A better understanding of KRAS-driven pancreatic cancer initiation.

02/04/2021

KRAS is one of the first oncogenes discovered 30 years ago. KRAS is mutated in 30% of cancers, but it is particularly prevalent in pancreatic cancer with 95% of patients harboring a KRAS mutation. Unfortunately, few treatment options are available for pancreatic cancer, highlighting the need to better understand KRAS-related mechanisms to identify candidates amenable to therapeutic targeting.

When Prof. Jacquemin started to work on pancreatic cancer a few years ago, he was surprised by the lack of antibodies detecting KRAS in healthy and cancerous tissues. However, the ability to detect proteins in tissues is an essential step in understanding their roles. Based on this observation, the Jacquemin’s team tried to develop new antibodies; although these antibodies were more sensitive compared to existing ones, they were not enough efficient to detect KRAS in tissues.

To overcome this issue, his team developed new CRISPR-edited mouse models in which KRAS (wild-type and oncogenic forms) are fused in-frame with a fluorescent protein. For the first time ever, these models allowed the visualization of KRAS expression pattern in the pancreas both in normal and cancer conditions. These experiments were conducted by Dr. Mohamad Assi, a postdoctoral researcher at the FNRS. Thanks to these models, they found that contrary the prevalent idea, KRAS is not ubiquitously expressed in the pancreas, but only in a small proportion of pancreatic cells. Interestingly, in the presence of pancreatic inflammation, a pathological condition required for pancreatic cancer initiation, the majority of pancreatic cells started to express KRAS. Also, with inflammation, pancreatic cells increased the expression of many proteins essential for KRAS activity, which are called KRAS effectors. In collaboration with the team of Prof. Mariano Barbacid, in Madrid, they have shown that one key effector, called C-RAF, was essential for pancreatic cancer initiation in the presence of inflammation. Overall, these new mouse models allowed to identify an essential mechanism for pancreatic cancer initiation and highlighted the need to consider therapeutic strategies targeting oncogene expression.

These mouse models, which were developed by the transgenesis platform of the de Duve Institute, will be also useful to study other cancer types (e.g. lungs) and different aspects of organ development during embryogenesis.

 

Article describing this research

Dynamic regulation of expression of KRAS and its effectors determines the ability to initiate tumorigenesis in pancreatic acinar cells

Assi M, Achouri Y, Loriot A, Dauguet N, Dahou H, Baldan J, Libert M, Fain JS, Guerra C, Bouwens L, Barbacid M, Lemaigre FP and Jacquemin P.

Cancer Res.

 

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