Biology subjects

Hamer, S.

Publications and source records attributed to Hamer, S..

5 recordsLinked to original sources

bioRxiv2025

The Role of Phenotypic Plasticity in Adaptation to Treatment and Prospective Plasticity Drivers in Hepatoblastoma

Hepatoblastoma (HB) is a paediatric liver cancer, associated with one of the lowest mutational burdens compared to other cancers. Despite this, HBs exhibit diverse phenotypes. It has been proposed that hijacking of early developmental plasticity is especially relevant to chemotherapy response in childhood cancers, however the underlying mechanisms of plasticity in HB remain poorly understood. Plasticity in HB requires investigation after treatment at a more granular temporal scale to further elucidate its role in treatment adaptation. In this work, we aim to study the role of plasticity in treatment adaptation and its underlying mechanisms by integrating heritable and expressed static DNA barcode technology with single-cell sequencing. The synergy between these approaches allows for simultaneous lineage tracing of single clones and phenotyping of single cells. We identify the phenotypic states that exist in HB preclinical models and explore the phenotypic transitions that occur following treatment, which could be important for cells to survive, persist and eventually recover. Expression and accessibility landscapes reveal prospective targets that could be markers or drivers of the plasticity which enables treatment adaptation in HB. By homing in on the clonal, transcriptomic and epigenetic dynamics post treatment, these results examine in greater detail the role of plasticity in treatment adaptation in HB.

cancer biology↗

bioRxiv2024

Serial 'deep-sampling PCR of fragmented DNA reveals the wide range of Trypanosoma cruzi burden among chronically infected hosts and allows accurate monitoring of parasite load following treatment

Infection with the protozoan parasite Trypanosoma cruzi is generally well-controlled by host immune responses, but appears to be rarely eliminated. The resulting persistent, low-level infection results in cumulative tissue damage with the greatest impact generally in the heart in the form of chagasic cardiomyopathy. The relative success in immune control of T. cruzi infection usually averts acute phase death but has the negative consequence that the low-level presence of T. cruzi in hosts is challenging to detect unequivocally. Thus, it is difficult to identify those who are actively infected and, as well, problematic to gauge the impact of treatment, particularly in the evaluation of the relative efficacy of new drugs. In this study we employ DNA fragmentation and high numbers of replicate PCR reaction ( deep-sampling) to extend the quantitative range of detecting T. cruzi in blood by at least 3 orders of magnitude relative to current protocols. When combined with sampling blood at multiple time points, deep sampling of fragmented DNA allowed for detection of T. cruzi in all infected hosts in multiple host species. In addition, we provide evidence for a number of characteristics not previously rigorously quantified in the population of hosts with naturally acquired T. cruzi infection, including, a > 6-log variation between chronically infected individuals in the stable parasite levels, a continuing decline in parasite load during the second and third years of infection in some hosts, and the potential for parasite load to change dramatically when health conditions change. Although requiring strict adherence to contamination-prevention protocols and significant resources, deep-sampling PCR provides an important new tool for assessing new therapies and for addressing long-standing questions in T. cruzi infection and Chagas disease. Author SummaryInfection by the protozoan Trypanosoma cruzi normally results in a life-long, but low-level parasitization of muscle tissues, often leading to chagasic heart disease. A major challenge in the Chagas disease field has been the difficulty in detecting and quantifying parasite load in infected hosts. In this study we show that collection of serial blood samples and performance of sometimes high numbers of replicate PCR reactions on fragmented blood DNA, allows detection and quantification of relative parasite load in non-human primates, dogs, and humans with naturally acquired T. cruzi infection. This deep-sampling approach reveals a mostly stable, 100,000-fold or greater difference in parasite load among chronically infected hosts and can detect alterations in parasite levels due to changes in health status or following therapeutic treatment in individual hosts, thus providing a powerful tool for assessing treatment outcomes in T. cruzi infection, including for evaluation of new therapeutics. Additionally, the ability to accurately and sensitively monitor parasite load in hosts provides the means to address highly contentious issues in the Chagas field, including the relative role of parasites and hosts in establishing the persistent parasite burden and the relationship between parasite burden and the presence and severity of clinical disease.

microbiology↗

bioRxiv2024

Chemotherapy-driven de novo Wnt pathway activation dictates a dynamic shift to a drug-tolerant state in breast cancer cells

The efficacy of chemotherapy is often hindered by the enrichment of a population of cancer cells that enter a drug-tolerant persister (DTP) state, mimicking embryonic diapause, yet the underlying mechanisms of this transition remain poorly understood. This study demonstrates that both parental and chemotherapy-induced Wnt-active (WntHigh) cells in Triple-negative breast cancer exhibit transcriptional and functional properties characteristic of DTP cells, including a diapause transcriptional signature, reduced MYC expression, reversible restricted proliferation, and pronounced chemoresistance. Our findings reveal that the de novo activation of the Wnt signaling pathway, triggered by the transcriptional upregulation of components essential for canonical Wnt ligand-secretion and -activation, is critical for enriching the diapause-DTP (DTPDiap) population across various chemotherapy regimens. The diapause-DTP/WntHigh population can be selectively ablated by concomitant, rather than sequential, pharmacological inhibition of Wnt ligand-secretion alongside chemotherapy, highlighting new vulnerabilities in DTPDiap cell-emergence and potentially yielding a therapeutic opportunity against DTPs. This study shows that activation of Wnt signaling pathway is sufficient and necessary for the induction of a DTPDiap state and enhances our understanding of the introductory mechanisms driving DTP cell-enrichment upon chemotherapy.

cancer biology↗

bioRxiv2023

Dynamic Plasticity Systems Direct Early Adaptation to Treatment in Neuroblastoma

Neuroblastoma, like many aggressive cancers, exhibits phenotypic heterogeneity, contributing to therapy resistance and disease progression. However, direct evidence of how phenotypic plasticity influences tumour evolution remains limited. Using a multi-resolution quantitative approach, we define the principles, types, and dynamics of plasticity in neuroblastoma at unprecedented resolution. We demonstrate that intrinsic plasticity is a model-dependent process that enables the coexistence of drug-sensitive and drug-resistant states in environmentally stable conditions, positioning plasticity as a bet-hedging strategy that allows tumours to anticipate environmental changes. Additionally, we show plasticity varies across lineages and single-cell-derived clones, establishing that it is not merely an induced response but a heritable and selectable trait. By simultaneously mapping plasticity at and clonal dynamics in evolving neuroblastoma populations, we show plasticity is shaped by selective pressures, reinforcing its role as a fundamental driver of neuroblastoma evolution in a treatment- and genetic background-dependent manner. We define three distinct modes of plasticityled adaptation. In the selection of the plasticity model, strong selective pressure temporarily constrains phenotypic transitions, but they reemerge with greater dynamics once the stressor is removed, favouring the selection of highly plastic clones. In the adaptive plasticity model, phenotypic transitions actively reshape tumour heterogeneity, allowing for rapid adaptation to treatment while minimising the impact of clonal selection. Finally, in the plasticity equilibrium model, phenotypic transitions persist at baseline, maintaining a state of phenotypic fluidity, with clonal selection ultimately dictating tumour evolution. These findings highlight the diverse, context-dependent strategies that neuroblastoma populations employ to navigate selective pressures and therapy resistance, emphasizing the need for plasticity-targeting therapeutic approaches to disrupt tumour adaptation and improve treatment outcomes. TeaserNatural selection and phenotypic transitions shape adaptive evolution, guiding neuroblastoma survival under treatment pressure.

cancer biology↗

bioRxiv2022

Prophylactic low-dose, bi-weekly benznidazole treatment fails to prevent Trypanosoma cruzi infection in dogs under intense transmission pressure

Trypanosoma cruzi naturally infects a wide variety of wild and domesticated mammals, in addition to humans. Depending on the infection dose and other factors, the acute infection can be life-threatening, and in all cases, the risk of chagasic heart disease is high in persistently infected hosts. Domestic, working, and semi-feral dogs in the Americas are at significant risk of T. cruzi and in certain settings in the southern United States, the risk of new infections can exceed 30% per year, even with the use of vector control protocols. In this study, we explored whether intermittent low-dose treatment with the trypanocidal compound benznidazole (BNZ) during the transmission season, could alter the number of new infections in dogs in an area of known, intense transmission pressure. Preliminary studies in mice suggested that twice-weekly administration of BNZ could prevent or truncate infections when parasites were delivered at the mid-point between BNZ doses. Pre-transmission season screening of 126 dogs identified 53 dogs (42.1%) as T. cruzi infection positive, based upon blood PCR and Luminex-based serology. Serial monitoring of the 67 uninfected dogs during the high transmission season (May to October) revealed 15 (22.4%) new infections, 6 in the untreated control group and 9 in the group receiving BNZ prophylaxis, indicating no impact of this prophylaxis regimen on the incidence of new infections. Although these studies suggest that rigorously timed and more potent dosing regimen may be needed to achieve an immediate benefit of prophylaxis, additional studies would be needed to determine if drug prophylaxis reduced disease severity despite this failure to prevent new infections. Author SummaryTrypanosoma cruzi, the parasite that causes Chagas disease, circulates extensively in the southern U.S. and working dog populations in south-central Texas are at very high risk of infection, and morbidity and early mortality due to this infection. In this study, we used low level administration of an FDA-approved drug during the transmission season to attempt to prevent new infections in these dogs. Although that effort failed, the study revealed new information about the transmission dynamics and generation of antibody responses and immune control of infection in this high-transmission setting.

microbiology↗