Preventing integrin cargo loading into small extracellular vesicles impairs organotropic metastasis of PDAC

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers suggested to become the 2^nd leading cause of cancer-related mortality in the near future. PDAC is characterized by early invasion and aggressive metastatic growth. Thus, it is vital to elucidate the molecular mechanisms governing different metastasis patterns, such as pre-dominant liver or lung metastasis. Recently, tumor-derived small extracellular vesicles (sEVs, exosomes) with specific integrin patterns were shown to shape organ-specific pre-metastatic niches for tumors. sEVs derive of endo-lysosomal structures, where they are formed as intraluminal vesicles with a size of 30-150 nm and are released at the plasma membrane. sEVs transfer a variety of bioactive cargos, such as lipids, proteins, miRNA, mRNAs to reprogram recipient cells. Compared to normal cells, sEVs are released by tumor cells at much higher rates. We have recently shown that Protein Kinase D1 (PRKD1) is a novel regulator of sEV secretion. PRKD1 is strongly downregulated in 72% of PDAC, likely by promotor methylation. The loss of PRKD1 expression in PDAC drastically enhanced sEV-release and these sEVs directed metastasis predominantly to the lung in Prkd1^KOKC mice. Organotropic lung metastasis was facilitated by upregulation of integrins α6β4 in cells and on the secreted sEVs. The respective integrins are recycled from the cell surface and packaged into Prkd1^KO-derived sEVs by their tetraspanin-binding partner CD82. Once in the lung, Prkd1^KO-sEVs educate lung fibroblasts to generate a pre-metastatic niche via expression of S100A proteins. Blocking of CD82 impaired loading of integrin α6β4 into sEVs and prevented the establishment of lung metastases in subcutaneous NSG-xenograft models. Thus, this concept offers a novel strategy to target further metastatic dissemination and recurrence. The formation of pre-metastatic niches in the liver is also governed by sEVs expressing integrins αvβ5 and is dependent on sEV-uptake by Kupffer cells. We are currently elucidating how integrin αvβ5 is recycled from the cell surface into sEVs, and whether tetraspanins are involved in this process. Hence, targeting pre-metastatic niche formation by sEVs may represent a viable approach to inhibit further PDAC tumor dissemination.

Publication History

Article published online:
07 September 2021