Imperial College London

ProfessorLucaMagnani

Faculty of MedicineDepartment of Surgery & Cancer

Chair in Cancer Adaptation and Evolution
 
 
 
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Contact

 

+44 (0)20 7594 2808l.magnani CV

 
 
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Location

 

137ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

99 results found

Trasanidis N, Katsarou A, Ponnusamy K, Shen Y-A, Kostopoulos I, Bergonia B, Keren K, Reema P, Xiao X, Szydlo RM, Sabbattini PMR, Roberts IAG, Auner HW, Naresh KN, Chaidos A, Wang T-L, Magnani L, Caputo VS, Karadimitris Aet al., 2022, Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma, BLOOD, Vol: 139, Pages: 1939-1953, ISSN: 0006-4971

Journal article

Magnani L, 2022, Genetic and epigenetic driven variation in regulatory regions activity contribute to adaptation and evolution under endocrine treatment

<jats:title>Abstract</jats:title> <jats:p>Comprehensive profiling of hormone-dependent breast cancer (HDBC) has identified hundreds of protein-coding alterations contributing to cancer initiation1,2, but only a handful have been linked to endocrine therapy resistance, potentially contributing to 40% of relapses1,3–9. If other mechanisms underlie the evolution of HDBC under adjuvant therapy is currently unknown. In this work, we employ integrative functional genomics to dissect the contribution of cis-regulatory elements (CREs) to cancer evolution by focusing on 12 megabases of non-coding DNA, including clonal enhancers10, gene promoters, and boundaries of topologically associating domains11. Massive parallel perturbation in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance12,13 and endocrine therapy resistance9. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies non-coding changes involved in therapy resistance. Overall, our data uncover actionable transient transcriptional programs critical for dormant persister cells and unveil new regulatory nodes driving evolutionary trajectories towards disease progression</jats:p>

Journal article

Magnani L, 2022, Long-term multi-modal recording reveals unpredictable nongenetic adaptation routes in dormant breast cancer cells.

<jats:title>Abstract</jats:title> <jats:p>Patients diagnosed with hormone dependent breast cancer (HDBC) receive five or more years of adjuvant endocrine therapies (ET). Adjuvant treatment delays relapse1,2 by targeting hidden micro-metastatic deposits, yet up to 50% of treated patients experience recurrent disease, often many years after surgery1. The mechanisms driving these subtype-specific clinical dynamics are largely unknown but likely involve dormancy2. We developed two approaches to study the long-term fate of dormant cells in unprecedented details. Firstly, we took advantage of a rare cohort of patients treated upfront with first line ETs until progression to dissect the contribution of genomic events to tumour awakening. Next, we developed a first of its kind in vitro evolutionary study to systematically record adaptive strategies of individual clonal lineages in parallel unperturbed systems during a period of several months. Collectively our data suggest that ETs induce an inherently unstable persister dormant state in a stochastically selected fraction of lineages. Over time, single cells spontaneously escape dormancy and divergently adapt via heritable transcriptional reprogramming, often developing distinct collateral resistance. Overall, this study uncovers previously unsuspected roles for non-genetic plasticity during dormancy with profound clinical implications for breast cancer.</jats:p>

Journal article

De Angelis R, Giuggioli D, Bajocchi G, Dagna L, Zanframundo G, Foti R, Cacciapaglia F, Cuomo G, Ariani A, Rosato E, Guiducci S, Girelli F, Riccieri V, Zanatta E, Bosello S, Cavazzana I, Ingegnoli F, Santis MD, Murdaca G, Abignano G, Romeo N, Della Rossa A, Caminiti M, Iuliano A, Ciano G, Beretta L, Bagnato G, Lubrano E, De Andres I, Giollo A, Saracco M, Agnes C, Lumetti F, Spinella A, Magnani L, Campochiaro C, De Luca G, Codullo V, Visalli E, Masini F, Gigante A, Bellando-Randone S, Pellegrino G, Pigatto E, Dall'Ara F, Lazzaroni MG, Generali E, Mennillo G, Barsotti S, Mariano GP, Calabrese F, Furini F, Vultaggio L, Parisi S, Peroni CL, Risa AM, Rozza D, Zanetti A, Carrara G, Landolfi G, Scirè CA, Bianchi G, Fusaro E, Sebastiani GD, Govoni M, D'Angelo S, Cozzi F, Doria A, Iannone F, Salvarani C, Matucci-Cerinic M, Ferri C, Systemic sclerosis PRogression INvestiGation group SPRINGet al., 2022, Sex-related Differences in Systemic Sclerosis: A Multicenter Cross-sectional Study From the National Registry of the Italian Society for Rheumatology., J Rheumatol, Vol: 49, Pages: 176-185, ISSN: 0315-162X

OBJECTIVE: There is still a great deal to learn about the influence of sex in systemic sclerosis (SSc). In this respect, national registries provide large and homogeneous patient cohorts for analytical studies. We therefore investigated a wide-ranging and well-characterized SSc series with the aim of identifying sex differences in disease expression, with a special focus on demographic, clinical, and serological characteristics. METHODS: A multicenter SSc cohort of 2281 patients, including 247 men, was recruited in the Italian Systemic sclerosis PRogression INvestiGation (SPRING) registry. Demographic data, disease manifestations, serological profile, and internal organ involvement were compared. RESULTS: The overall female/male ratio was 8.2:1. Female/male ratios for limited cutaneous SSc, diffuse cutaneous SSc, and SSc sine scleroderma subsets were 8.7:1, 4.9:1, and 10.7:1, respectively. A shorter time from onset of Raynaud phenomenon to SSc diagnosis, an increased prevalence of the diffuse cutaneous subset, renal crisis, and digital ulcers were found in males, whereas a significantly higher percentage of sicca syndrome, serum antinuclear antibodies, antiextractable nuclear antigens, anti-La/SSB, and anticentromere protein B was detected in the female group. Males exhibited lower left ventricular ejection fraction, as well as higher prevalence of conduction blocks, arrhythmias, ground glass, and honeycombing. Moreover, forced vital capacity and total lung capacity were medially lower in men than in women. Finally, males were more frequently treated with immunosuppressive drugs. CONCLUSION: Our study further supports the presence of several sex-related differences in patients with SSc. These differences were pronounced in the severity of cutaneous, peripheral vascular, and cardiopulmonary involvement for male patients, whereas an increased prevalence of sicca syndrome and a specific autoantibody profile characterized the female sex.

Journal article

Trasanidis N, Katsarou A, Ponnusamy K, Shen Y-A, Kostopoulos IV, Bergonia B, Keren K, Reema P, Xiao X, Szydlo RM, Sabbattini PMR, Roberts IAG, Auner HW, Naresh KN, Chaidos A, Wang T-L, Magnani L, Caputo VS, Karadimitris Aet al., 2021, Systems medicine dissection of chromosome 1q amplification reveals oncogenic regulatory circuits and informs targeted therapy in cancer

<jats:title>Abstract</jats:title><jats:p>Understanding the biological and clinical impact of copy number aberrations (CNA) in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring adverse prognosis in several cancers, including the blood cancer, multiple myeloma (MM). Although several chr1q genes portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here we integrate patient multi-omics datasets with genetic variables to identify 103 adverse prognosis genes in chr1q-amp MM. Amongst these, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways, whilst in co-operation with FOXM1, activates a proliferative gene signature which predicts adverse prognosis across multiple cancers. Notably, pharmacological disruption of the PBX1-FOXM1 axis, including with a novel PBX1 inhibitor is selectively toxic against chr1q-amp cancer cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapy strategies in cancer.</jats:p><jats:sec><jats:title>Significance</jats:title><jats:p>We provide a comprehensive systems medicine strategy to unveil oncogenic circuitries and inform novel precision therapy decisions against CNA in cancer. This first clinical multi-omic analysis of chr1q-amp in MM identifies a central PBX1-FOXM1 regulatory axis driving high-risk prognosis, as a novel therapeutic target against chr1q-amp in cancer.</jats:p></jats:sec>

Journal article

Ciriello G, Magnani L, 2021, The many faces of cancer evolution, ISCIENCE, Vol: 24

Journal article

Rosano D, Sofyali E, Dhiman H, Ivanoiu D, Slaven N, Hong SP, Rocca A, Bravaccini S, Ravaioli S, Noberini R, Bonaldi T, Magnani Let al., 2021, Unperturbed dormancy recording reveals stochastic awakening strategies in endocrine treated breast cancer cells

<jats:title>Abstract</jats:title><jats:p>Hormone dependent breast cancer (HDBC) is the most commonly diagnosed tumor type in women. Adjuvant endocrine therapies (ET) have been the cornerstone in the clinical management of HDBC patients for over forty years. A vast proportion of HDBC patients incur long periods of clinical dormancy following ET, with tumour awakening appearing at a steady pace for up to 25 years (Pan et al., 2017). Extensive genomic studies have demonstrated that 15-30% of clinical relapses develop recurrent genomic changes which contribute to drug resistance (i.e. ESR1 activating mutations) (Bertucci et al., 2019; Magnani et al., 2017; Razavi et al., 2018). However, even in these cases, there is no conclusive evidence around the pre-existence vs. <jats:italic>de novo</jats:italic> nature of these events. We previously showed that ETs can trigger and select for dormancy in subpopulations of breast cancer (Hong et al., 2019). In this work we took two novel approaches to investigate the dormancy and awakening roadmap of HDBC cells at unprecedented detail. Firstly, we leveraged a rare cohort of n=5 patients which were treated with primary adjuvant ETs in the absence of surgery (TRACING-HT) to dissect the contribution of genomic aberrations to tumor awakening. Next, we developed a first of its kind evolutionary study <jats:italic>in vitro</jats:italic> to systematically annotate cancer cells adaptive strategies at single cell level in unperturbed systems during a period of several months (TRADITIOM). Collectively our data suggest that ETs steer HDBC cells into an inherently unstable dormant state. Over time, routes to awakening emerge sporadically and spontaneously in single lineages. Each dormant cell retains an intrinsic awakening probability which we propose is a function of epigenetic decay. Awakening occurs without an external trigger and involves multiple apparent endpoint phenotypes that cannot be fully ex

Journal article

Borgoni S, Sofyali E, Soleimani M, Wilhelm H, Mueller-Decker K, Will R, Noronha A, Beumers L, Verschure PJ, Yarden Y, Magnani L, van Kampen AHC, Moerland PD, Wiemann Set al., 2020, Time-Resolved Profiling Reveals ATF3 as a Novel Mediator of Endocrine Resistance in Breast Cancer, CANCERS, Vol: 12

Journal article

Borgoni S, Sofyalı E, Soleimani M, Wilhelm H, Müller-Decker K, Will R, Noronha A, Verschure PJ, Yarden Y, Magnani L, van Kampen AHC, Moerland PD, Wiemann Set al., 2020, Time-resolved profiling reveals ATF3 as a novel mediator of endocrine resistance in breast cancer

<jats:title>Abstract</jats:title><jats:p>Breast cancer is one of the leading causes of death for women worldwide. Patients whose tumors express Estrogen Receptor α (ERα) account for around 70% of cases and are mostly treated with targeted endocrine therapy. However, 40% of these tumors eventually relapse due to resistance development and further treatment of these patients is highly ineffective. In this study we profiled the early phases of the resistance development process to uncover drivers of this phenomenon. Time-resolved analysis revealed that ATF3, a member of the ATF/CREB family of transcription factors, acts as a novel regulator of the response to therapy via rewiring of central signaling processes towards the adaptation to endocrine treatment. ATF3 was found to be essential in controlling crucial processes such as proliferation, cell cycle and apoptosis during the early response to treatment through the regulation of MAPK/AKT signaling pathways. Its essential role was confirmed <jats:italic>in vivo</jats:italic> in a mouse model and elevated expression of ATF3 was verified in patient datasets, adding clinical relevance to our findings. This study proposes ATF3 as a novel mediator of endocrine resistance development in breast cancer and elucidates its role in the regulation of downstream pathways activities.</jats:p>

Journal article

Tsolaki E, Doran W, Overbeck J, Magnani L, Olivo A, Herrmann IK, Bertazzo Set al., 2020, Nano-analytical Characterization of Breast Tissue Biopsies Reveals an Association between Spherical Nano and Micro Particles and Invasive Malignant Breast Tumours

<jats:title>Summary</jats:title><jats:p>The presence of calcifications on mammograms is a widely used diagnostic marker for breast cancer. While the clinicopathological analysis of breast tissue is well-developed, an in-depth characterisation of the properties of calcifications at the micro and nano scale remained elusive. In this work, we use nano-analytical methods to investigate the calcification present in healthy breast tissue, as well as in benign and malignant breast tumour tissue biopsies. While polycrystalline apatite with lower crystallinity can be found in all breast tissue samples, we show that magnesium-containing nano and micro spherical particles are found only in malignant invasive breast cancers. These particles are present exclusively in the vasculature and their concentration increases with cancer progression. The discovery of these spherical particles provides new insights into the characteristics of breast calcification associated with malignant tumours and opens new research pathways to a better understanding of breast tumours and their microenvironment in general.</jats:p>

Journal article

Acar A, Nichol D, Fernandez-Mateos J, Cresswell GD, Barozzi I, Hong SP, Trahearn N, Spiteri I, Stubbs M, Burke R, Stewart A, Caravagna G, Werner B, Vlachogiannis G, Maley CC, Magnani L, Valeri N, Banerji U, Sottoriva Aet al., 2020, Exploiting evolutionary steering to induce collateral drug sensitivity in cancer, Nature Communications, Vol: 11, Pages: 1-14, ISSN: 2041-1723

Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another drug. These evolutionary trade-offs can be exploited using ‘evolutionary steering’ to control the tumour population and delay resistance. However, recapitulating cancer evolutionary dynamics experimentally remains challenging. Here, we present an approach for evolutionary steering based on a combination of single-cell barcoding, large populations of 108–109 cells grown without re-plating, longitudinal non-destructive monitoring of cancer clones, and mathematical modelling of tumour evolution. We demonstrate evolutionary steering in a lung cancer model, showing that it shifts the clonal composition of the tumour in our favour, leading to collateral sensitivity and proliferative costs. Genomic profiling revealed some of the mechanisms that drive evolved sensitivity. This approach allows modelling evolutionary steering strategies that can potentially control treatment resistance.

Journal article

Cresswell GD, Nichol D, Spiteri I, Tari H, Zapata L, Heide T, Maley CC, Magnani L, Schiavon G, Ashworth A, Barry P, Sottoriva Aet al., 2020, Mapping the breast cancer metastatic cascade onto ctDNA using genetic and epigenetic clonal tracking, Nature Communications, Vol: 11, Pages: 1-12, ISSN: 2041-1723

Circulating tumour DNA (ctDNA) allows tracking of the evolution of human cancers at high resolution, overcoming many limitations of tissue biopsies. However, exploiting ctDNA to determine how a patient’s cancer is evolving in order to aid clinical decisions remains difficult. This is because ctDNA is a mix of fragmented alleles, and the contribution of different cancer deposits to ctDNA is largely unknown. Profiling ctDNA almost invariably requires prior knowledge of what genomic alterations to track. Here, we leverage on a rapid autopsy programme to demonstrate that unbiased genomic characterisation of several metastatic sites and concomitant ctDNA profiling at whole-genome resolution reveals the extent to which ctDNA is representative of widespread disease. We also present a methylation profiling method that allows tracking evolutionary changes in ctDNA at single-molecule resolution without prior knowledge. These results have critical implications for the use of liquid biopsies to monitor cancer evolution in humans and guide treatment.

Journal article

Coleman I, Corleone G, Arram J, Ng H-C, Magnani L, Luk Wet al., 2020, GeDi: applying su x arrays to increase the repertoire of detectable SNVs in tumour genomes, BMC Bioinformatics, Vol: 21, ISSN: 1471-2105

BackgroundCurrent popular variant calling pipelines rely on the mapping coordinates of each input read to a reference genome in order to detect variants. Since reads deriving from variant loci that diverge in sequence substantially from the reference are often assigned incorrect mapping coordinates, variant calling pipelines that rely on mapping coordinates can exhibit reduced sensitivity.ResultsIn this work we present GeDi, a suffix array-based somatic single nucleotide variant (SNV) calling algorithm that does not rely on read mapping coordinates to detect SNVs and is therefore capable of reference-free and mapping-free SNV detection. GeDi executes with practical runtime and memory resource requirements, is capable of SNV detection at very low allele frequency (<1%), and detects SNVs with high sensitivity at complex variant loci, dramatically outperforming MuTect, a well-established pipeline.ConclusionBy designing novel suffix-array based SNV calling methods, we have developed a practical SNV calling software, GeDi, that can characterise SNVs at complex variant loci and at low allele frequency thus increasing the repertoire of detectable SNVs in tumour genomes. We expect GeDi to find use cases in targeted-deep sequencing analysis, and to serve as a replacement and improvement over previous suffix-array based SNV calling methods.

Journal article

Magnani L, Barozzi I, Hong S, 2020, Single cell transcriptomics reveals multi-step adaptations to endocrine therapy, 42nd Annual San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

Rocca A, Ravaioli S, Fonzi E, Barozzi I, Perone Y, Magnani L, Pirini F, Martinelli G, Bravaccini Set al., 2020, Breast cancer subtype classification using NanoString and RNAseq technologies, 42nd Annual San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

Zoppoli G, Garuti A, Belfiore A, Bonizzi G, Ferrando L, Vingiani A, Colleoni M, Munzone E, Magnani L, Viale G, Ballestrero A, Pruneri Get al., 2020, Ultra-deep multigene profiling of matched primary and metastatic hormone receptor positive breast cancer patients relapsed after adjuvant endocrine treatment reveals novel aberrations in the estrogen receptor pathway, 42nd Annual San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

Mensa E, Guescini M, Giuliani A, Bacalini MG, Ramini D, Corleone G, Ferracin M, Fulgenzi G, Graciotti L, Prattichizzo F, Sorci L, Battistelli M, Monsurro V, Bonfigli AR, Cardelli M, Recchioni R, Marcheselli F, Latini S, Maggio S, Fanelli M, Amatori S, Storci G, Ceriello A, Stocchi V, De Luca M, Magnani L, Rippo MR, Procopio AD, Sala C, Budimir I, Bassi C, Negrini M, Garagnani P, Franceschi C, Sabbatinelli J, Bonafe M, Olivieri Fet al., 2020, Small extracellular vesicles deliver miR-21 and miR-217 as pro-senescence effectors to endothelial cells, JOURNAL OF EXTRACELLULAR VESICLES, Vol: 9

Journal article

Zhang Y, Takahashi Y, Hong SP, Liu F, Bednarska J, Goff P, Novak P, Shevchuk A, Gopal S, Barozzi I, Magnani L, Sakai H, Suguru Y, Fujii T, Gorelkin P, Majouga A, Weiss D, Edwards C, Ivanov A, Klenerman D, Sviderskaya E, Edel J, Korchev Yet al., 2019, High-resolution label-free 3D mapping of extracellular pH of single living cells, Nature Communications, Vol: 10, Pages: 1-9, ISSN: 2041-1723

Dynamic mapping of extracellular pH (pHe) at the single-cell level is critical for understanding the role of H+ in cellular and subcellular processes, with particular importance in cancer. While several pHe sensing techniques have been developed, accessing this information at the single-cell level requires improvement in sensitivity, spatial and temporal resolution. We report on a zwitterionic label-free pH nanoprobe that addresses these long-standing challenges. The probe has a sensitivity >0.01 units, 2 ms response time, and 50 nm spatial resolution. The technology was incorporated into a double-barrel nanoprobe integrating pH sensing with feedback-controlled distance sensing via Scanning Ion Conductance Microscopy. This allows for the simultaneous 3D topographical imaging and pHe monitoring of living cancer cells. These classes of nanoprobes were used for real-time high spatiotemporal resolution pHe mapping at the subcellular level and revealed tumour heterogeneity of the peri-cellular environments of melanoma and breast cancer cells.

Journal article

Trasanidis N, Katsarou A, Bergonia B, Keren K, Kostopoulos IV, Ponnusamy K, Paudel R, Xiao X, Auner HW, Roberts I, Naresh K, Chaidos A, Magnani L, Caputo VS, Karadimitris Aet al., 2019, PBX1 Co-Operates with FOXM1 to Regulate Myeloma Cell Proliferation and to Define an Ultra High-Risk chr1q Gain Myeloma Patient Subgroup, BLOOD, Vol: 134, ISSN: 0006-4971

Journal article

Hong SP, Lombardo Y, Chan TE, Corleone G, Rotmensz N, Magnani L, Bravaccini S, Rocca A, Pruneri G, McEwen KR, Coombes RC, Barozzi Iet al., 2019, Single-cell transcriptomics reveals multi-step adaptations to endocrine therapy, Nature Communications, Vol: 10, ISSN: 2041-1723

Resistant tumours are thought to arise from the action of Darwinian selection on genetically heterogenous cancer cell populations. However, simple clonal selection is inadequate to describe the late relapses often characterising luminal breast cancers treated with endocrine therapy (ET), suggesting a more complex interplay between genetic and non-genetic factors. Here, we dissect the contributions of clonal genetic diversity and transcriptional plasticity during the early and late phases of ET at single-cell resolution. Using single-cell RNA-sequencing and imaging we disentangle the transcriptional variability of plastic cells and define a rare sub population of pre-adapted (PA) cells which undergoes further transcriptomic reprogramming and copy number changes to acquire full resistance. We find evidence for sub-clonal expression of a PA signature in primary tumours and for dominant expression in clustered circulating tumour cells. We propose a multi-step model for ET resistance development and advocate the use of stage-specific biomarkers.

Journal article

Perone Y, Farrugia AJ, Rodriguez-Meira A, Gyorffy B, Ion C, Uggetti A, Chronopoulos A, Marrazzo P, Faronato M, Shousha S, Davies C, Steel JH, Patel N, Del Rio Hernandez A, Coombes C, Pruneri G, Lim A, Calvo F, Magnani Let al., 2019, Author Corrections: SREBP1 drives keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ER alpha breast cancer, Nature Communications, Vol: 10, ISSN: 2041-1723

Journal article

Ottaviani S, Stebbing J, Frampton AE, Zagorac S, Krell J, de Giorgio A, Trabulo SM, Nguyen VTM, Magnani L, Feng H, Giovannetti E, Funel N, Gress TM, Jiao LR, Lombardo Y, Lemoine NR, Heeschen C, Castellano Let al., 2019, Author Correction: TGF-beta induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression, Nature Communications, Vol: 10, ISSN: 2041-1723

Journal article

Nguyen VTM, Barozzi I, Faronato M, Lombardo Y, Steel JH, Patel N, Darbre P, Castellano L, Gyorffy B, Woodley L, Rodriguez-Meira A, Patten DK, Vircillo V, Periyasamy M, Ali S, Frige G, Minucci S, Coombes RC, Magnani Let al., 2019, Author Correction: Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion, Nature Communications, Vol: 10, ISSN: 2041-1723

Journal article

Perone Y, Farrugia AJ, Meira AR, Győrffy B, Ion C, Uggetti A, Chronopoulos A, Marrazzo P, Faronato M, Shousha S, Davies C, Steel JH, Patel N, del Rio Hernandez A, Coombes C, Pruneri G, Lim A, Calvo F, Magnani Let al., 2019, SREBP1 drives Keratin 80-dependent cytoskeletal changes and invasive behavior in endocrine resistant ERα breast cancer, Nature Communications, Vol: 10, ISSN: 2041-1723

Approximately 30% of ERα breast cancer patients relapse with metastatic disease following adjuvant endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain undergoes epigenetic reprogramming in aromatase inhibitors (AI)-resistant cells, leading to Keratin-80 (KRT80) upregulation. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion and cellular stiffening, collectively promoting cancer cell invasion. Shearwave elasticity imaging performed on prospectively recruited patients confirms KRT80 levels correlate with stiffer tumors. Immunohistochemistry showed increased KRT80-positive cells at relapse and, using several clinical endpoints, KRT80 expression associates with poor survival. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.

Journal article

Perone Y, Rodríguez Meira A, Farruggia A, Győrffy B, Ion C, Pruneri G, Lim A, Calvo F, Magnani Let al., 2019, OR34-2 SREBP1 Drives KRT80-Dependent Cytoskeletal Changes and Invasive Behaviour in Endocrine-Resistant ERα Breast Cancer, Journal of the Endocrine Society, Vol: 3

Journal article

Acar A, Nichol D, Fernandez-Mateos J, Cresswell GD, Barozzi I, Hong SP, Spiteri I, Stubbs M, Burke R, Stewart A, Vlachogiannis G, Maley CC, Magnani L, Valeri N, Banerji U, Sottoriva Aet al., 2019, Exploiting evolutionary herding to control drug resistance in cancer

<jats:title>Abstract</jats:title><jats:p>Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased growth rate or increased sensitivity to another drug due to evolutionary trade-offs. This weakness can be exploited in the clinic using an approach called ‘evolutionary herding’ that aims at controlling the tumour cell population to delay or prevent resistance. However, recapitulating cancer evolutionary dynamics experimentally remains challenging. Here we present a novel approach for evolutionary herding based on a combination of single-cell barcoding, very large populations of 10<jats:sup>8</jats:sup>–10<jats:sup>9</jats:sup>cells grown without re-plating, longitudinal non-destructive monitoring of cancer clones, and mathematical modelling of tumour evolution. We demonstrate evolutionary herding in non-small cell lung cancer, showing that herding allows shifting the clonal composition of a tumour in our favour, leading to collateral drug sensitivity and proliferative fitness costs. Through genomic analysis and single-cell sequencing, we were also able to determine the mechanisms that drive such evolved sensitivity. Our approach allows modelling evolutionary trade-offs experimentally to test patient-specific evolutionary herding strategies that can potentially be translated into the clinic to control treatment resistance.</jats:p>

Journal article

Varghese V, Magnani L, Harada N, Mauri F, Szydlo R, Yao S, Lam E, Kenny Let al., 2019, FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression, Scientific Reports, Vol: 9, ISSN: 2045-2322

Resistance to 5-Fluoruracil (5-FU) has been linked to elevated expression of the main target, thymidylate synthase (TYMS), which catalyses the de novo pathway for production of deoxythymidine monophosphate. The potent oncogenic forkhead box transcription factor, FOXM1 is is regulated by E2F1 which also controls TYMS. This study reveals a significant role of FOXM1 in 5-FU resistance. Overexpression and knock-down studies of FOXM1 in colon cancer cells suggest the importance of FOXM1 in TYMS regulation. ChIP and global ChIP-seq data also confirms that FOXM1 can also potentially regulate other 5-FU targets, such as TYMS, thymidine kinase 1 (TK-1) and thymidine phosphorylase (TYMP). In human colorectal cancer tissue specimens, a strong correlation of FOXM1 and TYMS staining was observed. Elevated FOXM1 and TYMS expression was also observed in acquired 5-FU resistant colon cancer cells (HCT116 5-FU Res). A synergistic effect was observed following treatment of CRC cells with an inhibitor of FOXM1, thiostrepton, in combination with 5-FU. The combination treatment decreased colony formation and migration, and induced cell cycle arrest, DNA damage, and apoptosis in CRC cell lines. In summary, this research demonstrated that FOXM1 plays a pivotal role in 5-FU resistance at least partially through the regulation of TYMS.

Journal article

Ferrari N, Ranftl R, Chicherova I, Slaven ND, Moeendarbary E, Farrugia AJ, Lam M, Semiannikova M, Westergaard MCW, Tchou J, Magnani L, Calvo Fet al., 2019, Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts, Nature Communications, Vol: 10, ISSN: 2041-1723

Aggressive behaviours of solid tumours are highly influenced by the tumour microenvironment. Multiple signalling pathways can affect the normal function of stromal fibroblasts in tumours, but how these events are coordinated to generate tumour-promoting cancer-associated fibroblasts (CAFs) is not well understood. Here we show that stromal expression of Dickkopf-3 (DKK3) is associated with aggressive breast, colorectal and ovarian cancers. We demonstrate that DKK3 is a HSF1 effector that modulates the pro-tumorigenic behaviour of CAFs in vitro and in vivo. DKK3 orchestrates a concomitant activation of β-catenin and YAP/TAZ. Whereas β-catenin is dispensable for CAF-mediated ECM remodelling, cancer cell growth and invasion, DKK3-driven YAP/TAZ activation is required to induce tumour-promoting phenotypes. Mechanistically, DKK3 in CAFs acts via canonical Wnt signalling by interfering with the negative regulator Kremen and increasing cell-surface levels of LRP6. This work reveals an unpredicted link between HSF1, Wnt signalling and YAP/TAZ relevant for the generation of tumour-promoting CAFs.

Journal article

Hong SP, Chan TE, Lombardo Y, Corleone G, Rotmensz N, Pruneri G, McEwen KR, Coombes RC, Barozzi I, Magnani Let al., 2018, Single-cell Transcriptomics reveals multi-step adaptations to endocrine therapy

<jats:title>Abstract</jats:title><jats:p>Resistant tumours are thought to arise from the action of Darwinian selection on genetically heterogenous cancer cell populations. However, simple clonal selection is inadequate to describe the late relapses often characterising luminal breast cancers treated with endocrine therapy (ET), suggesting a more complex interplay between genetic and non-genetic factors. Partially, this is due to our limited understanding on the effect of ET at the single cell level. In the present study, we dissect the contributions of clonal genetic diversity and transcriptional plasticity during the early and late phases of ET at single-cell resolution. Using single-cell RNA-sequencing and imaging we disentangle the transcriptional variability of plastic cells and define a rare sub-population of pre-adapted (PA) cells which undergoes further transcriptomic reprogramming and copy number changes to acquire full resistance. PA cells show reduced oestrogen receptor α activity but increased features of quiescence and migration. We find evidence for sub-clonal expression of this PA signature in primary tumours and for dominant expression in clustered circulating tumour cells. We propose a multi-step model for ET resistance development and advocate the use of stage-specific biomarkers.</jats:p>

Journal article

Perone Y, Farrugia AJ, Meira AR, Győrffy B, Ion C, Uggetti A, Patten D, Chronopoulos A, Faronato M, Shousha S, Steel JH, Davies C, Patel N, Rio Hernandez AD, Coombes C, Pruneri G, Lim A, Calvo F, Magnani Let al., 2018, SREBP1 drives KRT80-dependent cytoskeletal changes and invasive behavior in endocrine resistant ERα breast cancer

<jats:title>Abstract</jats:title><jats:p>Approximately 30% of women diagnosed with ERα breast cancer relapse with metastatic disease following adjuvant treatment with endocrine therapies<jats:sup>1,2</jats:sup>. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain (TAD)<jats:sup>3</jats:sup> undergoes epigenetic reprogramming in cells that develop resistance to aromatase inhibitors (AI), leading to keratin 80 (KRT80) upregulation. In agreement, an increased number of KRT80-positive cells are observed at relapse <jats:italic>in vivo</jats:italic> while KRT80 expression associates with poor outcome using several clinical endpoints. KRT80 expression is driven by <jats:italic>de novo</jats:italic> enhancer activation by sterol regulatory element-binding protein 1<jats:sup>4</jats:sup> (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion maturation and cellular stiffening, which collectively promote cancer cell invasion. Shear-wave elasticity imaging of prospective patients shows that KRT80 levels correlate with stiffer tumors <jats:italic>in vivo</jats:italic>. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.</jats:p>

Journal article

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