Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells

• Published in: Nature (London) Vol. 611; no. 7936; pp. 603 - 613
• Main Authors: Cañellas-Socias, Adrià, Cortina, Carme, Hernando-Momblona, Xavier, Palomo-Ponce, Sergio, Mulholland, Eoghan J., Turon, Gemma, Mateo, Lidia, Conti, Sefora, Roman, Olga, Sevillano, Marta, Slebe, Felipe, Stork, Diana, Caballé-Mestres, Adrià, Berenguer-Llergo, Antonio, Álvarez-Varela, Adrián, Fenderico, Nicola, Novellasdemunt, Laura, Jiménez-Gracia, Laura, Sipka, Tamara, Bardia, Lidia, Lorden, Patricia, Colombelli, Julien, Heyn, Holger, Trepat, Xavier, Tejpar, Sabine, Sancho, Elena, Tauriello, Daniele V. F., Leedham, Simon, Attolini, Camille Stephan-Otto, Batlle, Eduard
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17-11-2022; Nature Publishing Group
• Subjects: Ablation; Animals; Cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Colorectal Neoplasms - therapy; Disease Models, Animal; Disease Progression; Gene expression; Humanities and Social Sciences; Humans; Immunotherapy; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - cytology; Lymphocytes, Tumor-Infiltrating - immunology; Medical prognosis; Membrane proteins; Metastases; Metastasis; Mice; multidisciplinary; Neoadjuvant Therapy; Neoplasm Metastasis - genetics; Neoplasm Metastasis - pathology; Neoplasm Metastasis - prevention & control; Neoplasm Metastasis - therapy; Neoplasm Proteins - deficiency; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - pathology; Neoplasm Recurrence, Local - prevention & control; Neoplasm Recurrence, Local - therapy; Neoplasm, Residual - genetics; Neoplasm, Residual - pathology; Pancreatic cancer; Patients; Population genetics; Receptors, Cell Surface - deficiency; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Science; Science (multidisciplinary); Surgery; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Transcriptomes; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-022-05402-9

Around 30–40% of patients with colorectal cancer (CRC) undergoing curative resection of the primary tumour will develop metastases in the subsequent years
1
. 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 cells
2
–
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 EMP1
high
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.
A poor prognosis gene programme in patients with colorectal cancer is expressed by a unique tumour cell population that we name high-relapse cells (HRCs), and ablation of cells expressing the HRC marker EMP1 or neoadjuvant immunotherapy prevented metastatic recurrence in mice.