Hepatocellular carcinoma (HCC) is currently the 4th leading cause of cancer death worldwide. Its very poor prognosis is explained by significant tumour aggressiveness and a low survival rate (5-year survival: <5%). It is characterized by great tumour heterogeneity between different patients as a result of distinct (epi-)genetic modifications and alterations in gene expression making conventional chemo- and radiotherapy ineffective. Moreover, the identification of new biomarkers in early stages of HCC development remains an urgent need still not achieved.

Over the pars few years, Maina lab (IBDM), have performed -omics analyses of mouse model (Alb-R26Met) that recapitulated different aspects of human HCCs, and compared the data obtained with those from human patients in order to identify new putative HCC targets and/or markers. Among the identified targets, ADAMTSL5, a gene not yet linked to tumour carcinogenesis, came up.

ADAMTSL5 is overexpressed in a large percentage of HCC patients (between 50 and 70% of HCC patients; 5 different endorsed cohorts). Moreover, the targeting of ADAMTSL5 (by shRNA) depleted the tumorigenic properties of HCC cells both in vitro and in vivo. All of these data illustrate the clinical relevance of ADAMTSL5 overexpression in a subgroup of HCC patients, indicating its relevance as putative novel marker and target for HCC treatment (Arechederra et al. J Hepatol 2020).

My postdoctoral work aims to understand functionally and mechanistically ADAMTSL5 function in hepatocellular carcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is considered as a poor prognosis cancer, the survival rate of patients barely reaching 5%, 5 years after diagnosis. In the absence of progress in diagnosis and treatments, it would even become, in Europe, the 2nd cause of cancer mortality by 2030.

Since the diagnosis is often made late, when the disease has already spread locally or is accompanied by significant metastatic development, the chances of survival for patients with PDAC are greatly reduced. About 70% of patient’s death are the result of metastases. As a heterogeneous and chemo-/radio-resistant cancer, the current treatments proposed are not effective.

It is essential to identify new markers of PDAC aggressiveness and to develop therapeutic strategies targeting tumour invasion.

To properly invade the microenvironment and form metastases, a tumour cell must first detach from the primary tumour. This requires a modulation of the intercellular adhesion molecules expression such as cadherins. In PDAC, a decrease (or extinction) of the E-cadherin is often associated with the increase in the expression of two others classicals cadherins: N- and P-cadherin.

Once detached and to facilitate its migration, the tumour cell will degrade the basal lamina and the extracellular matrix. This second process requires local enrichment of proteases capable of remodelling the extracellular matrix. As with other solid tumours, structures located at the migration front of tumoural cells, called invadopodia, can be observed in PDACs. Invadopodia are actin-rich protrusions which allow the secretion of various proteases at the origin of the degradation of the surrounding extracellular matrix.

My thesis work was divided in 2 aims:

1. Determine the nature of the classical cadherins (E-, N- and P-cadherin) involved in the invasion of pancreatic tumour cells
2. Dissect the molecular mechanisms by which cadherins regulate the cell invasion. I mainly focused on the involvement of cadherins organization, dynamics and activity of invadopodia.