Cx43 phosphorylation sites regulate pancreatic cancer metastasis

Pancreatic ductal adenocarcinoma (PDA) is aggressive, highly metastatic and characterized by a robust desmoplasia. Connexin proteins that form gap junctions have been implicated in tumor suppression for over 30 years. Cx43, the most widely expressed connexin, regulates cell behaviors, including migration and proliferation. Thus, we hypothesized that Cx43 could regulate PDA progression. Phosphorylation of Cx43 by Casein Kinase 1 (CK1) regulates gap junction assembly. We interbred the well-established Kras(LSL-G12D/+;p48Cre/+) (KC) mouse model of PDA with homozygous knock-in mutant Cx43 mice bearing amino acid substitution at CK1 sites (Cx43(CK1A)) and found profound and surprising effects on cancer progression. Crossing the Cx43(CK1A) mouse onto the KC background (termed KC;Cx(CK1A)) led to significant extension of lifespan, from a median of 370 to 486 days (p = 0.03) and a decreased incidence of metastasis (p = 0.045). However, when we examined early stages of disease, we found more rapid onset of tissue remodeling in the KC;Cx(CK1A) mouse followed by divergence to a cystic phenotype. During tumorigenesis, gap junctions are increasingly present in stromal cells of the KC mice but are absent from the KC;Cx43(CK1A) mice. Tail vein metastasis assays with cells derived from KC or KC;Cx(CK1A) tumors showed that KC;Cx(CK1A) cells could efficiently colonize the lung and downregulate Cx43 expression, arguing that inhibition of metastasis was not occurring at the distal site. Instead, stromal gap junctions, their associated signaling events or other unknown Cx43-dependent events facilitate metastatic capacity in the primary tumor.

Automated summary

Pancreatic ductal adenocarcinoma (PDA) is characterized by aggressive nature, high metastasis, and strong desmoplasia. Connexin protein Cx43 plays a crucial role in regulating PDA progression through modulation of cell behaviors and gap junction assembly. Mutation in Cx43 phosphorylation sites can significantly impact cancer progression, leading to extended lifespan and reduced metastasis in mouse models. Moreover, stromal gap junctions and associated signaling events mediated by Cx43 may facilitate the metastatic capacity of primary tumors.