New strategies are needed to predict and overcome metastatic progression and therapy resistance in prostate cancer. One potential clinical target is the stem cell transcription factor SOX2, which has a critical role in prostate development and cancer. We thus investigated the impact of SOX2 expression on patient outcomes and its function within prostate cancer cells. Analyses of SOX2 expression among a case-control cohort of 1028 annotated tumor specimens demonstrated that SOX2 expression confers a more rapid time to metastasis and decreased patient survival after biochemical recurrence. SOX2 ChIP-Seq analyses revealed SOX2-binding sites within prostate cancer cells which differ significantly from canonical embryonic SOX2 gene targets, and prostate-specific SOX2 gene targets are associated with multiple oncogenic pathways. Interestingly, phenotypic and gene expression analyses after CRISPR-mediated deletion of SOX2 in castration-resistant prostate cancer cells, as well as ectopic SOX2 expression in androgen-sensitive prostate cancer cells, demonstrated that SOX2 promotes changes in multiple metabolic pathways and metabolites. SOX2 expression in prostate cancer cell lines confers increased glycolysis and glycolytic capacity, as well as increased basal and maximal oxidative respiration and increased spare respiratory capacity. Further, SOX2 expression was associated with increased quantities of mitochondria, and metabolomic analyses revealed SOX2-associated changes in the metabolism of purines, pyrimidines, amino acids and sugars, and the pentose phosphate pathway. Analyses of SOX2 gene targets with central functions metabolism (CERK, ECHS1, HS6SDT1, LPCAT4, PFKP, SLC16A3, SLC46A1, and TST) document significant expression correlation with SOX2 among RNA-Seq datasets derived from patient tumors and metastases. These data support a key role for SOX2 in metabolic reprogramming of prostate cancer cells and reveal new mechanisms to understand how SOX2 enables metastatic progression, lineage plasticity, and therapy resistance. Further, our data suggest clinical opportunities to exploit SOX2 as a biomarker for staging and imaging, as well as a potential pharmacologic target.
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Ectopic JAK–STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance
Nature Cancer Open Access 05 September 2022
Cellular and Molecular Life Sciences Open Access 23 June 2022
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We acknowledge Vander Griend and Szmulewitz lab members for their input; Dr. Brendan Looyenga at Calvin College for his gift of vectors used to generate knockout cell lines using CRISPR; support of the University of Illinois at Chicago Department of Pathology led by Dr. Fred Behm, as well as the University of Illinois at Chicago Research Histology and Tissue Imaging Core led by Dr. Peter Gann; Drs. Bruce Trock and Karen Sfanos of the Prostate Cancer Biorepository Network (PCBN) for help obtaining annotated tumor specimens and data; expert technical assistance of the Human Tissue Resource Center core facility led by Dr. Mark Lingen, and the assistance of Mary Jo Fekete; the Immunohistochemistry Core Facility run by Terri Li; the Northwestern University Metabolomics Core Facility for their assistance and service; the University of Chicago Genomics Facility led by Dr. Pieter Faber; support of the University of Chicago Committee on Cancer Biology, led by Dr. Kay Macleod and Stephen Kron; and support of Drs. Alan Diamond, Larisa Nonn, and Gail Prins at the University of Illinois at Chicago Departments of Pathology and Urology.
R01CA178431 (DJ Vander Griend), R00CA218885-04 (P.M.); University of Chicago Comprehensive Cancer Center Support Grant (P30CA014599); The Brinson Foundation; Alvin Baum Family Fund; The Pierce Foundation; and National Center for Advancing Translational Sciences (UL1TR002003). The Prostate Cancer Biorepository Network is funded by the Department of Defense Prostate Cancer Research Program Award No. W81XWH-14-2-0182, W81XWH-14-2-0183, W81XWH-14-2-0185, W81XWH-14-2-0186, and W81XWH-15-2-0062, and W81XWH-18-1-0411 (P.M.). L. de Wet was supported by the Goldblatt Foundation Fellowship; S. Kregel was supported by a Cancer Biology Training Grant (T32 CA 009594). P.M. is also supported by CPRIT (RR170050), Welch Foundation (I-2005-20190330) and Prostate Cancer Foundation (17YOUN12).
The authors declare no competing interests.
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de Wet, L., Williams, A., Gillard, M. et al. SOX2 mediates metabolic reprogramming of prostate cancer cells. Oncogene 41, 1190–1202 (2022). https://doi.org/10.1038/s41388-021-02157-x
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