1. Academic Validation
  2. Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells

Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells

  • Nature. 2022 Nov 9. doi: 10.1038/s41586-022-05402-9.
Adrià Cañellas-Socias 1 2 Carme Cortina 1 2 Xavier Hernando-Momblona 1 2 Sergio Palomo-Ponce 1 2 Eoghan J Mulholland 3 Gemma Turon 1 Lidia Mateo 1 Sefora Conti 4 Olga Roman 1 Marta Sevillano 1 2 Felipe Slebe 1 Diana Stork 1 Adrià Caballé-Mestres 1 Antonio Berenguer-Llergo 1 Adrián Álvarez-Varela 1 2 Nicola Fenderico 1 Laura Novellasdemunt 1 Laura Jiménez-Gracia 5 Tamara Sipka 1 Lidia Bardia 1 Patricia Lorden 5 Julien Colombelli 1 Holger Heyn 5 6 Xavier Trepat 4 7 8 9 Sabine Tejpar 10 Elena Sancho 1 2 Daniele V F Tauriello 1 11 Simon Leedham 3 12 13 Camille Stephan-Otto Attolini 1 Eduard Batlle 14 15 16
Affiliations

Affiliations

  • 1 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
  • 2 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain.
  • 3 Gastrointestinal Stem Cell Biology Lab, Wellcome Centre Human Genetics, University of Oxford, Oxford, UK.
  • 4 Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
  • 5 CNAG-CRG, Centre for Genomic Regulation, The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
  • 6 Universitat Pompeu Fabra (UPF), Barcelona, Spain.
  • 7 Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
  • 8 Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona, Spain.
  • 9 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
  • 10 Digestive Oncology, Department of Oncology, Katholieke Universiteit Leuven, Leuven, Belgium.
  • 11 Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 12 Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK.
  • 13 Oxford National Institute for Health Research Biomedical Research Centre, Oxford, UK.
  • 14 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. [email protected]
  • 15 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain. [email protected]
  • 16 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. [email protected]
Abstract

Around 30-40% of patients with colorectal Cancer (CRC) undergoing curative resection of the primary tumour will develop metastases in the subsequent years1. Therapies to prevent disease relapse remain an unmet medical need. Here we uncover the identity and features of the residual tumour cells responsible for CRC relapse. An analysis of single-cell transcriptomes of samples from patients with CRC revealed that the majority of genes associated with a poor prognosis are expressed by a unique tumour cell population that we named high-relapse cells (HRCs). We established a human-like mouse model of microsatellite-stable CRC that undergoes metastatic relapse after surgical resection of the primary tumour. Residual HRCs occult in mouse livers after primary CRC surgery gave rise to multiple cell types over time, including LGR5+ stem-like tumour cells2-4, and caused overt metastatic disease. Using Emp1 (encoding epithelial membrane protein 1) as a marker gene for HRCs, we tracked and selectively eliminated this cell population. Genetic ablation of EMP1high cells prevented metastatic recurrence and mice remained disease-free after surgery. We also found that HRC-rich micrometastases were infiltrated with T cells, yet became progressively immune-excluded during outgrowth. Treatment with neoadjuvant immunotherapy eliminated residual metastatic cells and prevented mice from relapsing after surgery. Together, our findings reveal the cell-state dynamics of residual disease in CRC and anticipate that therapies targeting HRCs may help to avoid metastatic relapse.

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