MEMBRANE TRAFFICKING

Principal Investigator

Staff

Research topic

Deconvolving the metabolic plasticity of breast cancer to identify targetable vulnerabilities.

Background

Metabolic plasticity is a hallmark of cancer, as shown by the addiction of cancers to metabolic alterations that support their anabolic and energy needs.
 

Breast cancer (BC) is the most frequently diagnosed cancer worldwide, accounting for ~7% of cancer related deaths yearly. The recognized molecular heterogeneity of BC poses relevant clinical challenges. A widely accepted classification stratifies BCs based on the status of hormone receptors (HR) and of the oncoprotein HER2. This classification largely informs patient treatment. Despite these advancements, some paramount clinical needs are still unmet, in particular:

• the assessment of risk recurrence within the Luminal (HR+/HER2-) subtypes, and
• the poor response of Triple negative tumors (TNBC, HR-/HER2-), an issue compounded by the lack of specific molecular markers, within this subgroup, for the development of targeted therapies.

Notwithstanding their clinical and molecular heterogeneity, BCs share common characteristics, first and foremost the alteration of cellular metabolism, in particular the elevation of glycolysis, which marks the more aggressive forms. Thus, a metabolic approach is a promising one to deconvolve the complexity of BC and to uncover targets for molecular therapies. The main goals of our research are to:

• identify genes/pathways whose alterations cause elevation of glycolysis and metabolic plasticity in BC;
• exploit these alterations to predict sensitivity to specific drugs.

Experimental approach

We pursue our goals by a dual approach:

• a biased candidate-based approach based on our long-standing experience in the field of membrane traffic
• an unbiased genome-wide approach, which exploits the detection of active glycolytic BCs in vivo by Positron Emission Tomography (PET).

Research achievements

A. Unbiased approach. A transcriptomic analysis of BCs, from patients who underwent FDG-PET, identified a 54-gene signature (PETsign) that recapitulates FDG uptake. PETsign is independently prognostic of clinical outcome in Luminal-type BCs. An orthogonal transcriptomic/metabolomic analysis revealed that PETsign predicts the metabolic status, readily identifying cell lines with enhanced glycolytic dependence and reduced reliance of fatty acid oxidation. Network analysis revealed that signaling pathways connected with various cytokines/growth factor and their receptors are paramount within the PETsign. Accordingly, activation of these pathways in BC cell lines caused a shift towards a glycolytic phenotype. Thus, PETsign is a metabolic/transcriptomic surrogate of FDG-PET that could find application in the management of BC patients (4).

B. Biased approach. We are investigating membrane trafficking proteins, because they control expression, stability and subcellular localization of plasma membrane receptors, nutrient transporters and enzymes. We are focusing on the so-called TBC-containing proteins, a family endowed with RabGAP and Rab-effector activities.

From the molecular perspective, orthogonal transcriptomic and metabolomic analyses have revealed that high expression levels of TBC1D7 and TBC1D22B lead to elevated glycolysis and lipid metabolism in BC cells (1, 3).

We found that among the members of the RabGAP family, increased expression of TBC1D7 and TBC1D22B correlates with poor prognosis in BCs, as confirmed in multivariate analysis, establishing them as independent predictors of unfavorable disease outcome. Specifically, TBC1D22B identifies Luminal BCs with reduced survival, while TBC1D7 serves as an independent prognostic marker for TNBCs (3).

Perspectives

We are integrating the hits of the two approaches to understand how the subversion of TBCs trafficking proteins alters the secretion/routing of the signaling molecules identified in the unbiased approach.

Many of the hits of the two approaches are already targetable with specific drugs. We are conducting preclinical studies to validate the efficacy of these drugs, propaedeutic to the design of clinical studies.

Publications

At this link, you can find all the scientific publications of the Principal Investigator.