CRISPR activation screen in mice identifies novel membrane proteins enhancing pulmonary metastatic colonisation

Louise van der Weyden, Victoria Harle, Gemma Turner, Victoria Offord, Vivek Iyer, Alastair Droop, Agnieszka Swiatkowska, Roy Rabbie, Andrew D Campbell, Owen Sansom, Pardo Calvo, Jyoti Choudhary, Ingrid Ferreira, Mark Tullett, Mark J Arends, Anneliese O Speak, David J Adams

Research output: Contribution to journalArticlepeer-review

Abstract

Melanoma represents ~5% of all cutaneous malignancies, yet accounts for the majority of skin cancer deaths due to its propensity to metastasise. To develop new therapies, novel target molecules must to be identified and the accessibility of cell surface proteins makes them attractive targets. Using CRISPR activation technology, we screened a library of guide RNAs targeting membrane protein-encoding genes to identify cell surface molecules whose upregulation enhances the metastatic pulmonary colonisation capabilities of tumour cells in vivo. We show that upregulated expression of the cell surface protein LRRN4CL led to increased pulmonary metastases in mice. Critically, LRRN4CL expression was elevated in melanoma patient samples, with high expression levels correlating with decreased survival. Collectively, our findings uncover an unappreciated role for LRRN4CL in the outcome of melanoma patients and identifies a potential therapeutic target and biomarker.
Original languageEnglish
JournalCommunications biology
Early online date23 Mar 2021
DOIs
Publication statusE-pub ahead of print - 23 Mar 2021

Keywords

  • Metastasis
  • colonisation
  • lung
  • melanoma
  • mouse
  • CRISPRa
  • dCas9
  • LRRN4CL
  • SLC4A3
  • TM4SF19
  • interferon

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