Flinck, M. | Search bioRxiv

bioRxiv2024

Tumor microenvironment acidosis favors pancreatic cancer stem cell properties and in vivo metastasis

The acidic tumor microenvironment favors cancer aggressiveness via incompletely understood pathways. Here, we asked whether acidic environments select for cancer stem cell (CSC) properties. Bulk RNA-seq of Panc-1 human pancreatic cancer cells adapted to extracellular pH 6.5 revealed upregulation of CSC markers including CD44, EpCam, Nestin and aldehyde dehydrogenases, and CSC pathway enrichment. We therefore assessed CSC characteristics of acid-adapted (AA) and non-adapted (Ctrl) PaTu8988s and MiaPaca-2 pancreatic cancer cells. Compared to Ctrl, AA cells exhibited increased ALDH- and {beta}-catenin activity and pancreatosphere-forming efficiency, classical CSC characteristics. Panc-1, PaTu8988s and MiaPaCa-2 AA cells differed in CSC marker expression, and AA cells did not exhibit typical flow cytometric CSC populations. However, single-nucleus sequencing identified the acid adaptation-induced emergence of a population with clear CSC characteristics. Finally, in an orthotopic mouse model, AA Panc-1 cells drove strongly increased aggressiveness and liver metastasis compared to Ctrl cells. We conclude that acid-adaptation of pancreatic cancer cells leads to enrichment of a CSC phenotype with unusual traits, providing new insight into how acidic tumor microenvironments favor cancer aggressiveness.

cancer biology↗

bioRxiv2023

MCT4 and CD147 co-localize with MMP14 in invadopodia and autolysosomes and collectively stimulate breast cancer cell invasion by increasing extracellular matrix degradation

The lactate-proton cotransporter MCT4 and its chaperone CD147 are upregulated in breast cancers, correlating with decreased patient survival. Here, we test the hypothesis that MCT4 and CD147 favor breast cancer invasion through interdependent effects on extracellular matrix (ECM) degradation. MCT4 and CD147 expression and membrane localization were strongly reciprocally interdependent in MDA-MB-231 invasive breast cancer cells. Knockdown (KD) and overexpression (OE) of MCT4 and/or CD174 in- and decreased, respectively, migration, invasion, and fluorescent gelatin degradation. OE of both proteins increased gelatin degradation and appearance of the matrix metalloprotease (MMP)-generated collagen-I cleavage product reC1M more than each protein alone, suggesting a concerted role in ECM degradation. MCT4 and CD147 co-localized strongly with invadopodia markers at the plasma membrane and with MMP14, the lysosomal marker LAMP-1, and in some cases the autophagosome marker LC3, in F-actin-decorated, large intracellular vesicles. We conclude that MCT4 and CD147 reciprocally regulate each other and support migration and invasiveness of MDA-MB-231 breast cancer cells in an interdependent manner. Mechanistically, this involves the MCT4-CD147-dependent stimulation of ECM degradation and specifically of MMP-mediated collagen-I degradation. We suggest that the MCT4-CD147 complex is co-delivered to invadopodia with MMP14.

cancer biology↗