Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer.

Nov 5, 2020

Contributor: Robert S Banh,Douglas E Biancur,Keisuke Yamamoto,Albert S W Sohn,Beth Walters,Miljan Kuljanin,Ajami Gikandi,Huamin Wang,Joseph D Mancias,Robert J Schneider,Michael E Pacold,Alec C Kimmelman

Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) tumors have a nutrient-poor, desmoplastic, and highly innervated tumor microenvironment. Although neurons can release stimulatory factors to accelerate PDAC tumorigenesis, the metabolic contribution of peripheral axons has not been explored. We found that peripheral axons release serine (Ser) to support the growth of exogenous Ser (exSer)-dependent PDAC cells during Ser/Gly (glycine) deprivation. Ser deprivation resulted in ribosomal stalling on two of the six Ser codons, TCC and TCT, and allowed the selective translation and secretion of nerve growth factor (NGF) by PDAC cells to promote tumor innervation. Consistent with this, exSer-dependent PDAC tumors grew slower and displayed enhanced innervation in mice on a Ser/Gly-free diet. Blockade of compensatory neuronal innervation using LOXO-101, a Trk-NGF inhibitor, further decreased PDAC tumor growth. Our data indicate that axonal-cancer metabolic crosstalk is a critical adaptation to support PDAC growth in nutrient poor environments.
Copyright © 2020 Elsevier Inc. All rights reserved.

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About The Expert

Robert S Banh

Department of Radiation Oncology, Perlmutter Cancer Center, New York University Medical Center, New York, NY 10016, USA.

Douglas E Biancur

Department of Radiation Oncology, Perlmutter Cancer Center, New York University Medical Center, New York, NY 10016, USA.

Keisuke Yamamoto

Department of Radiation Oncology, Perlmutter Cancer Center, New York University Medical Center, New York, NY 10016, USA.

Albert S W Sohn

Department of Radiation Oncology, Perlmutter Cancer Center, New York University Medical Center, New York, NY 10016, USA.

Beth Walters

Department of Microbiology and Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA.

Miljan Kuljanin

Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Hale Family Pancreatic Cancer Research Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Ajami Gikandi

Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Hale Family Pancreatic Cancer Research Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Huamin Wang

Department of Anatomical Pathology, M.D. Anderson Cancer Center, University of Texas, Houston, TX 77030, USA.

Joseph D Mancias

Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Hale Family Pancreatic Cancer Research Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Robert J Schneider

Department of Radiation Oncology, Perlmutter Cancer Center, New York University Medical Center, New York, NY 10016, USA; Department of Microbiology and Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA.

Michael E Pacold

Department of Radiation Oncology, Perlmutter Cancer Center, New York University Medical Center, New York, NY 10016, USA.

Alec C Kimmelman

Department of Radiation Oncology, Perlmutter Cancer Center, New York University Medical Center, New York, NY 10016, USA. Electronic address: alec.kimmelman@nyulangone.org.

References

PubMed