Biomedical subjects

Eddie L Imada

Publications and source records attributed to Eddie L Imada.

3 recordsLinked to original sources

PubMed2026

Recurrent mechanisms of biallelic epigenetic inactivation reveal new putative tumour suppressor genes in prostate cancer.

The inactivation of tumour suppressor genes is a key step in cancer development, and is usually achieved by homozygous loss. In prostate cancer, however, large genomic regions are often hemizygously lost, which complicates the identification of putative tumour suppressors in these regions. Here, we develop Epi2Hit, an integrative computational method that leverages whole genome sequencing, epigenomic profiling and gene expression to identify biallelic inactivation of tumour suppressor genes involving DNA methylation of promoter and enhancer regions of one allele and genomic loss of the other allele. We apply Epi2Hit to a cohort of 2,021 prostate cancers to discover tumour suppressor genes. In particular, we identify epigenetic biallelic inactivation of ZFHX3 at a recurrence level similar to TP53. Biallelic inactivation of ZFHX3, a transcriptional repressor, leads to upregulation of oncogenes, including MYC and a shorter time to metastasis. Finally, we provide evidence that epigenetic silencing as 2nd hit is particularly enriched in regions with nearby essential genes, precluding homozygous loss.

Prostatic Neoplasms↗

PubMed2026

Integrated signatures define mutational processes in prostate cancer.

Prostate cancer follows a long and heterogeneous disease course with incompletely understood aetiology1. Here we dissect the mutational processes shaping the genomes of 959 donors from the Pan Prostate Cancer Group and assess their clinical relevance. By integrating de novo extracted single-base substitution, insertion-deletion and copy-number signatures with six novel complex structural variant signatures, we identify eight integrated mutational footprints (IMFs) that collectively explain the mutational processes in 85% of primary prostate cancer genomes. IMFs were strongly influenced by regional biases in the genome, most prevalently androgen receptor-mediated mutagenesis and replication stress. Four IMFs, present in 37% of primary tumours, were significantly associated with shorter time to metastasis. These included reactive oxygen-species-driven mutagenesis and both canonical and non-canonical homologous recombination deficiency, the latter being enriched in patients of African ancestry. Extending to the metastatic setting, we found that IMFs predicted sensitivity to androgen receptor pathway inhibitors. Taken together, our study delineates the aetiologies and mutational processes that drive the genomic and clinical heterogeneity of prostate cancer, introduces IMFs as a unifying framework, and highlights their potential to improve both risk stratification and biomarker-guided treatment selection.

Journal Article↗

PubMed2026

TNIK Overexpression Is Sufficient for Chemoradiation Resistance in Limited-Stage Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is characterized by early metastasis, intrinsic chemoradiation resistance, and tumor recurrence. Besides the lack of potentially targetable oncogenic drivers, therapeutic advancements are also hindered by the scarcity of surgically resected tissue specimens ideal for profiling studies. We used patient-derived xenografts (PDX) to model SCLC chemoradiation resistance and identified chemoradiation resistance candidate genes using RNA sequencing. Additionally, we used human SCLC cell lines to confirm our in vivo results and delineate the underlying mechanism. Transcriptome profiling showed that the Traf2- and Nck-interacting kinase (TNIK) gene was consistently upregulated in an array of SCLC PDXs exposed to chemoradiation compared with monotherapy, which is consistent with previous observations of TNIK amplification in human samples. Genetic depletion (P < 0.01) or pharmacologic inhibition (P < 0.0001) of TNIK reduced in vitro clonogenic survival of TNIKhigh SCLC cells and promoted sensitivity to chemoradiation. In vivo, pharmacologic inhibition of TNIK enhanced chemoradiation sensitivity (P < 0.0001) of the H446 cell line-derived xenograft (CDX) in NOD-SCID mice. Furthermore, pharmacologic inhibition of TNIK in vivo demonstrated sensitivity (P < 0.0001) to chemoradiotherapy (CRT) in LX33 PDX. These results indicate that TNIK plays a role in conferring resistance to chemoradiation in SCLC cell lines and in vivo in SCLC CDX and PDX models. Delineating the mechanism behind radiosensitization suggested that TNIK inhibition may impair the DNA damage response in irradiated cells. Collectively, these findings suggest that TNIK may be a promising therapeutic target in limited-stage SCLC and support further investigation of TNIK inhibition in combination with standard CRT.

Humans↗