Exosomes từ môi trường khối u điều chỉnh đa dạng quá trình chuyển hóa của tế bào ung thư

eLife - Tập 5
Hongyun Zhao1,2, Lifeng Yang1,2, Joelle Baddour1,2, Abhinav Achreja1,2, Vincent Bernard3, Tyler J. Moss4, Juan C. Marini5, Thavisha Tudawe1, Elena G Seviour4, F Anthony San Lucas3, Héctor M. Álvarez3, Sonal Gupta3, Sourindra N. Maiti6, Laurence J.N. Cooper6, Donna M. Peehl7, Prahlad T. Ram4, Anirban Maitra3, Deepak Nagrath8,1,2
1Department of Chemical and Biomolecular Engineering, Rice University, Houston, United States
2Laboratory for Systems Biology of Human Diseases, Rice University, Houston, United States
3Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, United States
4Department of Systems Biology, University of Texas, MD Anderson, Houston, United States
5Baylor College of Medicine, Houston, United States
6Department of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, United States
7Department of Urology, School of Medicine, Stanford University, Stanford, United States
8Department of Bioengineering, Rice University, Houston, United States

Tóm tắt

Các nguyên bào sợi liên quan đến ung thư (CAFs) là thành phần tế bào chính trong môi trường vi mô của khối u ở hầu hết các loại ung thư đặc. Sự thay đổi chuyển hóa tế bào là một dấu hiệu đặc trưng của ung thư, và phần lớn tài liệu đã công bố tập trung vào các quá trình tự chủ của tế bào u cho những thích nghi này. Chúng tôi chứng minh rằng các exosome được tiết ra từ CAFs có nguồn gốc từ bệnh nhân có thể tái lập trình mạnh mẽ bộ máy chuyển hóa sau khi bị hấp thụ bởi các tế bào ung thư. Chúng tôi phát hiện ra rằng exosomes do CAFs tạo ra (CDEs) ức chế phosphorylation oxi hóa của ty thể, qua đó làm tăng quá trình glycolysis và carboxyl hóa giảm phụ thuộc vào glutamine trong các tế bào ung thư. Thông qua các thí nghiệm đánh dấu đồng vị 13C, chúng tôi làm rõ rằng các exosomes cung cấp amino acid cho các tế bào ung thư thiếu dinh dưỡng theo một cơ chế tương tự như sự kỵ khí lớn, mặc dù không phụ thuộc vào tín hiệu oncogenic-Kras như đã được mô tả trước đó. Sử dụng phân tích chuyển hóa trong exosome, chúng tôi cung cấp bằng chứng thuyết phục rằng CDEs chứa các chuyển hóa nguyên vẹn, bao gồm amino acid, lipid và các chất trung gian trong chu trình TCA, mà các tế bào ung thư sử dụng tích cực cho chuyển hóa carbon trung tâm và thúc đẩy sự phát triển của khối u trong điều kiện thiếu dinh dưỡng hoặc căng thẳng dinh dưỡng.

Từ khóa

#ung thư #exosomes #quá trình chuyển hóa #CAFs #vi môi trường khối u

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