Clinical implications of PTEN loss in prostate cancer

Jamaspishvili, Tamara; Berman, David M.; Ross, Ashley E.; Scher, Howard I.; Marzo, Angelo M. De; Squire, Jeremy A.; Lotan, Tamara L.

doi:10.1038/nrurol.2018.9

Cited by 488 publications

(406 citation statements)

References 152 publications

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“…Numerous recent studies have explored the genomic basis for development of localized prostate cancer, showing distinct evolutionary paths in nonindolent versus indolent disease. The fate of tumors to progress from their somatic progenitors is set early, with alterations in ATM, PTEN, and MYC subclones having predictive power for the existence of higher grade disease including occult oligometastases at the time of radical prostatectomy [9][10][11][12][13]. As the vast majority of these alterations occur as copy number gains or deletions, the percentage of the genome affected by large chromosomal rearrangements is similarly predictive of biochemical recurrence and poor outcome [10,14,15].…”

Section: Introductionmentioning

confidence: 99%

Low Abundance of Circulating Tumor DNA in Localized Prostate Cancer

Hennigan

Trostel

Terrigino

et al. 2019

Preprint

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Section: Introductionmentioning

confidence: 99%

Low Abundance of Circulating Tumor DNA in Localized Prostate Cancer

Hennigan

Trostel

Terrigino

et al. 2019

Preprint

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“…Although anoikis suppression is a generally relevant mechanisms for tumor progression, it may have particular clinical importance in slowly progressing cancers such as PCa where cancers can be diagnosed in indolent phase, and there is a strong need to be able to both predict and inhibit the likelihood of disease progression (4). Previously anoikis resistance in PCa cancer has been linked mechanistically to regulation of cell adhesion, cytoskeleton (1), PTEN inhibition (6), and AR activity (44).…”

Section: Discussionmentioning

confidence: 99%

“…Mechanistically anoikis resistance in PCa has been linked to changes in cell adhesion, cytoskeleton, as well as deregulated intracellular survival pathways (1). Tumor suppressor phosphatase PTEN is inactivated in a large fraction of high grade PCas (4), and prostate-specific PTEN deletion in a mouse model leads to metastatic PCa (5). Importantly, both PTEN deletion, and hyperactivity of PTEN downstream target AKT increases anoikis resistance (6–8).…”

Section: Introductionmentioning

confidence: 99%

PME-1 suppresses anoikis and is associated with therapy relapse of PTEN-deficient prostate cancers

Rupp

Aakula

Isomursu

et al. 2019

Preprint

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33Identification of novel mechanisms of apoptosis resistance of prostate cancer (PCa) 34 cells has translational importance. Here, we discover that inhibition of tumor 35 suppressor phosphatase PP2A by PME-1 inhibits anoikis (apoptosis in anchorage-36 independent conditions) in PTEN-deficient PCa cells. PME-1 physically associated 37 with the nuclear lamina and regulated its deformability in PCa cells. In addition, PME-38 1 deficient cells, with highly deformable nuclear lamina, were particularly vulnerable to 39 anoikis following cell detachment. As a molecular explanation for increased nuclear 40 lamina deformability, PME-1 depletion induced dephosphorylation of nuclear lamina 41 constituents, Lamin-A/C, Lamin-B1, Lamin-B2, LAP2A, LAP2B, and NUP98. PME-1 42 inhibition increased apoptosis also in an in ovo tumor model, and attenuated cell 43 survival in zebrafish circulation. Clinically, PCa patients with inhibition of both PP2A 44 and PTEN tumor suppressor phosphatases (PME-1 high /PTEN loss ), have less than 50% 455-year secondary-therapy free patient survival, which is significantly shorter than 46 survival of patients with only PTEN-deficient tumors. 47In summary, we discover that PME-1 overexpression supports anoikis 48 resistance in PTEN-deficient PCa cells. Further, increased nuclear lamina 49 deformability was identified as plausible target mechanism sensitizing PME-1-50 depleted cells to anoikis. Clinically, the results identify PME-1 as a novel candidate 51 biomarker for particularly aggressive PTEN-deficient PCa. 52 53 55 56 3 57 Clinical relevance 58 59 While organ-confined PCa is mostly manageable, the local and distant metastatic 60 progression of PCa remains a clinical challenge. Resistance to anoikis is critical for 61 PCa progression towards aggressive CRPC. Our data show that PME-1 expression in 62 human PCa cells protects the cells from apoptosis induction in anchorage-63 independent conditions both in vitro and in vivo. Clinically, our results identify PME-1 64 as a novel putative biomarker for extremely poor prognosis in PTEN-deficient PCa. 65 Taken together, our results demonstrate novel post-translational regulation of key 66 cancer progression mechanisms, with clear translational implications. 67 68 (4), and prostate-specific PTEN deletion in a mouse model leads to metastatic PCa 87 (5). Importantly, both PTEN deletion, and hyperactivity of PTEN downstream target 88 AKT increases anoikis resistance (6-8). On the other hand, recent studies in other 89cancer types indicate for a very delicate balance between nuclear lamina stiffness and 90 anchorage-independence, anoikis resistance, and cell migration. Whereas cell 91 migration in three dimensional contexts requires a sufficiently deformable nuclear 92 lamina to allow passage through physical restrictions (9-11), too deformable nuclei may limit cancer cell survival especially in anchorage-independent conditions (9, 12-94 15). Of nuclear lamina proteins, particularly inhibition of both Lamin-A/C and Lamin-95

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“…Examples with heavy mutation burden include ANKRD30A, an ankyrin-repeat containing gene linked with breast cancer 27 , and TPTE, a phosphatase linked to the PTEN pathway 28 (Figure 4c). Given their high mutation load and interactions with cancer pathways relevant to patient stratification schemes 29 , thesaurus mutations that fill gaps in their mutation profiles offer direct opportunities to test their translational relevance.…”

Section: Thesaurus Annotation Uncovers Recurrent Patterns In Gene Fammentioning

confidence: 99%

A pan-cancer landscape of somatic substitutions in non-unique regions of the human genome

Tarabichi

Demeulemeester

Verfaillie

et al. 2020

Preprint

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Around 13% of the human genome displays high sequence similarity with at least one other chromosomal position and thereby poses challenges for computational analyses such as detection of somatic events in cancer. We here extract features of sequencing data from across non-unique regions and employ a machine learning pipeline to describe a landscape of somatic substitutions in 2,658 cancers from the PCAWG cohort. We show mutations in non-unique regions are consistent with mutations in unique regions in terms of mutation load and substitution profiles, and can be validated with linked-read sequencing. This uncovers hidden mutations in ~1,700 coding sequences and thousands of regulatory elements, including known cancer genes, immunoglobulins, and highly mutated gene families.

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Clinical implications of PTEN loss in prostate cancer

Cited by 488 publications

References 152 publications

Low Abundance of Circulating Tumor DNA in Localized Prostate Cancer

Low Abundance of Circulating Tumor DNA in Localized Prostate Cancer

PME-1 suppresses anoikis and is associated with therapy relapse of PTEN-deficient prostate cancers

A pan-cancer landscape of somatic substitutions in non-unique regions of the human genome

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