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- In KRAS-mutant colorectal cancer, treatment pressure can redirect cell states rather than simply kill them.
- Tackling heterogeneity and plasticity—especially the emergence of the LGR5⁺ state—may be essential to improve outcomes.
- The study has been published in the journal Cancer Discovery.
A new study led by Dr. Eduard Batlle (ICREA Researcher at IRB Barcelona and CIBERONC researcher), Dr. Carme Cortina (IRB Barcelona) and Dr. Marc Martí-Renom (CNAG-CRG), in collaboration with Revolution Medicines, shows that metastatic colorectal cancers (mCRC) are highly diverse, made up of tumor cells that adopt different states and display distinct properties. Within a given tumor, cells can rapidly shift from one state to another—a key cancer feature known as transcriptional plasticity. This flexibility enables KRAS-mutant mCRC to withstand treatment with a novel targeted compound that selectively inhibit oncogenic KRAS signaling.
Using preclinical models of mCRC, the authors show that oncogenic KRAS induces a cell state associated with metastasis and poor prognosis. However, when mutant KRAS activity is blocked with a KRAS mutant-selective inhibitor, tumor cells switch from this state to a stem-like state marked by LGR5. These LGR5⁺ cells depend less on KRAS signaling, which may explain the limited benefit of KRAS-targeted approaches in colorectal cancer.
The team finds that this switch is driven by changes in gene-reading programs that control which genes are turned on or off and define cell identity, rather than by new DNA mutations—highlighting plasticity as the main escape route.
In preclinical models of colorectal cancer metastasis, combining KRAS-pathway inhibition with strategies that eliminate the emergent LGR5⁺ population produced stronger, longer-lasting responses.
The study also involved researchers from VHIO (Barcelona), the Research Institute of Molecular Pathology (IMP, Vienna), CIBERONC, Imperial College (London), the Francis Crick Institute (London), CSIC’s Instituto de Investigaciones Biomédicas Sols-Morreale (Madrid) and IdiPAZ (Madrid).
Related article:
A plastic EMP1⁺ to LGR5⁺ cell state conversion as a therapeutic bypass to KRAS-G12D inhibition in metastatic colorectal cancer.
Alessia Centonze, Adrià-Jaume Roura, Meritxell Novillo-Font, Cristina Giordano, Xavier Hernando-Momblona, Montserrat Llanses, Paula Prats, Marta Sevillano, Debora Cabot, Mireia Novell, Gabriel Pabst, Florian Andersch, Adrià Cañellas-Socias, Chong Zhang, Nikolaos Giakoumakis, Hugh Sparks, Chris Dunsby, Julien Colombelli, Asunción Fernández-Barral, Elena Sancho, Camille Stephan-Otto Attolini, Alberto Muñoz, Antonio Barbachano, Hector Palmer, Jordi Martinez-Quintanilla, Johannes Zuber, Cristina Blaj, Elsa Quintana, Carme Cortina*, Marc A. Martí-Renom* & Eduard Batlle*.
Cancer Discovery (2024).
About IRB Barcelona
The Institute for Research in Biomedicine (IRB Barcelona) pursues a society free of disease. To this end, it conducts multidisciplinary research of excellence to cure cancer and other diseases linked to ageing. It establishes technology transfer agreements with the pharmaceutical industry and major hospitals to bring research results closer to society, and organises a range of science outreach activities to engage the public in an open dialogue. IRB Barcelona is an international centre that hosts 400 researchers and more than 30 nationalities. Recognised as a Severo Ochoa Centre of Excellence since 2011, IRB Barcelona is a CERCA centre and member of the Barcelona Institute of Science and Technology (BIST).
