TCA cycle mode switch determines the fate of pirtobrutinib-tolerant persister cells in mantle cell lymphoma
Abstract
Abstract Bruton tyrosine kinase inhibitors (BTKis) and cell therapy have successfully been used to treat mantle cell lymphoma (MCL). However, therapy resistance inevitably emerges. Cancer cells can progressively develop stable resistance by traversing through a transient drug-tolerant persister (DTP) state. The mechanisms enabling DTP cells to reversibly adapt to therapies and evolve to acquire heterogeneity remain poorly understood, and characterizing DTP cells in MCL continues to pose a challenge for clinic translation. Here, using pirtobrutinib, a recently US Food and Drug Administration–approved noncovalent BTKi, we identified pirtobrutinib-tolerant persister cells exhibiting morphological variability by presenting a unique population of enlarged cells (giant cells) with reversible fate transitions. During treatment, giant cells enter a nonproliferative, dedifferentiated state, addicted to an activated cytosolic tricarboxylic acid (TCA) cycle coupled with the malate-aspartate shuttle to engage in biosynthesis. Upon drug removal, the TCA cycle shifts to oxidative catabolism, promoting giant cells to differentiate into regular-sized cells. Throughout the transition, acetyl coenzyme A modulates cell fate by fine-tuning stemness. Our biphasic model demonstrates that the metabolic switch governs the phenotypic plasticity of DTP cells in MCL, resulting in a dynamic presence of DTP cells across various developmental states in response to systemic therapies. Targeting giant cells before their differentiation offers a promising strategy to overcoming therapy resistance in MCL.
Article Details
Authors (29)
Wei Wang
Qingsong Cai
1Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
Yang Liu
Lei Nie
Department of Oncology Shanxi Provincial Cancer Hospital Xian China
Heng-Huan Lee
Fangfang Yan
Yue Fei
Yixin Yao
Yijing Li
College of Mining, Liaoning Technical University 1 , Fuxin 123000, Liaoning,
Lin Tan
Philip L. Lorenzi
Ying-Nai Wang
Jun Yao
Key Lab of Mesoscopic Chemistry, School of Chemistry and Chemical Engineering
Zhihong Chen
Joseph Mitchell McIntosh
1Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
Cheng-Tai Yu
1Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
Preetesh Jain
Vivian C. Jiang
1Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
Jovanny Vargas
1Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
Xiaolin Li
Energy and Environmental Directorate, Pacific Northwest National Laboratory
Tianci Zhang
Shaoying Li
David Santos
Selvi Thirumurthi
Erin Heather Seeley
7Department of Chemistry, Mass Spectrometry Imaging Facility at The University of Texas at Austin, Austin, TX
Lukas Mikolaj Simon
8Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Therapeutic Innovation Center at Baylor College of Medicine, Houston, TX
Christopher Flowers
1Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
Chi Young Ok
4Division of Pathology and Laboratory Medicine, Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
Michael Wang