Adhesion of pancreatic tumor cell clusters by desmosomal molecules enhances early liver metastases formation

TY - JOUR

T1 - Adhesion of pancreatic tumor cell clusters by desmosomal molecules enhances early liver metastases formation

AU - Dietrich, Niclas

AU - Castellanos-Martinez, Ramon

AU - Kemmling, Julia

AU - Heuser, Arnd

AU - Schnoor, Michael

AU - Schinner, Camilla

AU - Spindler, Volker

N1 - © 2024. The Author(s).

PY - 2024/8/6

Y1 - 2024/8/6

N2 - Desmosomes are intercellular adhesion complexes providing mechanical coupling and tissue integrity. Previously, a correlation of desmosomal molecule expression with invasion and metastasis formation in several tumor entities was described together with a relevance for circulating tumor cell cluster formation. Here, we investigated the contribution of the desmosomal core adhesion molecule desmoglein-2 (DSG2) to the initial steps of liver metastasis formation by pancreatic cancer cells using a novel ex vivo liver perfusion mouse model. We applied the pancreatic ductal adenocarcinoma cell line AsPC-1 with and without a knockout (KO) of DSG2 and generated mouse lines with a hepatocyte-specific KO of the known interacting partners of DSG2 (DSG2 and desmocollin-2). Liver perfusion with DSG2 KO AsPC-1 cells led to smaller circulating cell clusters and a reduced number of cells adhering to murine livers compared to control cells. While this was independent of the expression levels of desmosomal adhesion molecules in hepatocytes, we show that increased cluster size of cancer cells, which correlates with stronger cell-cell adhesion and expression of desmosomal molecules, is a major factor contributing to the early phase of metastatic spreading. In conclusion, impaired desmosomal adhesion results in reduced circulating cell cluster size, which is relevant for seeding and attachment of metastatic cells to the liver.

AB - Desmosomes are intercellular adhesion complexes providing mechanical coupling and tissue integrity. Previously, a correlation of desmosomal molecule expression with invasion and metastasis formation in several tumor entities was described together with a relevance for circulating tumor cell cluster formation. Here, we investigated the contribution of the desmosomal core adhesion molecule desmoglein-2 (DSG2) to the initial steps of liver metastasis formation by pancreatic cancer cells using a novel ex vivo liver perfusion mouse model. We applied the pancreatic ductal adenocarcinoma cell line AsPC-1 with and without a knockout (KO) of DSG2 and generated mouse lines with a hepatocyte-specific KO of the known interacting partners of DSG2 (DSG2 and desmocollin-2). Liver perfusion with DSG2 KO AsPC-1 cells led to smaller circulating cell clusters and a reduced number of cells adhering to murine livers compared to control cells. While this was independent of the expression levels of desmosomal adhesion molecules in hepatocytes, we show that increased cluster size of cancer cells, which correlates with stronger cell-cell adhesion and expression of desmosomal molecules, is a major factor contributing to the early phase of metastatic spreading. In conclusion, impaired desmosomal adhesion results in reduced circulating cell cluster size, which is relevant for seeding and attachment of metastatic cells to the liver.

KW - Animals

KW - Desmosomes/metabolism

KW - Pancreatic Neoplasms/pathology

KW - Cell Adhesion

KW - Mice

KW - Liver Neoplasms/secondary

KW - Cell Line, Tumor

KW - Humans

KW - Desmoglein 2/metabolism

KW - Carcinoma, Pancreatic Ductal/pathology

KW - Hepatocytes/metabolism

KW - Mice, Knockout

KW - Neoplastic Cells, Circulating/metabolism

U2 - 10.1038/s41598-024-68493-6

DO - 10.1038/s41598-024-68493-6

M3 - SCORING: Journal article

C2 - 39107343

VL - 14

SP - 18189

JO - SCI REP-UK

JF - SCI REP-UK

SN - 2045-2322

IS - 1

ER -