| First Author | Álvarez-Varela A | Year | 2022 |
| Journal | Nat Cancer | Volume | 3 |
| Issue | 9 | Pages | 1052-1070 |
| PubMed ID | 35773527 | Mgi Jnum | J:329187 |
| Mgi Id | MGI:7341942 | Doi | 10.1038/s43018-022-00402-0 |
| Citation | Alvarez-Varela A, et al. (2022) Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy. Nat Cancer 3(9):1052-1070 |
| abstractText | Colorectal cancer (CRC) patient-derived organoids predict responses to chemotherapy. Here we used them to investigate relapse after treatment. Patient-derived organoids expand from highly proliferative LGR5(+) tumor cells; however, we discovered that lack of optimal growth conditions specifies a latent LGR5(+) cell state. This cell population expressed the gene MEX3A, is chemoresistant and regenerated the organoid culture after treatment. In CRC mouse models, Mex3a(+) cells contributed marginally to metastatic outgrowth; however, after chemotherapy, Mex3a(+) cells produced large cell clones that regenerated the disease. Lineage-tracing analysis showed that persister Mex3a(+) cells downregulate the WNT/stem cell gene program immediately after chemotherapy and adopt a transient state reminiscent to that of YAP(+) fetal intestinal progenitors. In contrast, Mex3a-deficient cells differentiated toward a goblet cell-like phenotype and were unable to resist chemotherapy. Our findings reveal that adaptation of cancer stem cells to suboptimal niche environments protects them from chemotherapy and identify a candidate cell of origin of relapse after treatment in CRC. |
