Endocytosis, signaling and cancer
Signaling by the EGFR family of receptors is commonly deregulated in cancer. The internalization route of the EGFR is decisive in determining receptor fate and signaling outcomes. Depending on ligand concentration, EGFR internalization may occur either via clathrin-mediated endocytosis (CME) or via the non-clathrin mediated endocytosis (NCE) more recently identified by us [7-9]. CME is involved in receptor recycling and signal amplification, while the NCE pathway targets the EGFR for degradation, causing signal suppression. So NCE could potentially be a novel tumor suppressor pathway, while CME, which sustains EGFR signaling, might be an oncogenic pathway.

To establish the true pathological relevance of endocytosis we are using classical biochemistry and cell biology approaches to define the full molecular details and functional significance of the novel NCE pathway. However, the integration of the NCE and CME networks is impossible to understand without the help of a systems level approach. Therefore, we also have projects that combine mathematical modeling and wet-lab experiments, to define the parameters that trigger the switch between the two EGFR endocytic pathways. Finally, thanks to the Molecular Medicine for Care Program we have access to the necessary resources for preclinical research into the pathological relevance of EGFR endocytic pathways in cancer.

Stem cells and cancer
There is a general consensus that cancer stem cells (CSCs) are the driving force of some (if not many) tumors, including breast cancer. Only a minor fraction of the cells within a tumor are CSCs, and these possess stem cell (SC)-like properties including self-renewal, quiescence and unlimited replication potential. While the SC compartment is tightly controlled in normal tissues, the CSC compartment appears to be expanded in breast cancers: more aggressive, poorly differentiated tumors have a larger proportion of CSCs than less aggressive, more differentiated tumors [5]. The mechanisms governing CSC amplification remain unclear, but SC homeostasis depends on the continued asymmetric division of SCs to produce a single quiescent SC and a differentiating progenitor. This guarantees a constant population of SCs over time. Symmetric SC division, instead, produces two stem daughter cells, and increases SC numbers. Notch, p53 and the endocytic protein Numb are implicated in stem cell self-renewal and asymmetric cell division. We have shown that Numb controls p53 ubiquitination and degradation [6] and that Notch signaling is increased in Numb-deficient tumors [4]. Various projects in the lab aim to characterize the involvement of these three players in stem cell self-renewal mechanisms and in tumorigenesis.

Numb is asymmetrically distributed during normal breast SC division, but its dynamics of distribution are altered in CSCs. By analogy with Numb, the discovery of other asymmetrically distributed proteins may shed light on molecular mechanisms for normal SC homeostasis. We are therefore characterizing the proteomic profile of asymmetrically partitioned proteins during normal SC division to identify new cancer-relevant candidates for subsequent high-resolution studies.

Cancer-specific profiles
A simple search of the scientific literature highlights innumerable expression profiles describing any number of normal and pathological states. While these gene signatures have given an invaluable contribution to our scientific body of knowledge, their direct clinical applications have been few and far between. The studies published by others and by us [5, 10-18], have driven a number of high-resolution studies currently conducted in our lab on individual markers that potentially have significant clinical relevance as prognostic or therapeutic targets. Furthermore, some of our studies, in particular a lung cancer diagnostic signature and a stem cell expression profile, have been transferred to the Molecular Medicine for Care Program, for the development of new clinical applications. The know-how acquired through this work is also allowing us to perform new, independent studies on miRNA profiles in breast and ovarian cancers, to develop blood tests for their early diagnosis.