Biology subjects

Alsaleem, M.

Publications and source records attributed to Alsaleem, M..

3 recordsLinked to original sources

bioRxiv2026

Loss of piR-hsa-7221 regulation drives the expression of the LINE1-derived oncogenic lncRNA CASC9 in testicular cancer.

Testicular germ cell tumours (TGCTs) are the most common cancer in young males and are considered curable if they respond to platinum-based therapy. However, a significant number of refractory patients develop metastatic disease and the lack targeted therapy remains an unmet clinical need. To identify novel therapeutic targets, we investigated the epigenetic instability of TGCTs and characterised novel oncogenic gene networks regulated by transposable elements (TEs)-derived long noncoding RNAs (lncRNAs) which are controlled by PIWI-interacting RNAs (piRNAs). A TGCT-specific piRNA signature was identified by bioinformatics analysis of the The Cancer Genome Atlas (TCGA) TGCT dataset and analysis of piRNAs mapped to active LINE1 sequences identified piR-hsa-7221 as a transcriptional regulator of the lncRNA CASC9 in seminoma tumours. We show that piR-hsa-7221 binds to a complementary LINE1 LIPA5 sequence and regulates the expression of CASC9 driven by the LINE1 antisense promoter. Therefore, loss of piR-hsa-7221 drives the upregulation and oncogenic activity of CASC9, which as is impaired after silencing, leading to reduced cancer cell proliferation and invasion, as well as increased sensitivity to cisplatin treatment. These effects are associated with the regulation of the cell cycle, developmental pathways, extracellular matrix, hormone metabolism and immune responses, highlighting WNT signalling as a significant downstream target. Therefore, this novel epigenetic mechanism provides new insights into the role of piRNA-mediated regulation of oncogenic lncRNAs derived from active transposable elements. Importantly, the identification of piR-hsa-7221 and the lncRNA CASC9, together with the associated gene networks highlights novel therapeutic targets for the treatment of seminoma TGCTs.

cancer biology↗

bioRxiv2021

RANK is an independent biomarker of poor prognosis in estrogen receptor-negative breast cancer and a therapeutic target in patient-derived xenografts

Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor denosumab in BC patients, beyond its bone-related effects, is unclear. Here, we investigated the prognostic value of RANK expression and its functionality in human BC. We analyzed RANK and RANKL expression in more than 1500 BC cases (777 being estrogen receptor-negative (ER-)) from four independent cohorts. We confirmed that RANK is more frequently expressed in ER- tumors, but it is also found in a subset of ER+ tumors. In ER- BC, RANK expression was independently associated with poor outcome, especially in postmenopausal patients and those who received adjuvant chemotherapy. Gene expression analyses unraveled distinct biology associated with RANK in relation to ER expression and menopause, and evidenced enhanced RANK activation in ER- postmenopausal tumors, together with regulation of metabolic pathways. Functional studies and transcriptomic analyses in ER- RANK+ patients-derived orthoxenografts demonstrated that activation of RANK signaling pathway promotes tumor cell proliferation and stemness, and regulates multiple biological processes including tumor immune surveillance and metabolism. Our results demonstrate that RANK expression is an independent poor prognosis biomarker in postmenopausal ER- BC patients and support the rational of using RANK pathway inhibitors in combination with chemotherapy in ER- BC.

cancer biology↗

bioRxiv2019

Global kinome silencing combined with 3D invasion screening of the tumor microenvironment identifies fibroblast-expressed PIK3Cδ involvement in triple-negative breast cancer progression

As there is growing evidence for the tumor microenvironments (TME) role in tumorigenesis, we sought to investigate the role of fibroblast-expressed kinases in triple negative breast cancer (TNBC). Using a high-throughput kinome screen combined with 3D invasion assays, we identified fibroblast-expressed PIK3C{delta} (f-PIK3C{delta}) as a key regulator of progression. Although PIK3C{delta} has been mainly described in leucocytes, we detected high expression in primary fibroblasts derived from TNBC patients, while PIK3C{delta} was undetectable in cancer epithelial cell lines. Genetic and pharmacologic gain- and loss-of functions experiments verified the contribution of f-PIK3C{delta} in TNBC cell invasion. By employing an integrated secretomics and transcriptomics analysis, we revealed a paracrine mechanism via which f-PIK3C{delta} confers its pro-tumorigenic effects. Inhibition of f-PIK3C{delta} promoted the secretion of factors, including PLGF and BDNF, which subsequently led to upregulation of NR4A1 in TNBC cells where it acts as a tumor suppressor. Inhibition of PIK3C{delta} in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3C{delta} in cancer progression. Similar results were observed in the MMTV-PyMT transgenic BC mouse model, in addition to a decrease on tumor metastasis emphasizing the potential immune-independent effects of PIK3C{delta} inhibition. Finally, analysis of BC patient cohorts and TCGA datasets identified f-PIK3C{delta} (protein and mRNA levels) as an independent prognostic factor for overall and disease free survival, highlighting it as a therapeutic target for TNBC.

cancer biology↗