Biology subjects

Giersch, R. M.

Publications and source records attributed to Giersch, R. M..

6 recordsLinked to original sources

bioRxiv2026

Active and Passive Mechanical Deficits Precede Spinal Curvature in a Zebrafish Model of Idiopathic Scoliosis

Idiopathic scoliosis is a common spinal disorder characterized by progressive three-dimensional curvature of unknown cause. Although biomechanical imbalance has long been proposed to contribute to scoliosis, the early physiological states that precede curvature onset remain poorly understood. Here, we investigated this problem using zebrafish uts2r3 mutants, which develop fully penetrant juvenile-onset spinal curvature following disruption of urotensin signaling. Transcriptomic analysis before curvature revealed altered expression of muscle-associated genes, suggesting that Uts2r3 influences axial muscle development or function. However, immunofluorescence, birefringence imaging, and quantitative analysis of myotome morphology showed that mutants lack overt muscle architectural defects or dystrophic pathology. By contrast, direct measurements of isolated larval trunks revealed pre-curvature biomechanical abnormalities: namely, uts2r3 mutants generated reduced active force following electrical stimulation while also exhibiting increased passive resistance to stretch. These findings identify urotensin signaling as a regulator of axial tissue biomechanics during growth and suggest that scoliosis-like curvature can arise from an early imbalance between active force generation and passive tissue stiffness. SignificanceSpinal curvature is common, but the biological events that cause the spine to bend during growth remain poorly understood. Animal models, especially zebrafish, make it possible to study these events before curvature begins. Zebrafish lacking urotensin signaling develop spinal curves that arise during juvenile growth, similar to idiopathic scoliosis in humans. Here, we demonstrate that zebrafish lacking the urotensin pathway receptor Uts2r3 develop an abnormal biomechanical state prior to curve onset. Their axial tissues generate less active force when contracting and, at the same time, show increased passive resistance to stretch--an unexpected combination that reveals a distinct pre-curvature biomechanical state. These findings suggest that spinal curvature can arise from an early imbalance in tissue mechanics during growth and identify urotensin signaling as a pathway that helps preserve spinal morphology through a biomechanical mechanism.

developmental biology↗

bioRxiv2025

Variation in Natural Infection Outcomes and Cancer Cell Release from Soft-Shell Clams (Mya arenaria) with Bivalve Transmissible Neoplasia

Bivalve transmissible neoplasias (BTNs) are leukemia-like cancers found in at least 10 bivalve species, in which the cancer cells themselves transfer from one individual to another, spreading as an unusual form of infectious disease. Before the infectious etiology was known, there were reports of lethality and outbreaks of cancer in the soft-shell clam (Mya arenaria) on the east coast of North America. Using sensitive and specific qPCR assays, we followed the progression of BTN in naturally-infected soft-shell clams from Maine, USA. We observed variable outcomes, with about half of clams (9/21) progressing to high levels of cancer and death, about half exhibiting long-term non-progression (11/21), and a single animal showing regression of cancer. We also observe a significant decrease in survival in animals that progress to >10% cancer in their hemolymph, while we see no effect on survival in clams with BTN that are long-term non-progressors. As most bivalves do not physically contact each other, and BTN cells can survive in seawater, it has been proposed that BTN is spread through release of cancer cells into the water. We used qPCR to detect BTN-specific DNA in environmental DNA (eDNA) in the tanks of animals throughout this experiment. We show that cancer cell release can be detected in tank water of most clams with >24% cancer in their hemolymph, but not below this level. Cancer cell release is variable and occurs in bursts, but above 24% detection in eDNA correlates with progression of cancer in the hemolymph. This study demonstrates both the lethality of BTN and the presence of a block to the progression of BTN in a large portion of clams in a population with enzootic disease. This also further supports the hypothesis that BTN cells transmit through seawater and provides insights into the mechanisms of the transmission dynamics.

cancer biology↗

bioRxiv2024

Identification of an Outbreak of Bivalve Transmissible Neoplasia in Soft-Shell Clams (Mya arenaria) in the Puget Sound Using Hemolymph and eDNA Surveys

Bivalve transmissible neoplasia (BTN) is one of three known types of naturally transmissible cancer-- cancers in which the whole cancer cells move from individual to individual, spreading through natural populations. BTN is a lethal leukemia-like cancer that has been observed throughout soft-shell clam (Mya arenaria) populations on the east coast of North America, with two distinct sublineages circulating at low enzootic levels in New England, USA, and Prince Edward Island, Canada. Major cancer outbreaks likely due to Mya arenaria BTN (MarBTN) were reported in 1980s and the 2000s and the disease has been observed since the 1970s, but it has not been observed in populations of this clam species on the US west coast. In 2022, we collected soft-shell clams from several sites in Puget Sound, Washington, USA, and unexpectedly found high prevalence of BTN in two sites (Triangle Cove on Camano Island and near Stanwood in South Skagit Bay). Prevalence of BTN increased in subsequent years, reaching >75% in both sites in 2024, while it was not observed in other sites, suggesting the early stages of a severe disease outbreak following recent introduction. We observed that these cancer cells contain several somatic transposing insertion sites found only in the USA-sublineage of MarBTN, showing that it likely was recently transplanted from New England to this location. We then developed a sensitive environmental DNA (eDNA) assay, using qPCR to target somatic mutations in the MarBTN mitogenome, and showed that MarBTN can be detected in seawater at Triangle Cove, as well as several kilometers outside of the cove. We then used this assay to survey 50 sites throughout Puget Sound, confirming that the disease can be detected at high levels at Triangle Cove and South Skagit Bay, and showing that it extends beyond these known sites. However, while normal soft-shell clam mtDNA was widely detected, MarBTN was undetectable throughout most of Puget Sound and currently remains limited to the South Skagit Bay area and north Port Susan. These results identify a previously unknown severe outbreak of a transmissible cancer due to long-distance transplantation of disease from another ocean, and they demonstrate the utility of eDNA methods to track the spread of BTN through the environment.

ecology↗

bioRxiv2023

Multiple lineages of transmissible neoplasia in the basket cockle (Clinocardium nuttallii) with repeated horizontal transfer of mitochondrial DNA

Transmissible cancers are clonal lineages of neoplastic cells able to infect multiple hosts, spreading through populations in the environment as an infectious disease. Transmissible cancers have been identified in Tasmanian devils, dogs, and bivalves. Several lineages of bivalve transmissible neoplasias (BTN) have been identified in multiple bivalve species. In 2019 in Puget Sound, Washington, USA, disseminated neoplasia was observed in basket cockles (Clinocardium nuttallii), a species that is important to the culture and diet of the Suquamish Tribe as well as other tribes with traditional access to the species. To test whether disseminated neoplasia in cockles is a previously unknown lineage of BTN, a nuclear locus was amplified from cockles from Agate Pass, Washington, and sequences revealed evidence of transmissible cancer in several individuals. We used a combination of cytology and quantitative PCR to screen collections of cockles from eleven locations in Puget Sound and along the Washington coastline to identify the extent of contagious cancer spread in this species. Two BTN lineages were identified in these cockles, with one of those lineages (CnuBTN1) being the most prevalent and geographically widespread. Within the CnuBTN1 lineage, multiple nuclear loci support the conclusion that all cancer samples form a single clonal lineage. However, the mitochondrial alleles in each cockle with CnuBTN1 are different from each other, suggesting mitochondrial genomes of this cancer have been replaced multiple times during its evolution, through horizontal transmission. The identification and analysis of these BTNs are critical for broodstock selection, management practices, and repopulation of declining cockle populations, which will enable continued cultural connection and dietary use of the cockles by Coast Salish Tribes.

cancer biology↗

bioRxiv2022

Centuries of genome instability and evolution in soft-shell clam transmissible cancer

Transmissible cancers are infectious parasitic clones of malignant cells that metastasize to new hosts, living past the death of the founder animal in which the cancer initiated. Several lineages of transmissible cancer have recently been identified in bivalves, including one that has spread through the soft-shell clam (Mya arenaria) population along the east coast of North America. To investigate the evolutionary history of this transmissible cancer lineage, we assembled a highly contiguous 1.2 Gb soft-shell clam reference genome and characterized somatic mutations from cancer sequences. We show that all cancer cases observed descend from a single founder and cluster into two geographically distinct sub-lineages. We discover a previously unreported clock-like mutational signature that predicts the cancer lineage to be 344 to 877 years old, indicating that it spread undetected long before it was first observed in the 1970s. We observe high mutation density, widespread copy number gain, structural rearrangement, loss of heterozygosity, variable telomere lengths, mitochondrial genome expansion, and transposable element activity, all indicative of an unstable cancer genome. Our study reveals the ability for an invertebrate cancer lineage to survive for centuries while its genome continues to structurally mutate, likely contributing to the ability of this lineage to adapt as a parasitic cancer. SUMMARYThe genome of a contagious cancer in clams reveals structural instability of multiple types throughout the [~]500 years since its origin.

cancer biology↗

bioRxiv2021

Survival and detection of bivalve transmissible neoplasia from the soft-shell clam Mya arenaria (MarBTN) in seawater

Many pathogens can cause cancer, but cancer itself does not normally act as an infectious agent. However, transmissible cancers have been found in a few cases in nature: in Tasmanian devils, dogs, and several bivalve species. The transmissible cancers in dogs and devils are known to spread through direct physical contact, but the exact route of transmission of bivalve transmissible neoplasia (BTN) has not yet been confirmed. It has been hypothesized that cancer cells could be released by diseased animals and spread through the water column to infect/engraft into other animals. To test the feasibility of this proposed mechanism of transmission, we tested the ability of BTN cells from the soft-shell clam (Mya arenaria BTN, or MarBTN) to survive in artificial seawater. We found that BTN cells are highly sensitive to salinity, with acute toxicity at salinity levels lower than those found in their environment. BTN cells also survive longer at lower temperatures, with >48% of cells surviving a week in seawater at temperatures from 4{degrees}C to 16{degrees}C, and 49% surviving for more than two weeks at 4{degrees}C. With one clam donor, living cells were observed for more than eight weeks at 4{degrees}C. We also used qPCR of environmental DNA (eDNA) to detect the presence of BTN-specific DNA in the environment. We observed release of BTN-specific DNA into the water of aquaria from tanks with highly BTN-positive clams, and we detected BTN-specific DNA in seawater samples collected from BTN-endemic areas, although the level detected was much lower. Overall, these data show that BTN cells can survive well in seawater, and they are released into the water by diseased animals, supporting the hypothesis that BTN is spread from animal-to-animal by cells through seawater.

cancer biology↗