Cadherin-11 deficiency-induced changes in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the top five deadliest
forms of cancer with very few treatment options. The 5-year survival rate
for PDAC is 10% following diagnosis. Cadherin 11 (Cdh11), a cell-to-cell
adhesion molecule, has been suggested to promote tumor growth and
immunosuppression in PDAC, and Cdh11 inhibition significantly extended
survival in mice with PDAC. However, the mechanisms by which Cdh11
deficiency influences PDAC progression and anti-tumor immune responses
have yet to be fully elucidated. To investigate Cdh11-deficiency induced
changes in PDAC tumor microenvironment (TME), we crossed p48-Cre;
LSL-KrasG12D/+; LSL-Trp53R172H/+ (KPC) mice with Cdh11+/- mice and
performed single-cell RNA sequencing (scRNA-seq) of the non-immune (CD45-)
and immune (CD45+) compartment of KPC tumor-bearing Cdh11 proficient
(KPC-Cdh11+/+) and Cdh11 deficient (KPC-Cdh11+/-) mice.  Our
analysis showed that Cdh11 is expressed primarily in cancer-associated
fibroblasts (CAFs) and at low levels in epithelial cells undergoing
epithelial-to-mesenchymal transition (EMT). Cdh11 deficiency altered the
molecular profile of CAFs, leading to a decrease in the expression of
myofibroblast markers such as Acta2 and Tagln and cytokines such as Il6,
Il33 and Midkine (Mdk). We also observed a significant decrease in the
presence of monocytes/macrophages and neutrophils in KPC-Cdh11+/- tumors
while the proportion of T cells was increased. Additionally, myeloid
lineage cells from Cdh11-deficient tumors had reduced expression of
inflammatory cytokines that have previously been shown to play a role in
immune suppression. In summary, our data suggests that Cdh11 deficiency
significantly alters the fibroblast and immune microenvironments and
contributes to the downregulation of inflammatory cytokines, leading to an
increase in anti-tumor immunity and enhanced survival.