Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells

Adrià Cañellas-Socias, Carme Cortina, Xavier Hernando-Momblona, Sergio Palomo-Ponce, Eoghan J. Mulholland, Gemma Turon, Lidia Mateo, Sefora Conti, Olga Roman, Marta Sevillano, Felipe Slebe, Diana Stork, Adrià Caballé-Mestres, Antonio Berenguer-Llergo, Adrián Álvarez-Varela, Nicola Fenderico, Laura Novellasdemunt, Laura Jiménez-Gracia, Tamara Sipka, Lidia Bardia, Patricia Lorden, Julien Colombelli, Holger Heyn, Xavier Trepat, Sabine Tejpar, Elena Sancho, Daniele V. F. Tauriello, Simon Leedham, Camille Stephan-Otto Attolini and Eduard Batlle ()
Additional contact information
Adrià Cañellas-Socias: The Barcelona Institute of Science and Technology (BIST)
Carme Cortina: The Barcelona Institute of Science and Technology (BIST)
Xavier Hernando-Momblona: The Barcelona Institute of Science and Technology (BIST)
Sergio Palomo-Ponce: The Barcelona Institute of Science and Technology (BIST)
Eoghan J. Mulholland: University of Oxford
Gemma Turon: The Barcelona Institute of Science and Technology (BIST)
Lidia Mateo: The Barcelona Institute of Science and Technology (BIST)
Sefora Conti: The Barcelona Institute of Science and Technology (BIST)
Olga Roman: The Barcelona Institute of Science and Technology (BIST)
Marta Sevillano: The Barcelona Institute of Science and Technology (BIST)
Felipe Slebe: The Barcelona Institute of Science and Technology (BIST)
Diana Stork: The Barcelona Institute of Science and Technology (BIST)
Adrià Caballé-Mestres: The Barcelona Institute of Science and Technology (BIST)
Antonio Berenguer-Llergo: The Barcelona Institute of Science and Technology (BIST)
Adrián Álvarez-Varela: The Barcelona Institute of Science and Technology (BIST)
Nicola Fenderico: The Barcelona Institute of Science and Technology (BIST)
Laura Novellasdemunt: The Barcelona Institute of Science and Technology (BIST)
Laura Jiménez-Gracia: The Barcelona Institute of Science and Technology (BIST)
Tamara Sipka: The Barcelona Institute of Science and Technology (BIST)
Lidia Bardia: The Barcelona Institute of Science and Technology (BIST)
Patricia Lorden: The Barcelona Institute of Science and Technology (BIST)
Julien Colombelli: The Barcelona Institute of Science and Technology (BIST)
Holger Heyn: The Barcelona Institute of Science and Technology (BIST)
Xavier Trepat: The Barcelona Institute of Science and Technology (BIST)
Sabine Tejpar: Katholieke Universiteit Leuven
Elena Sancho: The Barcelona Institute of Science and Technology (BIST)
Daniele V. F. Tauriello: The Barcelona Institute of Science and Technology (BIST)
Simon Leedham: University of Oxford
Camille Stephan-Otto Attolini: The Barcelona Institute of Science and Technology (BIST)
Eduard Batlle: The Barcelona Institute of Science and Technology (BIST)

Nature, 2022, vol. 611, issue 7936, 603-613

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-05402-9

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