Biology subjects

Khani, F.

Publications and source records attributed to Khani, F..

6 recordsLinked to original sources

bioRxiv2024

Canonical AREs are tumor suppressive regulatory elements in the prostate

The androgen receptor (AR) is the central determinant of prostate tissue identity and differentiation, controlling normal, growth-suppressive prostate-specific gene expression1. It is also a key driver of prostate tumorigenesis, becoming "hijacked" to drive oncogenic transcription2-5. However, the regulatory elements determining the execution of the growth suppressive AR transcriptional program, and whether this can be reactivated in prostate cancer (PCa) cells remains unclear. Canonical androgen response element (ARE) motifs are the classic DNA binding element for AR6. Here, we used a genome-wide strategy to modulate regulatory elements containing AREs to define distinct AR transcriptional programs. We find that activation of these AREs is specifically associated with differentiation and growth suppressive transcription, and this can be reactivated to cause death in AR+ PCa cells. In contrast, repression of AREs is well tolerated by PCa cells, but deleterious to normal prostate cells. Finally, gene expression signatures driven by ARE activity are associated with improved prognosis and luminal phenotypes in human PCa patients. This study demonstrates that canonical AREs are responsible for a normal, growth-suppressive, lineage-specific transcriptional program, that this can be reengaged in PCa cells for potential therapeutic benefit, and genes controlled by this mechanism are clinically relevant in human PCa patients.

cancer biology↗

bioRxiv2023

Distinct mesenchymal cell states mediate prostate cancer progression

Alterations in tumor stroma influence prostate cancer progression and metastatic potential. However, the molecular underpinnings of this stromal-epithelial crosstalk are largely unknown. Here, we compare mesenchymal cells from four genetically engineered mouse models (GEMMs) of prostate cancer representing different stages of the disease to their wild-type (WT) counterparts by single-cell RNA sequencing (scRNA-seq) and, ultimately, to human tumors with comparable genotypes. We identified 8 transcriptionally and functionally distinct stromal populations responsible for common and GEMM-specific transcriptional programs. We show that stromal responses are conserved in mouse models and human prostate cancers with the same genomic alterations. We noted striking similarities between the transcriptional profiles of the stroma of murine models of advanced disease and those of of human prostate cancer bone metastases. These profiles were then used to build a robust gene signature that can predict metastatic progression in prostate cancer patients with localized disease and is also associated with progression-free survival independent of Gleason score. Taken together, this offers new evidence that stromal microenvironment mediates prostate cancer progression, further identifying tissue-based biomarkers and potential therapeutic targets of aggressive and metastatic disease.

cancer biology↗

bioRxiv2022

The cytidine deaminase APOBEC3G drives cancer mutagenesis and clonal evolution in bladder cancer

Mutagenic processes leave distinct signatures in cancer genomes. The mutational signatures attributed to APOBEC3 cytidine deaminases are pervasive in human cancers. However, data linking individual APOBEC3 proteins to cancer mutagenesis in vivo are limited. Here, we show that transgenic expression of human APOBEC3G promotes mutagenesis, genomic instability, and kataegis, leading to shorter survival in a murine bladder cancer model. Acting as mutagenic fuel, APOBEC3G increases the clonal diversity of bladder cancers, driving divergent cancer evolution. We characterize the single base substitution signature induced by APOBEC3G in vivo, showing the induction of a mutational signature different from that caused by APOBEC3A and APOBEC3B. Analysis of thousands of human cancers reveals the contribution of APOBEC3G to the mutational profiles of multiple cancer types, including bladder cancer. Our findings define the role of APOBEC3G in cancer mutagenesis and clonal heterogeneity. These results potentially inform future therapeutic efforts that restrict tumor evolution.

genomics↗

bioRxiv2021

The evolution of genomic, transcriptomic, and single-cell protein markers of metastatic upper tract urothelial carcinoma

The molecular characteristics of metastatic upper tract urothelial carcinoma (UTUC) are unknown. The genomic and transcriptomic differences between primary and metastatic UTUC is not well described either. We combined whole-exome sequencing, RNA-sequencing, and Imaging Mass Cytometry (IMC) of 44 tumor samples from 28 patients with high-grade primary and metastatic UTUC. IMC enables spatially resolved single-cell analyses to examine the evolution of cancer cell, immune cell, and stromal cell markers using mass cytometry with lanthanide metal-conjugated antibodies. We discovered that actionable genomic alterations are frequently discordant between primary and metastatic UTUC tumors in the same patient. In contrast, molecular subtype membership and immune depletion signature were stable across primary and matched metastatic UTUC. Molecular and immune subtypes were consistent between bulk RNA-sequencing and mass cytometry of protein markers from 340,798 single-cells. Molecular subtyping at the single cell level was highly conserved between primary and metastatic UTUC tumors within the same patient.

cancer biology↗

bioRxiv2021

SPOP mutation confers sensitivity to AR-targeted therapy in prostate cancer by reshaping the androgen-driven chromatin landscape

The normal androgen receptor (AR) cistrome and transcriptional program are fundamentally altered in prostate cancer (PCa). Here, we show that SPOP mutations, an early event in prostate tumorigenesis, reshape the chromatin landscape and AR-directed transcriptional program in normal prostate cells. Induction of SPOP mutation results in DNA accessibility and AR binding patterns found in human PCa. Consistent with dependency on this AR reprogramming, castration of SPOP mutant mouse models results in the loss of neoplastic phenotypes. Finally, human SPOP mutant PCa show improved response to AR-targeted therapies. Together, these results show that a single genomic alteration may be sufficient to reprogram the chromatin of normal prostate cells toward oncogenic phenotypes and that SPOP mutant tumors may be preferentially dependent on AR signaling through this mechanism.

cancer biology↗

bioRxiv2018

YBX2 Dysregulation is a Potential Cause for Late Maturation Arrest in Men with Non-Obstructive Azoospermia

IntroductionYBX2 protein binds to Y-box promotors and to mRNAs in the cytoplasm of pachytene spermatocytes and round spermatids in rodents. Knock-out of YBX2 leads to maturation arrest in animal models. YBX2 binds PRM1 and 2 mRNA, which is transcribed early and sequestrated for translation during late spermatogenesis.\n\nObjectiveThis study aimed to determine if the loss of YBX2 is associated with MA arrest due to the loss of sequestration of protamines in the human testis. As a second aim, we examined the expression of YBX2, and its transcription factors in maturation arrest (MA)(early and late) and normal controls in men.\n\nMethodsRNAseq was performed using RNA extracted from human testis samples from 44 men with non-obstructive azoospermia and ten from healthy controls. Differential expression was performed using JMPgenomics, FDR<0.001. FANTOM5 was used to predict enhancers and inhibitors of YBX2 expression. Immunofluorescence (IF) was used to stain testis tissue sections with antibodies against YBX2, SYCP3, and PRM2 in normal and MA samples. Flow cytometry was utilized to characterize YBX2 positive cells.\n\nResultsExpression of YBX2 mRNA was significantly downregulated in early and late MA compared to controls. Surprisingly, PRM1&2 mRNAs were also depleted in men with MA. Multifactorial regression analysis demonstrated a decrease in YBX2 expression in MA is due to decrease in COMP levels (p<0.0001). IF localized YBX2 protein in spermatocytes and round spermatids among fertile men, with rare YBX2 positive spermatocytes stained in LMA. PRM1&2 proteins were absent or abnormally sequestrated within spermatocytes.\n\nConclusionsDecrease in YBX2 protein expression in men with LMA leads to loss of translational suppression and lack of PRM1 and PRM2 necessary to complete spermatogenesis.

developmental biology↗