The role of endoplasmic reticulum stress in mediating drug resistance in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide, as it is characterized by a high chemo-resistance.

The main risk factor for HCC is liver cirrhosis, which is accompanied by an increased deposition of extracellular matrix, thereby increasing liver stiffness.

This increased liver stiffness induces mechanical stress and could activate the endoplasmic reticulum (ER) stress pathways.

ER-stress has been implicated in creating chemo-resistance in several solid tumors, however its role in HCC is not well defined.

We have previously shown that ER-stress-genes are upregulated in HCC and that the ER-stress sensor IRE1a can cleave specific miRNAs in liver cirrhosis.

Others have shown that increased matrix stiffness alters miRNA-expression, it remains unknown whether this is through an IRE1a-dependent mechanism.

By using innovative 3D in vitro models, an in vivo model known for its similarity to human HCC and patient-derived organoids, we aim to identify if liver stiffness induces ER-stress, whether this affects drug-response and if it alters the panel of secreted miRNAs that could be used as bio-markers for drug-response.

The long-term impact of our study is to increase the available treatment options for HCC-patients and open the window for ER-stress inhibitors as adjuvant treatments.

By identifying new predictive biomarkers, we expect to improve outcomes by enabling clinicians to use chemotherapy only in the patients who will benefit from it.