A green platform to study cancer glyco-signatures

Colorectal (CRC) and gastric (GC) cancers remain the top lethal cancers and targeted therapies are still very limited. These carcinomas are associated with a poor prognosis, primarily due to late disease diagnosis. Overexpression of the Human Epidermal Growth Factor Receptor 2 (ErbB2) is an important biomarker for treatment selection. The antibody Trastuzumab (Tz) is the first personalized therapeutic agent to treat ErbB2-positive gastric cancers. Unfortunately, the emergence of resistance severely compromises the clinical performance of Tz. Therefore, studying the mechanisms underlying therapeutic resistance can guide the design of personalized therapies, or improve the clinical performance of current anti-cancer agents. Glycosylation is the process by which a carbohydrate (glycan) is attached to a protein (glycoprotein). Aberrant glycosylation is a hallmark of cancer cells and plays a key role in acquisition of resistance to therapy. ErbB2 is highly glycosylated in GC cells, and harbors several cancer-associated carbohydrates (glycoforms) that impar the biding of Tz. However, the diversity of ErbB2 glycoforms hinders the identification and functional validation of those that are sensitive or resistant to Tz treatment. Customizing cancer glyco-structures is a challenge. Plants have entered the fight against cancer because they constitute low-cost and efficient hosts to produce human proteins in a timeframe of weeks without the need for genetic transformation. In terms of glycosylation, plants offer the advantage that their glycan repertoire is limited, thus enabling a stepwise overexpression of enzymes required to tailor a specific glycoform. In this project, we aim to use plant to produce ErbB2 proteins decorated with glycans that mimicking cancer glyco-signatures and use these molecular tools to elucidate the mechanisms underlying the resistance of GC-ErbB2+ to Trastuzumab. Using plants as protein bioreactors is a promising innovative, rapid and sustainable approach conduct studies likely to provide major insights into glycan-dependent interactions and help developing innovative therapies. With this project we hope to (i) elucidate the underlying mechanisms related drug resistance; (ii) identify biomarkers for early diagnosis and patient stratification and (iii) guide the development of antibodies and vaccines directed to specific glycans.