Faithfull Modeling of PTEN Loss Driven Diseases in the Mouse

Abstract Background PTEN is the most frequently lost tumor suppressor in primary prostate cancer (PCa) and its loss is associated with aggressive disease. However, the transcriptional changes associated with PTEN loss in PCa have not been described in detail. In this study, we highlight the transcriptional changes associated with PTEN loss in PCa. Methods Using a meta-analysis approach, we leveraged two large PCa cohorts with experimentally validated PTEN and ERG status by Immunohistochemistry (IHC), to derive a transcriptomic signature of PTEN loss, while also accounting for potential confounders due to ERG rearrangements. This signature was expanded to lncRNAs using the TCGA quantifications from the FC-R2 expression atlas. Results The signatures indicate a strong activation of both innate and adaptive immune systems upon PTEN loss, as well as an expected activation of cell-cycle genes. Moreover, we made use of our recently developed FC-R2 expression atlas to expand this signature to include many non-coding RNAs recently annotated by the FANTOM consortium. Highlighting potential novel lncRNAs associated with PTEN loss and PCa progression. Conclusion We created a PCa specific signature of the transcriptional landscape of PTEN loss that comprises both the coding and an extensive non-coding counterpart, highlighting potential new players in PCa progression. We also show that contrary to what is observed in other cancers, PTEN loss in PCa leads to increased activation of the immune system. These findings can help the development of new biomarkers and help guide therapy choices.

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PTEN loss correlates with T cell exclusion across human cancers

BMC Cancer ◽

10.1186/s12885-021-08114-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ziying Lin ◽

Lixia Huang ◽

Shao Li Li ◽

Jincui Gu ◽

Xiaoxian Cui ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Helper Cells ◽

Pi3k Pathway ◽

T Helper ◽

Immune Microenvironment ◽

Pten Loss ◽

Pathway Activation ◽

Tumor Types ◽

T Cell Exclusion

Abstract Background Recent evidences had shown that loss in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was associated with immunotherapy resistance, which may be attributed to the non-T-cell-inflamed tumor microenvironment. The impact of PTEN loss on tumor microenvironment, especially regarding T cell infiltration across tumor types is not well understood. Methods Utilizing The Cancer Genome Atlas (TCGA) and publicly available dataset of immunotherapy, we explored the correlation of PTEN expressing level or genomic loss with tumor immune microenvironment and response to immunotherapy. We further investigated the involvement of PI3K-AKT-mTOR pathway activation, which is known to be the subsequent effect of PTEN loss, in the immune microenvironment modulation. Results We reveal that PTEN mRNA expression is significantly positively correlated with CD4/CD8A gene expression and T cells infiltration especially T helpers cells, central memory T cell and effector memory T cells in multiples tumor types. Genomic loss of PTEN is associated with reduced CD8+ T cells, type 1 T helper cells, and increased type 2 T helper cells, immunosuppressed genes (e.g. VEGFA) expression. Furthermore, T cell exclusive phenotype is also observed in tumor with PI3K pathway activation or genomic gain in PIK3CA or PIK3CB. PTEN loss and PI3K pathway activation correlate with immunosuppressive microenvironment, especially in terms of T cell exclusion. PTEN loss predict poor therapeutic response and worse survival outcome in patients receiving immunotherapy. Conclusion These data brings insight into the role of PTEN loss in T cell exclusion and immunotherapy resistance, and inspires further research on immune modulating strategy to augment immunotherapy.

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DIPG-35. BIOLOGICAL MEDICINE FOR DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) ERADICATION: RESULTS OF THE THREE ARM BIOMARKER-DRIVEN RANDOMIZED BIOMEDE 1.0 TRIAL

Neuro-Oncology ◽

10.1093/neuonc/noaa222.083 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii293-iii294

Author(s):

Jacques Grill ◽

Gwenael Le Teuff ◽

Karsten Nysom ◽

Klas Blomgren ◽

Darren Hargrave ◽

...

Keyword(s):

Disease Progression ◽

Stereotactic Biopsy ◽

Diagnostic Yield ◽

Steering Committee ◽

Diffuse Intrinsic Pontine Glioma ◽

Open Label ◽

Pten Loss ◽

Multi Stage ◽

Open Label Phase ◽

Biological Medicine

Abstract Despite 50 years of clinical trials, no improvement of survival has been observed in DIPG and most children die within 2 years of diagnosis. Only radiotherapy transiently controls disease progression. The study was conceived as a randomized multi-arm multi-stage program. It started with an open-label phase-II trial comparing three drugs (everolimus, dasatinib, erlotinib) combined with irradiation, allocated according to the presence of their specific targets (PTEN-loss, EGFR-overexpression) defined with a stereotactic biopsy after central confirmation of the diagnosis (presence of histone H3K27M mutation or loss of K27 trimethylation). Targeted therapies were started concomitantly with radiotherapy and were continued until disease progression. No biopsy-related death was reported and diagnostic yield was excellent, with only 5 non-informative biopsies. Biopsy excluded the diagnosisof DIPG in 8% of the cases. At the 3rd interim analysis, based on 193 randomized patients, the IDMC concluded that the study was unlikely to show a difference of OS between the 3 drugs even if 250 patients would be randomized. The median OS from the time of diagnosis was 11.9, 10.5 and 10 months for everolimus, dasatinib and erlotinib. Treatment was discontinued due to toxicity in 2%, 13%, and 15%, respectively. BIOMEDE shows the feasibility of biologically-driven treatment in DIPG on a large international scale. Based on the better toxicity profile and the slightly better efficacy, although not statistically significant, the steering committee proposed that everolimus should be used as the control arm for the next BIOMEDE 2.0 trial.

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Nuclear PTEN deficiency and heterozygous PTEN loss have distinct impacts on brain and lymph node size

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2021.03.081 ◽

2021 ◽

Vol 555 ◽

pp. 81-88

Author(s):

Atsushi Igarashi ◽

Takashi Kato ◽

Hiromi Sesaki ◽

Miho Iijima

Keyword(s):

Lymph Node ◽

Pten Loss ◽

Lymph Node Size ◽

Node Size

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Fos cooperation with PTEN loss elicits keratoacanthoma not carcinoma, owing to p53/p21WAF-induced differentiation triggered by GSK3 inactivation and reduced AKT activity

Journal of Cell Science ◽

10.1242/jcs.021147 ◽

2008 ◽

Vol 121 (10) ◽

pp. 1758-1769 ◽

Cited By ~ 14

Author(s):

D. Yao ◽

C. L. Alexander ◽

J. A. Quinn ◽

W.-C. Chan ◽

H. Wu ◽

...

Keyword(s):

Induced Differentiation ◽

Pten Loss

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SPOP and CHD1 alterations in prostate cancer: Relationship with PTEN loss, tumor grade, perineural infiltration, and PSA recurrence

The Prostate ◽

10.1002/pros.24218 ◽

2021 ◽

Author(s):

Silvia Hernández‐Llodrà ◽

Laura Segalés ◽

Nuria Juanpere ◽

Tech Marta Lorenzo ◽

Marta Salido ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Grade ◽

Pten Loss ◽

Psa Recurrence

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Profilin-1; a novel regulator of DNA damage response and repair machinery in keratinocytes

Molecular Biology Reports ◽

10.1007/s11033-021-06210-6 ◽

2021 ◽

Author(s):

Chang-Jin Lee ◽

Min-Ji Yoon ◽

Dong Hyun Kim ◽

Tae Uk Kim ◽

Youn-Jung Kang

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Dna Damage Response ◽

Recovery Time ◽

Actin Polymerization ◽

Loss Of Function ◽

Dna Double Strand Breaks ◽

Pten Loss ◽

Damage Response ◽

Specific Regulation

AbstractProfilin-1 (PFN1) regulates actin polymerization and cytoskeletal growth. Despite the essential roles of PFN1 in cell integration, its subcellular function in keratinocyte has not been elucidated yet. Here we characterize the specific regulation of PFN1 in DNA damage response and repair machinery. PFN1 depletion accelerated DNA damage-mediated apoptosis exhibiting PTEN loss of function instigated by increased phosphorylated inactivation followed by high levels of AKT activation. PFN1 changed its predominant cytoplasmic localization to the nucleus upon DNA damage and subsequently restored the cytoplasmic compartment during the recovery time. Even though γH2AX was recruited at the sites of DNA double strand breaks in response to DNA damage, PFN1-deficient cells failed to recruit DNA repair factors, whereas control cells exhibited significant increases of these genes. Additionally, PFN1 depletion resulted in disruption of PTEN-AKT cascade upon DNA damage and CHK1-mediated cell cycle arrest was not recovered even after the recovery time exhibiting γH2AX accumulation. This might suggest PFN1 roles in regulating DNA damage response and repair machinery to protect cells from DNA damage. Future studies addressing the crosstalk and regulation of PTEN-related DNA damage sensing and repair pathway choice by PFN1 may further aid to identify new mechanistic insights for various DNA repair disorders.

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