Extracellular Matrix Collagen I Differentially Regulates the Metabolic Plasticity of Pancreatic Ductal Adenocarcinoma Parenchymal Cell and Cancer Stem Cell

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 10 percent largely due to the intense fibrotic desmoplastic reaction, characterized by high levels of extracellular matrix (ECM) collagen I that constitutes a niche for a subset of cancer cells, the cancer stem cells (CSCs). Cancer cells undergo a complex metabolic adaptation characterized by changes in metabolic pathways and biosynthetic processes. The use of the 3D organotypic model in this study allowed us to manipulate the ECM constituents and mimic the progression of PDAC from an early tumor to an ever more advanced tumor stage. To understand the role of desmoplasia on the metabolism of PDAC parenchymal (CPC) and CSC populations, we studied their basic metabolic parameters in organotypic cultures of increasing collagen content to mimic in vivo conditions. We further measured the ability of the bioenergetic modulators (BMs), 2-deoxyglucose, dichloroacetate and phenformin, to modify their metabolic dependence and the therapeutic activity of paclitaxel albumin nanoparticles (NAB-PTX). While all the BMs decreased cell viability and increased cell death in all ECM types, a distinct, collagen I-dependent profile was observed in CSCs. As ECM collagen I content increased (e.g., more aggressive conditions), the CSCs switched from glucose to mostly glutamine metabolism. All three BMs synergistically potentiated the cytotoxicity of NAB-PTX in both cell lines, which, in CSCs, was collagen I-dependent and the strongest when treated with phenformin + NAB-PTX. Metabolic disruption in PDAC can be useful both as monotherapy or combined with conventional drugs to more efficiently block tumor growth.

Dichloroacetate for Cancer Treatment: Some Facts and Many Doubts

“…As noted above, 2-deoxyglucose, the inhibitor of glycolysis, has shown beneficial effects in experiments with colon cancer [186], pancreatic cancer cells [307]. In another case, 2DG markedly increased DCA anti-cancer effects in Lewis lung carcinoma.…”

“…In one, when different metabolic modifiers were tested against human pancreatic cancer xenografts in mice, the most effective regarding tumor growth inhibition was phenformin (5 out 12 individuals) and DCA (2 out of 6) [306]. DCA and other metabolic modifiers such as 2-deoxyglucose and phenformin increased cytotoxicity of paclitaxel albumin nanoparticles (nab paclitaxel) on pancreatic cancer cells [307]. Another study demonstrated that radioresistant PDAC cells over-expressed PDK and this resistance was reversed by DCA.…”

Dichloroacetate for Cancer Treatment: Some Facts and Many Doubts

“…In one, when different metabolic modifiers were tested against human pancreatic cancer xenografts in mice, the most effective at tumor growth inhibition were phenformin (5 of 12 individuals) and DCA (2 of 6) [ 306 ]. DCA and other metabolic modifiers, such as 2-deoxyglucose and phenformin, increased the cytotoxicity of paclitaxel albumin nanoparticles (nab paclitaxel) in pancreatic cancer cells [ 307 ]. Another study demonstrated that radioresistant PDAC cells overexpressed PDK and this resistance was reversed by DCA.…”

“…As noted above, 2-deoxyglucose, the inhibitor of glycolysis, has shown beneficial effects in experiments with colon cancer [ 186 ] and pancreatic cancer cells [ 307 ]. In another case, 2DG markedly increased the anticancer effects of DCA on a Lewis lung carcinoma animal model.…”

Targeting Glucose Metabolism in Cancer Cells as an Approach to Overcoming Drug Resistance

“…Different studies using cancer cell lines demonstrated the responsibility of EMT in radio-or chemotherapy-driven resistance [81,92,93]. In fact, conventional anticancer drugs are mainly directed toward rapidly dividing cells, with EMT being associated with stem cell properties in cancer cells [94]. Furthermore, EMT can be involved in microenvironment modifications, causing the loss of cell-cell adherence and extracellular matrix remodeling, as well as in the interaction with the immune system, contributing to chemotherapy resistance [95][96][97].…”