Abstract
The prognosis of locally advanced colorectal cancer (CRC) is currently unsatisfactory. This is mainly due to drug resistance, recurrence, and subsequent metastatic dissemination, which are sustained by the cancer stem cell (CSC) population. The main driver of the CSC gene expression program is Wnt signaling, and previous reports indicate that Wnt3a can activate p38 MAPK. Besides, p38 was shown to feed into the canonical Wnt/β-catenin pathway. Here we show that patient-derived locally advanced CRC stem cells (CRC-SCs) are characterized by increased expression of p38α and are “addicted” to its kinase activity. Of note, we found that stage III CRC patients with high p38α levels display reduced disease-free and progression-free survival. Extensive molecular analysis in patient-derived CRC-SC tumorspheres and APCMin/+ mice intestinal organoids revealed that p38α acts as a β-catenin chromatin-associated kinase required for the regulation of a signaling platform involved in tumor proliferation, metastatic dissemination, and chemoresistance in these CRC model systems. In particular, the p38α kinase inhibitor ralimetinib, which has already entered clinical trials, promoted sensitization of patient-derived CRC-SCs to chemotherapeutic agents commonly used for CRC treatment and showed a synthetic lethality effect when used in combination with the MEK1 inhibitor trametinib. Taken together, these results suggest that p38α may be targeted in CSCs to devise new personalized CRC treatment strategies.
Highlights
Colorectal cancer (CRC) is the third most frequent malignancy but the second leading cause of death for tumor worldwide[1]
Since cancer stem cell (CSC) are involved in drug resistance and disease recurrence, we evaluated the potential of ralimetinib as a sensitizing agent in chemoresistant CRC stem cells (CRC-SCs) as part of a synergistic approach with currently used chemotherapeutics (CHTs), such as 5-FU, CDDP, CPT-11, or trametinib, a MEK1 inhibitor that is already approved for clinical use (Fig. 6D)
Our results showed that combined treatment with ralimetinib and CHTs or trametinib almost completely abolishes CRC-SC clonogenic activity compared to each single treatment (Figs. 6G; S7C)
Summary
Stage III CRC patients are eligible for adjuvant and combination therapies but still have a poor prognosis. Experiments performed in patient-derived stage III CRC-SC tumorspheres cultured with or without a Wnt/ β-catenin pathway inhibitor (PRI-724) or activator (Wnt3a alone or in combination with LiCl) confirmed p38α– β-catenin nuclear/cytoplasmic co-localization under all treatment conditions in these cells (Fig. S2C) These results prompted us to ascertain whether p38α directly interacts with β-catenin. A live/dead staining assay performed on patient-derived CRC-SC tumorspheres cultured in Matrigel showed a marked reduction in cell survival upon combined treatment with ralimetinib and CHTs or trametinib in this reconstituted 3D culture system (Fig. 7D). Overall, these data indicate that p38α inhibition makes chemoresistant patient-derived CRC-SCs more sensitive to 5-FU, CDDP, CPT-11, and trametinib, and prone to apoptosis. These data were confirmed by the reduced number (Fig. 8B) and size (Fig. 8C) of organoids after treatment with both inhibitors
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