TY - JOUR
T1 - Secretory Mucin 5AC Promotes Neoplastic Progression by Augmenting KLF4-Mediated Pancreatic Cancer Cell Stemness
AU - Ganguly, Koelina
AU - Krishn, Shiv Ram
AU - Rachagani, Satyanarayana
AU - Jahan, Rahat
AU - Shah, Ashu
AU - Nallasamy, Palanisamy
AU - Rauth, Sanchita
AU - Atri, Pranita
AU - Cox, Jesse L.
AU - Pothuraju, Ramesh
AU - Smith, Lynette M.
AU - Ayala, Sudhua
AU - Evans, Christopher
AU - Ponnusamy, Moorthy P.
AU - Kumar, Sushil
AU - Kaur, Sukhwinder
AU - Batra, Surinder K.
N1 - Funding Information:
We greatly appreciate the kind technical help of Ms. Kavita Mallya, UNMC (Omaha, NE). We also thank Dr. Jessica Mercer for her editorial contributions. The authors/work on this manuscript were supported, in parts, by grants from the NIH (R01 CA247471, RO1 CA210637, RO1CA206444, RO1 CA183459, UO1 CA200466, PO1 CA217798, R44 CA224619, R41 CA213718, and R41 CA235984).
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Secreted mucin 5AC (MUC5AC) is the most abundantly over-expressed member of the mucin family during early pancreatic intraepithelial neoplasia stage I (PanIN-I) of pancreatic cancer. To comprehend the contribution of Muc5ac in pancreatic cancer pathology, we genetically ablated it in an autochthonous murine model (KrasG12D; Pdx-1cre, KC), which mirrors the early stages of pancreatic cancer development. Neoplastic onset and the PanIN lesion progression were significantly delayed in Muc5ac knockout (KrasG12D; Pdx-1 cre; Muc5ac-/-, KCM) animals with a 50% reduction in PanIN-2 and 70% reduction in PanIN-3 lesions compared with 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. Furthermore, the silencing of MUC5AC in human pancreatic cancer 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 pancreatic cancer cells. Mechanistically, MUC5AC potentiated oncogenic signaling through integrin avb5, 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 pancreatic cancer onset and progression. Significance: This study elucidates that de novo expression of MUC5AC promotes cancer cell stemness during Kras-driven pancreatic tumorigenesis and can be targeted for development of a novel therapeutic regimen.
AB - Secreted mucin 5AC (MUC5AC) is the most abundantly over-expressed member of the mucin family during early pancreatic intraepithelial neoplasia stage I (PanIN-I) of pancreatic cancer. To comprehend the contribution of Muc5ac in pancreatic cancer pathology, we genetically ablated it in an autochthonous murine model (KrasG12D; Pdx-1cre, KC), which mirrors the early stages of pancreatic cancer development. Neoplastic onset and the PanIN lesion progression were significantly delayed in Muc5ac knockout (KrasG12D; Pdx-1 cre; Muc5ac-/-, KCM) animals with a 50% reduction in PanIN-2 and 70% reduction in PanIN-3 lesions compared with 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. Furthermore, the silencing of MUC5AC in human pancreatic cancer 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 pancreatic cancer cells. Mechanistically, MUC5AC potentiated oncogenic signaling through integrin avb5, 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 pancreatic cancer onset and progression. Significance: This study elucidates that de novo expression of MUC5AC promotes cancer cell stemness during Kras-driven pancreatic tumorigenesis and can be targeted for development of a novel therapeutic regimen.
UR - http://www.scopus.com/inward/record.url?scp=85100396531&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100396531&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-20-1293
DO - 10.1158/0008-5472.CAN-20-1293
M3 - Article
C2 - 33127746
AN - SCOPUS:85100396531
VL - 81
SP - 91
EP - 102
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 1
ER -