Cancer metastasis is the process of detrimental systemic spread and the primary cause of cancer-related fatalities. Successful metastasis formation requires tumor cells to be proliferative and invasive; however, cells cannot be effective at both tasks simultaneously. Tumor cells compensate for this trade-off by changing their phenotype during metastasis formation through phenotypic plasticity. Given the changing selection pressures and competitive interactions that tumor cells face, it is poorly understood how plasticity shapes the process of metastasis formation. Here, we develop an ecology-inspired mathematical model with phenotypic plasticity and resource competition between phenotypes to address this knowledge gap. We find that phenotypically plastic tumor cell populations attain a stable phenotype equilibrium that maintains tumor cell heterogeneity. Considering treatment types inspired by chemo- and immunotherapy, we highlight that plasticity can protect tumors against interventions. Turning this strength into a weakness, we corroborate current clinical practices to use plasticity as a target for adjuvant therapy. We present a parsimonious view of tumor plasticity-driven metastasis that is quantitative and experimentally testable, and thus potentially improving the mechanistic understanding of metastasis at the cell population level, and its treatment consequences.

Pancreatic ductal adenocarcinoma (PDAC) is mostly diagnosed at advanced or even metastasized stages, limiting the prognoses of patients. Metastasis requires high tumor cell plasticity, implying phenotypic switching in response to changing environments. Here, epithelial–mesenchymal transition (EMT), being associated with an increase in cancer stem cell (CSC) properties, and its reversion are important. Since it is poorly understood whether different CSC phenotypes exist along the EMT axis and how these impact malignancy-associated properties, we aimed to characterize CSC populations of epithelial and mesenchymal-like PDAC cells. Single-cell cloning revealed CSC (Holoclone) and non-CSC (Paraclone) clones from the PDAC cell lines Panc1 and Panc89. The Panc1 Holoclone cells showed a mesenchymal-like phenotype, dominated by a high expression of the stemness marker Nestin, while the Panc89 Holoclone cells exhibited a SOX2-dominated epithelial phenotype. The Panc89 Holoclone cells showed enhanced cell growth and a self-renewal capacity but slow cluster-like invasion. Contrarily, the Panc1 Holoclone cells showed slower cell growth and self-renewal ability but were highly invasive. Moreover, cell variants differentially responded to chemotherapy. In vivo, the Panc1 and Panc89 cell variants significantly differed regarding the number and size of metastases, as well as organ manifestation, leading to different survival outcomes. Overall, these data support the existence of different CSC phenotypes along the EMT axis in PDAC, manifesting different metastatic propensities.

Galectins are β-galactoside-binding proteins with numerous functions. Some of them are involved in proliferation and metastasis of cancer, making them promising therapeutic targets. As different plant glycans have been shown to bind to galectins, plant saccharides might be potential galectin inhibitors. To produce plant galactans rich in galactose and smaller in size, we degraded arabinogalactan-proteins from Echinacea purpurea and Zostera marina as well as arabinogalactan from larch. As galectin (Gal)-3 and -9 both have been described to be involved in cancer development, we quantified the binding capacities of the different galactans to both galectins by biolayer-interferometry. Our results revealed that all plant-derived galactans and Yariv reagents with terminal galactose and lactose residues bind to Gal-3 in micromolar ranges. Surprisingly, only the higher charged galactans from Zostera marina showed affinity to Gal-9. Investigations of two different pancreatic cancer cell lines (Panc1 and Panc89) and different cell variants thereof revealed that Gal-3 was expressed by both cell lines with a significantly higher Gal-3 level in Panc1 cells compared to Panc89 cells. Conversely, Gal-9 was only detected in Panc89 cells. The findings revealed that galactans are promising sources to develop galectin antagonists and plant galactans from different species express specificities for distinct galectins.

Galectins are β-galactoside-binding proteins with numerous functions. Some of them are involved in proliferation and metastasis of cancer, making them promising therapeutic targets. As different plant glycans have been shown to bind to galectins, plant saccharides might be potential galectin inhibitors. To produce plant galactans rich in galactose and smaller in size, we degraded arabinogalactan-proteins from Echinacea purpurea and Zostera marina as well as arabinogalactan from larch. As galectin (Gal)-3 and -9 both have been described to be involved in cancer development, we quantified the binding capacities of the different galactans to both galectins by biolayer-interferometry. Our results revealed that all plant-derived galactans and Yariv reagents with terminal galactose and lactose residues bind to Gal-3 in micromolar ranges. Surprisingly, only the higher charged galactans from Zostera marina showed affinity to Gal-9. Investigations of two different pancreatic cancer cell lines (Panc1 and Panc89) and different cell variants thereof revealed that Gal-3 was expressed by both cell lines with a significantly higher Gal-3 level in Panc1 cells compared to Panc89 cells. Conversely, Gal-9 was only detected in Panc89 cells. The findings revealed that galactans are promising sources to develop galectin antagonists and plant galactans from different species express specificities for distinct galectins.

Cancer metastasis is the process of detrimental systemic spread and the primary cause of cancer-related fatalities. Successful metastasis formation requires tumor cells to be proliferative and invasive; however, cells cannot be effective at both tasks simultaneously. Tumor cells compensate for this trade-off by changing their phenotype during metastasis formation through phenotypic plasticity. Given the changing selection pressures and competitive interactions that tumor cells face, it is poorly understood how plasticity shapes the process of metastasis formation. Here, we develop an ecology-inspired mathematical model with phenotypic plasticity and resource competition between phenotypes to address this knowledge gap. We find that phenotypically plastic tumor cell populations attain a stable phenotype equilibrium that maintains tumor cell heterogeneity. Considering treatment types inspired by chemo- and immunotherapy, we highlight that plasticity can protect tumors against interventions. Turning this strength into a weakness, we corroborate current clinical practices to use plasticity as a target for adjuvant therapy. We present a parsimonious view of tumor plasticity-driven metastasis that is quantitative and experimentally testable, and thus potentially improving the mechanistic understanding of metastasis and its treatment consequences.