TY - JOUR
T1 - Muc16 depletion diminishes KRAS-induced tumorigenesis and metastasis by altering tumor microenvironment factors in pancreatic ductal adenocarcinoma
AU - Lakshmanan, Imayavaramban
AU - Marimuthu, Saravanakumar
AU - Chaudhary, Sanjib
AU - Seshacharyulu, Parthasarathy
AU - Rachagani, Satyanarayana
AU - Muniyan, Sakthivel
AU - Chirravuri-Venkata, Ramakanth
AU - Atri, Pranita
AU - Rauth, Sanchita
AU - Nimmakayala, Rama Krishna
AU - Siddiqui, Jawed Akhtar
AU - Gautam, Shailendra K.
AU - Shah, Ashu
AU - Natarajan, Gopalakrishnan
AU - Parte, Seema
AU - Bhyravbhatla, Namita
AU - Mallya, Kavita
AU - Haridas, Dhanya
AU - Talmon, Geoffrey A.
AU - Smith, Lynette M.
AU - Kumar, Sushil
AU - Ganti, Apar Kishor
AU - Jain, Maneesh
AU - Ponnusamy, Moorthy P.
AU - Batra, Surinder K.
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/11/25
Y1 - 2022/11/25
N2 - MUC16, membrane-bound mucin, plays an oncogenic role in pancreatic ductal adenocarcinoma (PDAC). However, the pathological role of MUC16 in the PDAC progression, tumor microenvironment, and metastasis in cooperation with KrasG12D and Trp53R172H mutations remains unknown. Deletion of Muc16 with activating mutations KrasG12D/+ and Trp53R172H/+ in mice significantly decreased progression and prolonged overall survival in KrasG12D/+; Trp53R172H/+; Pdx-1-Cre; Muc16−/− (KPCM) and KrasG12D/+; Pdx-1-Cre; Muc16−/− (KCM), as compared to KrasG12D/+; Trp53R172H/+; Pdx-1-Cre (KPC) and KrasG12D/+; Pdx-1-Cre (KC) mice, respectively. Muc16 knockout pancreatic tumor (KPCM) displays decreased tumor microenvironment factors and significantly reduced incidence of liver and lung metastasis compared to KPC. Furthermore, in silico data analysis showed a positive correlation of MUC16 with activated stroma and metastasis-associated genes. KPCM mouse syngeneic cells had significantly lower metastatic and endothelial cell binding abilities than KPC cells. Similarly, KPCM organoids significantly decreased the growth rate compared to KPC organoids. Interestingly, RNA-seq data revealed that the cytoskeletal proteins Actg2, Myh11, and Pdlim3 were downregulated in KPCM tumors. Further knockdown of these genes showed reduced metastatic potential. Overall, our results demonstrate that Muc16 alters the tumor microenvironment factors during pancreatic cancer progression and metastasis by changing the expression of Actg2, Myh11, and Pdlim3 genes.
AB - MUC16, membrane-bound mucin, plays an oncogenic role in pancreatic ductal adenocarcinoma (PDAC). However, the pathological role of MUC16 in the PDAC progression, tumor microenvironment, and metastasis in cooperation with KrasG12D and Trp53R172H mutations remains unknown. Deletion of Muc16 with activating mutations KrasG12D/+ and Trp53R172H/+ in mice significantly decreased progression and prolonged overall survival in KrasG12D/+; Trp53R172H/+; Pdx-1-Cre; Muc16−/− (KPCM) and KrasG12D/+; Pdx-1-Cre; Muc16−/− (KCM), as compared to KrasG12D/+; Trp53R172H/+; Pdx-1-Cre (KPC) and KrasG12D/+; Pdx-1-Cre (KC) mice, respectively. Muc16 knockout pancreatic tumor (KPCM) displays decreased tumor microenvironment factors and significantly reduced incidence of liver and lung metastasis compared to KPC. Furthermore, in silico data analysis showed a positive correlation of MUC16 with activated stroma and metastasis-associated genes. KPCM mouse syngeneic cells had significantly lower metastatic and endothelial cell binding abilities than KPC cells. Similarly, KPCM organoids significantly decreased the growth rate compared to KPC organoids. Interestingly, RNA-seq data revealed that the cytoskeletal proteins Actg2, Myh11, and Pdlim3 were downregulated in KPCM tumors. Further knockdown of these genes showed reduced metastatic potential. Overall, our results demonstrate that Muc16 alters the tumor microenvironment factors during pancreatic cancer progression and metastasis by changing the expression of Actg2, Myh11, and Pdlim3 genes.
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U2 - 10.1038/s41388-022-02493-6
DO - 10.1038/s41388-022-02493-6
M3 - Article
C2 - 36271032
AN - SCOPUS:85140309342
SN - 0950-9232
VL - 41
SP - 5147
EP - 5159
JO - Oncogene
JF - Oncogene
IS - 48
ER -