Luciana Melo-Garcia

The University of Texas MD Anderson Cancer Center

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Katayoun Rezvani

The University of Texas MD Anderson Cancer Center

Adrien Labriet

Université Laval

Paul Lin

The University of Texas MD Anderson Cancer Center

David Marín

The University of Texas MD Anderson Cancer Center

Enli Liu

The University of Texas MD Anderson Cancer Center

Jamie Tran

The University of Texas MD Anderson Cancer Center

Emily L. Ensley

The University of Texas MD Anderson Cancer Center

Jun Gu

Peking University

ÉL

Éric Lévesque

Université Laval

Hélène Hovington

Centre hospitalier universitaire de Québec

Cooperative Institutions

The University of Texas MD Anderson Cancer Center

Université Laval

Centre hospitalier universitaire de Québec

Centre hospitalier de l'Université Laval

Quebec Research and Development Centre

University of North Carolina at Chapel Hill

Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology

Baylor College of Medicine

University of Tübingen

Wilfrid Laurier University

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Alternative promoters control UGT2B17-dependent androgen catabolism in prostate cancer and its influence on progression

British Journal of Cancer (2020)

Éric Lévesque Adrien Labriet Hélène Hovington Éric P. Allain Luciana Melo-Garcia

Perturbation of the major UGT2B17-dependent androgen catabolism pathway has the potential to affect prostate cancer (PCa) progression. The objective was to evaluate UGT2B17 protein expression in primary tumours in relation to hormone levels, disease characteristics and cancer evolution.We conducted an analysis of a high-density prostate tumour tissue microarray consisting of 239 localised PCa cases treated by radical prostatectomy (RP). Cox proportional hazard ratio analysis was used to evaluate biochemical recurrence (BCR), and a linear regression model evaluated variations in circulating hormone levels measured by mass spectrometry. The transcriptome of UGT2B17 in PCa was established by using RNA-sequencing data.UGT2B17 expression in primary tumours was associated with node-positive disease at RP and linked to circulating levels of 3α-diol-17 glucuronide, a major circulating DHT metabolite produced by the UGT2B17 pathway. UGT2B17 was an independent prognostic factor linked to BCR after RP, and its overexpression was associated with development of metastasis. Finally, we demonstrated that distinctive alternative promoters dictate UGT2B17-dependent androgen catabolism in localised and metastatic PCa.The androgen-inactivating gene UGT2B17 is controlled by overlooked regulatory regions in PCa. UGT2B17 expression in primary tumours influences the steroidome, and is associated with relevant clinical outcomes, such as BCR and metastasis.

Biochemical recurrence

breakpoint cluster region

Dihydrotestosterone

10.1038/s41416-020-0749-2

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Metabolic Reprogramming of GMP Grade Cord Tissue Derived Mesenchymal Stem Cells Enhances Their Suppressive Potential in GVHD

Frontiers in Immunology (2021)

Mayela Carolina Mendt May Daher Rafet Başar Mayra Shanley Bijender Kumar

Acute graft-vs.-host (GVHD) disease remains a common complication of allogeneic stem cell transplantation with very poor outcomes once the disease becomes steroid refractory. Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for the treatment of GVHD, but so far this strategy has had equivocal clinical efficacy. Therapies using MSCs require optimization taking advantage of the plasticity of these cells in response to different microenvironments. In this study, we aimed to optimize cord blood tissue derived MSCs (CBti MSCs) by priming them using a regimen of inflammatory cytokines. This approach led to their metabolic reprogramming with enhancement of their glycolytic capacity. Metabolically reprogrammed CBti MSCs displayed a boosted immunosuppressive potential, with superior immunomodulatory and homing properties, even after cryopreservation and thawing. Mechanistically, primed CBti MSCs significantly interfered with glycolytic switching and mTOR signaling in T cells, suppressing T cell proliferation and ensuing polarizing toward T regulatory cells. Based on these data, we generated a Good Manufacturing Process (GMP) Laboratory protocol for the production and cryopreservation of primed CBti MSCs for clinical use. Following thawing, these cryopreserved GMP-compliant primed CBti MSCs significantly improved outcomes in a xenogenic mouse model of GVHD. Our data support the concept that metabolic profiling of MSCs can be used as a surrogate for their suppressive potential in conjunction with conventional functional methods to support their therapeutic use in GVHD or other autoimmune disorders.

Reprogramming

Regenerative Medicine

10.3389/fimmu.2021.631353

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Citations (16)