| First Author | Ganguly K | Year | 2021 |
| Journal | Cancer Res | Volume | 81 |
| Issue | 1 | Pages | 91-102 |
| PubMed ID | 33127746 | Mgi Jnum | J:301318 |
| Mgi Id | MGI:6505708 | Doi | 10.1158/0008-5472.CAN-20-1293 |
| Citation | Ganguly K, et al. (2020) Secretory mucin 5AC promotes neoplastic progression by augmenting KLF4-mediated pancreatic cancer cell stemness. Cancer Res |
| abstractText | Secreted mucin 5AC (MUC5AC) is the most abundantly overexpressed member of the mucin family during early pancreatic intraepithelial neoplasia stage I (PanIN-I) of pancreatic cancer (PC). To comprehend the contribution of Muc5ac in PC pathology, we genetically ablated it in an autochthonous murine model (KrasG12D; Pdx-1cre, KC), which mirrors the early stages of PC development. Neoplastic onset and the PanIN lesion progression were significantly delayed in Muc5ac knockout (KrasG12D; Muc5ac-/-; Pdx-1cre, KCM) animals with a 50% reduction in PanIN-2 and 70% reduction in PanIN-3 lesions compared to KC at 50 weeks of age. High-throughput RNA-sequencing analysis from pancreatic tissues of KCM animals revealed a significant decrease in cancer stem cell (CSC) markers Aldh1a1, Klf4, EpCAM, and CD133. Further, the silencing of MUC5AC in human PC cells reduced their tumorigenic propensity, as indicated by a significant decline in tumor formation frequency by limiting dilution assay upon subcutaneous administration. The contribution of MUC5AC in CSC maintenance was corroborated by a significant decrease in tumor burden upon orthotopic implantation of MUC5AC-depleted PC cells. Mechanistically, MUC5AC potentiated oncogenic signaling through integrin alphavbeta5, pSrc (Y416), and pSTAT3 (Y705). Phosphorylated STAT3, in turn, upregulated Klf4 expression, thereby enriching the self-renewing CSC population. A strong positive correlation of Muc5ac with Klf4 and pSTAT3 in the PanIN lesions of KC mouse pancreas reinforces the crucial involvement of MUC5AC in bolstering the CSC-associated tumorigenic properties of Kras-induced metaplastic cells, which leads to PC onset and progression. |
