invadopodia. This effect includes
the interaction with integrin-linked proteins, and the regulation of the crosstalk with mesothelial
cells (MCs), key cellular components of the omental metastatic niche. However, a direct interaction
of β-arr with integrin in the metastatic niche establishment is unexplored. In this framework,
Staphylococcus aureus detected in the oncobioma of the female reproductive tract produces toxin
superantigens (SAgs), including SEA and SEB, are capable to stimulate T cells to secrete
inflammatory cytokines and chemokines, which can further support metastatic progression. Based
on this evidence, we propose to investigate whether an integrated intβ1/β-arr1 signalling and a
Sags-dependent inflammatory circuit could contribute to a cancer cell plasticity and an interactive
symbiosis with MCs, priming HG-SOC cells for metastatic colonization. The specific targeting of
these drivers in the context of tumour/stroma interactions will be evaluated as innovative
approaches to preventing ovarian cancer spread. By using HG-SOC cells, omental-derived MCs, T
cells, and 3D organotypic models, our specific aims are to:
1. Dissect the function of β-arr1 with Intβ1 in cell-matrix adhesion, cytoskeleton remodelling, and
actomyosin contractility of HG-SOC cells, dictating reinforcement of invasive signalling and the
crosstalk with MCs, gaining the access to submesothelial ECM.
2. Explore how SAgs-stimulated inflammatory T cells support changes in cancer cells and their
interaction with MCs, and the putative role of β-arr in these processes.
3. Evaluate whether combinatory inhibition of Intβ1, with the peptide ATN-161, and CD28, with
p1TA and p2TA mimetic peptides, as free therapeutics and as functionalization of engineered
polymer nanoparticles might interrupt tumour/stroma signalling reciprocity, and metastatic
progression, defining an innovative therapeutic strategy for the selective treatment of ovarian
cancer.
This project might shed light on new molecular effectors regulating intβ1 signalling in driving HG-
SOC metastatic processes, cooperating with oncobiome, which may be pharmacologically tractable,
and provide a relevant model platform for translational studies.