Exploiting oxidative phosphorylation to promote the stem and immunoevasive properties of pancreatic cancer stem cells

Abstract

Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer death, has a 5-year survival rate of approximately 7–9%. The ineffectiveness of anti-PDAC therapies is believed to be due to the existence of a subpopulation of tumor cells known as cancer stem cells (CSCs), which are functionally plastic, and have exclusive tumorigenic, chemoresistant and metastatic capacities. Herein, we describe a 2D in vitro system for long-term enrichment of pancreatic CSCs that is amenable to biological and CSC-specific studies. By changing the carbon source from glucose to galactose in vitro, we force PDAC cells to utilize OXPHOS, resulting in enrichment of CSCs defined by increased CSC biomarker and pluripotency gene expression, greater tumorigenic potential, induced but reversible quiescence, increased OXPHOS activity, enhanced invasiveness, and upregulated immune evasion properties. This CSC enrichment method can facilitate the discovery of new CSC-specific hallmarks for future development into targets for PDAC-based therapies.

A Cancer Cell Cluster Marked by LincRNA MEG3 Leads Pancreatic Ductal Adenocarcinoma Metastasis

“…Differentially expressed genes of LINC01133 marked Cluster 0 were also input into IPA and the top Ingenuity Canonical Pathways and Upstream Regulators were also presented. Top pathways, including Oxidative Phosphorylation, EIF2 Signaling and Mitochondrial Dysfunction, were closely associated with stem and immunoevasive properties ( 33 ), tumor biology ( 42 ) and cancer metabolic phenotypes ( 43 ) of pancreatic cancer. Taken together, these ingenuity canonical pathways and upstream regulator analysis consistently confirmed our observation in scRNA-seq data and further identified the MEG + metastatic cancer cell cluster as the leader of cancer cell EMT and metastasis.…”

“…FIGURE 6 | Elevated MEG3 transcript in cancer cells of PDAC mouse models(33). Transcript levels of MEG3 in normal epithelial cells and PDAC cancer cells of mouse models were visualized by split violin plots (A) and UMAPs (B).…”

CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer

“…As the fourth most leading cause of cancer-related death in the world, pancreatic cancer (PC) is usually diagnosed at an advanced stage [ 1 ]. The rising mortality rates from PC has projected it will become the second common cause of tumor-related mortality by the year 2030 [ 2 ].…”

Conflicting metabolic alterations in cancer stem cells and regulation by the stromal niche

“…This mechanism suggests that metabolic interactions between CSCs and their niche cells are important, especially for the maintenance of CSC mitochondrial OXPHOS. Consistently, a recent study revealed that pancreatic cancer cells are forced to utilize mitochondrial OXPHOS, increase expression of CSC biomarkers and pluripotency genes, and upregulate immune evasion properties through the accumulation of protumor immune cells [ 47 ]. Given these findings, it is possible that elucidation of the relationship between CSCs and their stromal niche will lead to the development of more effective therapies targeting CSC-specific metabolism in combination with conventional therapies, including immunotherapy.…”