Ian G Mills

Tumour cells sustain their high proliferation rate through metabolic reprogramming, whereby cellular metabolism shifts from oxidative phosphorylation to aerobic glycolysis, even under normal oxygen levels. Hypoxia-inducible factor 1A (HIF1A) is a major regulator of this process, but its activation under normoxic conditions, termed pseudohypoxia, is...

Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance, other factors such as c-Myc and the E2F family also play a role in later stage disease. HES6 is a transcription co-factor associated with stem cell characteristics in neural tissue. Here we show that HE...

Prostate cancer treatment is dominated by strategies to control androgen receptor (AR) activity. AR has an impact on prostate cancer development through the regulation of not only transcription networks but also genomic stability and DNA repair, as manifest in the emergence of gene fusions. Whole-genome maps of AR binding sites and transcript profi...

The proto-oncogene c-Myc paradoxically activates both proliferation and apoptosis. In the pathogenic state, c-Myc-induced apoptosis is bypassed via a critical, yet poorly understood escape mechanism that promotes cellular transformation and tumorigenesis. The accumulation of unfolded proteins in the ER initiates a cellular stress program termed the...

Clathrin-mediated endocytosis involves cargo selection and membrane budding into vesicles with the aid of a protein coat. Formation of invaginated pits on the plasma membrane and subsequent budding of vesicles is an energetically demanding process that involves the cooperation of clathrin with many different proteins. Here we investigate the role o...

Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prost...

Background As healthcare moves from a one-size-fits-all approach towards precision care, individual risk prediction is an important step in disease prevention and early detection. Biobank-linked healthcare systems can generate knowledge about genomic risk and test the impact of implementing that knowledge in care. Risk-stratified prostate cancer sc...

Therapy resistance is attributed to over 80% of cancer deaths per year emphasizing the urgent need to overcome this challenge for improved patient outcomes. Despite its widespread use in colorectal cancer (CRC) treatment, resistance to 5-fluorouracil (5FU) remains poorly understood. Here, we investigate the transcriptional responses of CRC cells to...

Hyperpolarised magnetic resonance imaging (HP-¹³C-MRI) has shown promise as a clinical tool for detecting and characterising prostate cancer. Here we use a range of spatially resolved histological techniques to identify the biological mechanisms underpinning differential [1-¹³C]lactate labelling between benign and malignant prostate, as well as in...

Background Understanding the role of circulating proteins in prostate cancer risk can reveal key biological pathways and identify novel targets for cancer prevention. Methods We investigated the association of 2002 genetically predicted circulating protein levels with risk of prostate cancer overall, and of aggressive and early onset disease, usin...

Membrane trafficking, a fundamental cellular process encompassing the transport of molecules to specific organelles, endocytosis at the plasma membrane and protein secretion, is crucial for cellular homeostasis and signalling. Cancer cells adapt membrane trafficking to enhance their survival and metabolism, and understanding these adaptations is vi...

The availability of protein measurements and whole exome sequence data in the UK Biobank enables investigation of potential observational and genetic protein-cancer risk associations. We investigated associations of 1463 plasma proteins with incidence of 19 cancers and 9 cancer subsites in UK Biobank participants (average 12 years follow-up). Emerg...

Cancer cells frequently exhibit hyperactivation of transcription, which can lead to increased sensitivity to compounds targeting the transcriptional kinases, in particular CDK9. However, mechanistic details of CDK9 inhibition‐induced cancer cell‐selective anti‐proliferative effects remain largely unknown. Here, we discover that CDK9 inhibition acti...

Background It is important to identify molecular features that improve prostate cancer (PCa) risk stratification before radical treatment with curative intent. Molecular analysis of historical diagnostic formalin‐fixed paraffin‐embedded (FFPE) prostate biopsies from cohorts with post‐radiotherapy (RT) long‐term clinical follow‐up has been limited....

Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prost...

Approximately 1 in 8 men in Canada will be diagnosed with prostate cancer (PCa) in their lifetime, with ~20% presenting with high-risk disease. A standard treatment is radiotherapy (RT) and while many patients respond well to RT, up to 40% of men with high-risk disease can recur, often within the prostate. It can be challenging to salvage prostate...

Hyper-activation of transcription is frequent in cancer, which often leads to increased sensitivity to compounds targeting the transcriptional kinases, in particular cyclin-dependent kinase 9 (CDK9). However, mechanistic details as to why CDK9 inhibition selectively kills cancer cells remain largely unknown. Here, we report that CDK9 inhibition act...

Background: Understanding the role of circulating proteins in prostate cancer risk can reveal key biological pathways and identify novel targets for cancer prevention. Methods: We investigated the association of 2,002 genetically predicted circulating protein levels with risk of prostate cancer overall, and of aggressive and early onset disease, us...

Introduction Prostate cancer (PCa) is a multifocal disease driven by heterogenous spatial and temporal branching evolution of tumour clones. Spatial transcriptomic analysis has revealed, clonally distributed copy number alterations even in histologically benign regions. We aim to evaluate if the genetic signature comprised within these genetically...

Purpose The primary objective was to establish whether blood-based leucine-rich alpha-2-glycoprotein (LRG1) can predict outcomes in patients with locally advanced prostate cancer undergoing androgen-deprivation therapy (ADT) and radiotherapy (RT) and to determine how it may relate to 92 immune-oncology (I-O)-related proteins in this setting. Metho...

Background Extension of prostate cancer beyond the primary site by local invasion or nodal metastasis is associated with poor prognosis. Despite significant research on tumour evolution in prostate cancer metastasis, the emergence and evolution of cancer clones at this early stage of expansion and spread are poorly understood. We aimed to delineate...

Background Peroxisomes are central metabolic organelles that have key roles in fatty acid homoeostasis. As prostate cancer (PCa) is particularly reliant on fatty acid metabolism, we explored the contribution of peroxisomal β-oxidation (perFAO) to PCa viability and therapy response. Methods Bioinformatic analysis was performed on clinical transcrip...

While radical prostatectomy remains the mainstay of prostate cancer (PCa) treatment, 20 to 40% of patients develop postsurgical biochemical recurrence (BCR). A particularly challenging clinical cohort includes patients with intermediate-risk disease whose risk stratification would benefit from advanced approaches that complement standard-of-care di...

Understanding prostate carcinogenesis is crucial not only for identifying new treatment targets but also for developing effective strategies to manage the asymptomatic form of the disease. There is a lack of consensus about predicting the indolent form of the disease prostate cancer, leading to uncertainties regarding treatment initiation. This rev...

Genetic signatures have added a molecular dimension to prognostics and therapeutic decision-making. However, tumour heterogeneity in prostate cancer and current sampling methods could confound accurate assessment. Based on previously published spatial transcriptomic data from multifocal prostate cancer, we created virtual biopsy models that mimic c...

Hyperpolarised magnetic resonance imaging (HP-13C-MRI) has shown promise as a clinical tool for detecting and characterising prostate cancer. Here we have used a range of spatially resolved histological techniques to identify the biological mechanisms underpinning differential [1-13C]lactate labelling between benign and malignant prostate, as well...

Magnetic resonance imaging (MRI) is increasingly used to triage patients for prostate biopsy. However, 9% to 24% of clinically significant (cs) prostate cancers (PCas) are not visible in MRI. We aimed to identify histomic and transcriptomic determinants of MRI visibility and their association to metastasis, and PCa‐specific death (PCSD). We studied...

Background Understanding the role of circulating proteins in prostate cancer risk can reveal key biological pathways and identify novel targets for cancer prevention. Methods We investigated the association of 2,002 genetically predicted circulating protein levels with risk of prostate cancer overall, and of aggressive and early onset disease, usin...

Recent advances in attention-based multiple instance learning (MIL) have improved our insights into the tissue regions that models rely on to make predictions in digital pathology. However, the interpretability of these approaches is still limited. In particular, they do not report whether high-attention regions are positively or negatively associa...

Purpose It is important to identify molecular features that improve prostate cancer (PCa) risk stratification before radical treatment with curative intent. Molecular analysis of historical diagnostic formalin-fixed paraffin-embedded (FFPE) prostate biopsies from cohorts with post-radiotherapy (RT) long-term clinical follow-up has been limited. Uti...

Prostate cancer is typically of acinar adenocarcinoma type but can occasionally present as neuroendocrine and/or ductal type carcinoma. These are associated with clinically aggressive disease, and the former often arises on a background of androgen deprivation therapy, although it can also arise de novo. Two prostate cancer cases were sequenced by...

Background Proteins are essential for the development and progression of cancer and for the human body's defense against tumor onset. The availability of a large panel of protein measurements and whole exome sequence data in the UK Biobank has enabled the simultaneous examination of plasma protein associations with risk across multiple cancer sites...

Objective To review the current status of germline and somatic (tumour) genetic testing for prostate cancer (PCa), and its relevance for clinical practice. Methods A narrative synthesis of various molecular profiles related to their clinical context was carried out. Current guidelines for genetic testing and its feasibility in clinical practice we...

Despite breakthroughs in immune checkpoint inhibitors (ICI), the majority of tumors, including those poorly infiltrated by CD8+ T cells or heavily infiltrated by immunosuppressive immune effector cells, are unlikely to result in clinically meaningful tumor responses. Radiation therapy (RT) has been combined with ICI to potentially overcome this res...

Background: The Unfolded Protein Response (UPR) is a key homeostatic mechanism that is activated during endoplasmic reticulum (ER) stress caused by both intrinsic (genomic instability, metabolic demand) and extrinsic (chemo/radiotherapy, nutrient deprivation, hypoxia) factors. IRE1 is the main UPR transducer, signalling the transcription factor XBP...

Defining the transition from benign to malignant tissue is fundamental to improve early diagnosis of cancer. We provide an unsupervised approach (SpatialInferCNV) to study spatial genome integrity, in situ, to gain molecular insight into clonal relationships. We employed spatially resolved transcriptomics (Visium, 10x Genomics) to infer spatial cop...

Background and Aims: Prostate cancer (PCa) is highly reliant on lipids for energy, hence targeting fatty acid oxidation (FAO) is a highly promising approach to the treatment of PCa. Recent work by our group and others have shown that FAO is critical for cell viability and survival, and is one of the key drivers of treatment resistance. Although FAO...

The emergence of castration-resistant prostate cancer remains an area of unmet clinical need. We recently identified a subpopulation of normal prostate progenitor cells, characterized by an intrinsic resistance to androgen deprivation and expression of LY6D. We here demonstrate that conditional deletion of PTEN in the murine prostate epithelium cau...

Prostate cancer is often treated by perturbing androgen receptor signalling. CACNA1D, encoding CaV1.3 ion channels is upregulated in prostate cancer. Here we show how hormone therapy affects CACNA1D expression and CaV1.3 function. Human prostate cells (LNCaP, VCaP, C4-2B, normal RWPE-1) and a tissue microarray were used. Cells were treated with ant...

Genetic signatures have added a molecular dimension to prognostics and therapeutic decision-making. However, tumour heterogeneity in prostate cancer and current sampling methods could confound accurate assessment. Based on previously published spatial transcriptomic data from multifocal prostate cancer, we created virtual biopsy models that mimic c...

Extension of prostate cancer beyond the primary site into the surrounding organs by local invasion or nodal metastasis is associated with poor prognosis. The emergence and evolution of cancer clones at this early stage of expansion and spread has not been studied in detail. We performed whole genome sequencing on 42 prostate cancer samples from the...

Epithelial cancers are typically heterogeneous with primary prostate cancer being a typical example of histological and genomic variation. Prostate cancer is the second most common male cancer in western industrialized countries. Prior studies of primary prostate cancer tumor genetics revealed extensive inter and intra-patient tumor heterogeneity....

Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a serine/threonine-protein kinase, that is involved in maintaining various physiological and cellular processes within the cell that regulate energy homeostasis and cell growth. CaMKK2 regulates glucose metabolism by the activation of downstream kinases, AMP-activated protein kinase (...

Peroxisomes are central metabolic organelles that have key roles in fatty acid homeostasis, including β-oxidation, and emerging evidence has linked aberrant peroxisome metabolism to cancer development and progression. While targeting mitochondrial β-oxidation in prostate cancer (PCa) has gained significant attention in recent years, the contributio...

Background After radical prostatectomy (RP), depending on stage, up to 40% of patients with prostate cancer (PCa) will experience biochemical failure (BF). Despite salvage therapy, approximately one-third of these patients will need permanent hormone therapy (pHT) and are at risk of progression to castration-resistant PCa (CRPC). Prognostic markers...

Understanding the impact of radiotherapy on the evolution of treatment resistant prostate cancer is critical for selecting effective treatment combinations. Whilst activation of Type 1 interferon signalling is a hallmark of how cells respond to viral infection, in cancer cells, multiple stresses are known to activate this same response. In this stu...

Background Up to 80% of cases of prostate cancer present with multifocal independent tumour lesions leading to the concept of a field effect present in the normal prostate predisposing to cancer development. In the present study we applied Whole Genome DNA Sequencing (WGS) to a group of morphologically normal tissue ( n = 51), including benign pros...

Defining the transition from benign to malignant tissue is fundamental to improving early diagnosis of cancer1. Here we use a systematic approach to study spatial genome integrity in situ and describe previously unidentified clonal relationships. We used spatially resolved transcriptomics2 to infer spatial copy number variations in >120,000 regions...

Triggered by the urgent need for greater accuracy in predicting the biological behaviour of diseases, foremost cancer, the search for the ideal biomarker—a molecule, gene or any other characteristic that can be objectively measured and evaluated—is relentless. The search for exemplary candidates has been encouraged by the rapid progress in profilin...

Co-targeting of O-GlcNAc transferase (OGT) and the transcriptional kinase CDK9 is toxic to prostate cancer cells. As OGT is an essential glycosyltransferase, identifying an alternative target showing similar effects is of great interest. Here, we used a multiomics approach (transcriptomics, metabolomics and proteomics) to better understand the mech...

Introduction: Defining the transition from benign to malignant tissue is fundamental to improve early diagnosis of cancer. In order to obtain spatial information of clonal genetic events, prior studies have used methods such as laser capture microdissection, which results in assessment of small regions or even single cells. These studies have an in...

Resistance to androgen receptor-targeted therapy due to tumor heterogeneity and clonal evolution is a key challenge for improving prostate cancer outcomes. Despite this, the transcriptomic and chromatin accessibility changes contributing to the emergence of resistance remain incompletely understood at the level of individual cells. Using single-cel...

We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC)...

Introduction: Defining the transition from benign to malignant tissue is fundamental to improve early diagnosis of cancer. In order to obtain spatial information of clonal genetic events, prior studies have used methods such as laser capture microdissection, which results in assessment of small regions or even single cells. These studies have an in...

Androgen receptor (AR) is a major driver of prostate cancer initiation and progression. O-GlcNAc transferase (OGT), the enzyme that catalyzes the covalent addition of UDP-N-acetylglucosamine (UDP-GlcNAc) to serine and threonine residues of proteins, is often highly expressed in prostate cancer with its expression correlated with high Gleason score....

Background miR-346 was identified as an activator of Androgen Receptor (AR) signalling that associates with DNA damage response (DDR)-linked transcripts in prostate cancer (PC). We sought to delineate the impact of miR-346 on DNA damage, and its potential as a therapeutic agent. Methods RNA-IP, RNA-seq, RNA-ISH, DNA fibre assays, in vivo xenograft...

Inhibiting androgen signaling using androgen signaling inhibitors (ASI) remains the primary treatment for castrate-resistant prostate cancer. Acquired resistance to androgen receptor (AR)-targeted therapy represents a major impediment to durable clinical response. Understanding resistance mechanisms, including the role of AR expressed in other cell...

Background Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associ...

Background Numerous epidemiological studies have investigated the role of blood lipids in prostate cancer (PCa) risk, though findings remain inconclusive to date. The ongoing research has mainly involved observational studies, which are often prone to confounding. This study aimed to identify the relationship between genetically predicted blood lip...

Hyperpolarised magnetic resonance imaging (HP-13 C-MRI) is an emerging clinical technique to detect [1-13 C]lactate production in prostate cancer (PCa) following intravenous injection of hyperpolarised [1-13 C]pyruvate. Here we differentiate clinically-significant PCa from indolent disease in a low/intermediate-risk population by correlating [1-13...