Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism

Hongyun Zhao,Anirban Maitra,Abhinav Achreja,Juan C Marini,Deepak Nagrath,Tyler Moss,Sonal Gupta,Thavisha Tudawe,Vincent Bernard,Donna Peehl,Laurence Cooper,Lifeng Yang,Hector Alvarez,Prahlad T Ram,Elena G Seviour,F Anthony San Lucas,Joelle Baddour,Sourindra N Maiti

doi:10.7554/elife.10250

Abstract

Cancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers. Altered cellular metabolism is a hallmark of cancer, and much of the published literature has focused on neoplastic cell-autonomous processes for these adaptations. We demonstrate that exosomes secreted by patient-derived CAFs can strikingly reprogram the metabolic machinery following their uptake by cancer cells. We find that CAF-derived exosomes (CDEs) inhibit mitochondrial oxidative phosphorylation, thereby increasing glycolysis and glutamine-dependent reductive carboxylation in cancer cells. Through 13C-labeled isotope labeling experiments we elucidate that exosomes supply amino acids to nutrient-deprived cancer cells in a mechanism similar to macropinocytosis, albeit without the previously described dependence on oncogenic-Kras signaling. Using intra-exosomal metabolomics, we provide compelling evidence that CDEs contain intact metabolites, including amino acids, lipids, and TCA-cycle intermediates that are avidly utilized by cancer cells for central carbon metabolism and promoting tumor growth under nutrient deprivation or nutrient stressed conditions.

Highlights

The understanding of interaction mechanisms between cancer cells and the tumor microenvironment (TME) is crucial for developing therapies that can arrest tumor progression and metastasis
In line with results obtained in prostate cancer cells, we found that oxygen consumption rate (OCR) of both BxPC3 and MiaPaCa-2 cells were decreased in presence of pancreatic CAFderived exosomes (CDEs) (Figure 7D)
In line with the results obtained in prostate cancers, we found that exosomes from pancreatic Cancer-associated fibroblasts (CAFs) significantly increased the reductive glutamine metabolism (Figure 7H–J, Figure 7—figure supplement 4)

Summary

Introduction

The understanding of interaction mechanisms between cancer cells and the tumor microenvironment (TME) is crucial for developing therapies that can arrest tumor progression and metastasis. Recent studies have identified the TME as a key player in regulating cancer cell growth (Whiteside, 2008). The TME is comprised of a variety of cell types including cancer-associated fibroblasts cells (CAFs), immune cells, and angiogenic elements, CAFs are the major constituent of the TME in many cancers (Whiteside, 2008; Allinen et al, 2004; Feig et al, 2012). Accumulating evidence suggests that paracrine signals from cancer cells can both recruit and activate CAFs within the TME, and

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