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Targeting KRAS may be critical to ablate the stemness characteristics of cancer cells and block tumor emergence, relapse and metastasis.

KRAS is highly mutated in many deadly cancers, such as pancreatic, lung and colon cancer. It has therefore become the primary target in RAS drug development.

Others and we recently showed that a specific arm of KRAS signaling drives cancer cell stemness. Evidence suggests that cancer stem cells are the most critical cell type in many tumors. They give rise to the cellular diversity of a tumor and can efficiently seed new tumors, e.g. during metastasis.

 

  • Understanding the exact composition and functioning of RAS nanocluster, may resolve how exactly specific RAS signaling emerges from the plasma membrane.

RAS nanocluster are transient, nanoscale signaling complexes of RAS proteins in the plasma membrane. They are the sites where RAS effectors become recruited to and they are necessary for RAS signal transmission.

We believe that there are distinct, HRAS, NRAS and KRAS specific nanocluster components. Hence, if we drug-target such a specific component, we may be able to shut down signaling of only one of the RAS isoforms. This may be necessary depending on the cancer type and beneficial to avoid unwanted side-effects from targeting all of the RAS isoforms.

 

  • Galectin-1 is a cancer cell stemness-promoting component specifically of HRAS nanocluster.

Galectin-1 increases HRAS nanocluster and signaling apparently by stabilizing dimers of the effector Raf. We therefore argue that targeting of galectin-1 with the right type of inhibitor is important. If applied in tumors with the correct expression signature galectin-1 inhibitors may hold significant potential for the treatement of certain cancers.

 

  • We furthermore characterized the functioning of other cancer signaling associated modulators of RAS plasma membrane organization, such as ASPP2 (Apoptosis Stimulating of p53 Protein 2) and SPRED1 (Sprouty-related proteins with an EVH1 domain).

Interestingly, the tumor suppressor ASPP2 acts as a nanocluster promoter (or sensor) for all three RAS isoforms and can antagonize the activity of galectin-1. Thus it increases signaling output from typical RAS effector pathways, like PI3K (AKT-mTORC1) and RAF (MEK-ERK). It efficiently induces apoptosis owing to its p53 engaging activity. How exactly ASPP2 acts on RAS nanoclusters and what its role in cellular physiology is, is still poorly understood.

SPRED1 is another tumor suppressor and also mutated in a developmental disease belonging to the so-called RASopathies. We showed that SPRED1 shuttles to the plasma membrane via Raf-dimers to specifically block KRAS signaling. Given the RAF-dimer promoting activity of galectin-1, it can in fact promote the negative activity of SPRED1 on KRAS. It is not known, whether also other members of the SPRED and related SPROUTY family operate in a RAS isoform specific manner.

Fondation Cancer project

Analysis of the signal transduction network upstream of L-plastin Ser5 phosphorylation in breast cancer cells and tissues (PLASTIN)