Reprogramming Aggressive Metastatic States with a Functional Map of Colorectal Cancer Plasticity

Time period:

1 December 2025 – 30 November 2029

Project leader:

Sanja Vickovic

Project member:

Neville Sanjana, Alba Corman, Soobeom Lee, Andrea Sottoriva, Francesco Cambuli, Lukas Arnroth

Funder:

Swedish Research Council

Type of award:

Project grant

Total funding:

5,400,000 SEK

Colorectal cancer (CRC) is the third most common and second deadliest cancer, with metastatic CRC remaining largely incurable due to therapy resistance and immune evasion. CRC cells undergo molecular state transitions that dictate prognosis and determine treatment success, yet the regulatory mechanisms governing these shifts remain poorly understood, limiting therapeutic interventions. Current models fail to capture CRC plasticity at sufficient resolution, requiring new approaches to functionally dissect tumor-state transitions.To address this, we will build a functional CRC map by integrating multiomic patient-derived atlases with in vitro models. We will engineer RNA-based fluorescent sensors (RADARs) to transform complex transcriptional programs into real-time fluorescence-based readouts, enabling scalable tracking of CRC plasticity. Next, we will perform a dual CRISPRi/ORF screen to interrogate both loss- and gain-of-function events, systematically identifying regulators that drive or constrain CRC transitions. Finally, we will conduct genetic and pharmacologic screens to identify druggable targets capable of reprogramming aggressive CRC states into treatable phenotypes.By linking genetic dependencies to therapeutic vulnerabilities, this project will create a functional and predictive CRC map, providing a foundational resource for precision medicine. This framework will enable targeted therapeutic strategies, accelerating the development of treatments for metastatic CRC.