Biology subjects

Weiss, J. M.

Publications and source records attributed to Weiss, J. M..

16 recordsLinked to original sources

bioRxiv2026

Metabolic maintenance of breast cancer cells and metastases throughE-cadherin/YAP-dependent pyruvate carboxylase expression

Epithelial-mesenchymal transition (EMT) and glycolytic metabolism are well-characterized drivers of cancer progression and metastasis. However, most primary breast tumors and metastases express E-cadherin and the epithelial phenotype is associated with mitochondrial oxidative metabolism, yet the causality and relevance of these relationships and their underlying mechanisms remain poorly understood. Using a 3D culture model with mechano-stimulation, we found that E-cadherin promotes mitochondrial oxidative phosphorylation (OXPHOS) while reducing oxidative stress. Through pharmacological and genetic manipulations of inflammatory breast cancer (IBC) and/or triple negative breast cancer (TNBC) cell lines, we identified pyruvate carboxylase (PC) as an E-cadherin effector. Critically, restoring PC in E-cadherin-silenced cells rescued mitochondrial oxygen consumption and protection from oxidative stress. Co-expression of E-cadherin and PC was confirmed in breast cancer tissues and experimental lung metastases. Mechanistically, E-cadherin induced PC expression and OXPHOS via AKT-mediated activation of YAP/ /TEAD transcription factors, which are better known as supporting EMT. Clinically relevant AKT and TEAD inhibitors reduced both PC expression and oxidative respiration. Importantly, PC inhibition as monotherapy attenuated established experimental lung metastases and primary tumor burden in mice. Taken together, these findings reveal that E-cadherin-mediated cell-cell adhesions directly support mitochondrial metabolism through AKT-YAP/TEAD-PC signaling, identifying a therapeutic vulnerability in metastatic epithelial TNBC.

cancer biology↗

bioRxiv2026

Long-read MitoScope reveals tissue-resolved somatic mitochondrial variation and landscape of nuclear-embedded mitochondrial sequences

The mitochondrial genome (mtDNA), rich in repeats and prone to nuclear mitochondrial DNA segments (NUMTs), drives somatic mosaicism implicated in cancer, metabolic syndromes, and neurodegeneration, yet short-read sequencing yields incomplete catalogs, mapping artifacts, and false heteroplasmies. Here, we introduce MitoScope, a scalable long-read workflow to assemble mtDNA, perform high-fidelity variant calling, resolve heteroplasmy, and characterize NUMTs in benchmarking tissues from the Somatic Mosaicism Across Human Tissues (SMaHT) Network. MitoScope shows high sensitivity and precision, determines copy number, and uncovers low-frequency variants. We define an age- and tissue-dependent landscape of mtDNA mosaicism, including low-frequency pathogenic heteroplasmies, a bimodal heteroplasmy spectrum shaped by purifying selection, and age-accumulating deletions enriched for microhomology. Parallel profiling of NUMTs identifies high-confidence events with >2-fold more NUMTs than short-read surveys--with evidence of nonrandom trinucleotide contexts at breakpoints. These findings expose pervasive, tissue-resolved somatic mtDNA and NUMT instability with direct relevance for variant interpretation, aging, and human disease.

genomics↗

bioRxiv2026

Closed-loop error damping in human BCI using pre-error motor cortex activity

Intracortical brain-computer interfaces (BCIs) are used to decode motor intent from neural population activity; their main clinical application is to restore function for individuals with motor or communication deficits. However, when trying to reconstruct movement trajectories, such as in computer cursor control, even state-of-the-art decoders fall short of able-bodied performance during online BCI control. This calls for alternative approaches to improve the usability of motor BCIs. Here, we leveraged an error signal, i.e. a neural correlate of faulty motor control that can be detected from neural activity. By detecting this error signal in parallel to performing movement decoding, it is possible to perform error modulation, i.e. real-time error detection and correction during a closed-loop motor BCI task. We analyzed data from four individuals with upper limb impairment due to cervical spinal cord injury who each used an intracortical BCI to perform a continuous cursor control task with visual feedback. A classifier was trained to detect the error signal and was used to perform online error detection during BCI control to limit ongoing errors (defined as movement of the controller away from its target) without requiring any specific action from the participants. Our contribution is three-fold. First, we show that the error signal has a pre-error component. Cortical activity was already significantly modulated before the onset of the kinematically-defined error, theoretically allowing for earlier detection. Second, we show that error modulation significantly improves performance during online BCI control of cursor kinematics. Finally, we show that the error signal can be robustly leveraged across contexts, as error modulation improves performance in more complex motor tasks (involving for instance grasp and drag actions) or other environments without task-specific calibration. Overall, our results suggest that the error signal can be robustly disentangled from motor intent in cortical activity, and that even a simple linear classifier can enable error modulation in parallel to a continuous kinematic decoder, yielding more reliable and accurate BCI control.

neuroscience↗

bioRxiv2026

Donor-specific assemblies enhance somatic structural variant detection in complex genomic regions

Structural variants (SVs) contribute substantially to genomic variation and disease, but detecting somatic SVs (sSVs) remains difficult due to reference bias, mosaicism, and enrichment in repetitive regions. Linear reference genomes, like GRCh38 and CHM13, do not fully capture individual genomic structure, which can obscure true somatic variation. Donor-specific assemblies (DSAs) generated from the same genome where sSVs are being assayed provide a personalized alternative, yet their performance for sSV detection has not been systematically assessed. As part of the Somatic Mosaicism across Human Tissues (SMaHT) Network, we benchmark a DSA for sSV discovery in the COLO829 melanoma cell line with a matched normal sample from the same individual. We compare sSV detection across GRCh38, CHM13, and the COLO829BL_DSA using three different sSV callers (Delly, Severus, and Sniffles2) and sequence data from multiple long-read platforms. The COLO829BL_DSA identifies 1.8-fold more manually validated sSVs than linear references, in regions both shared with GRCh38 and CHM13 and unique to the COLO829BL_DSA. Variants detected only with the COLO829BL_DSA are often found in satellite and other repeat-rich regions that are difficult to resolve using standard references. In addition, several COLO829BL_DSA-specific sSVs are located in genes, some of which are associated with cancer. Overall, these results underscore the utility of DSAs in improving sSV detection.

genomics↗

bioRxiv2025

A telomere-to-telomere map of somatic mutation burden and functional impact in cancer

Oncogenesis involves widespread genetic and epigenetic alterations, yet the full spectrum of somatic variation genome-wide remains unresolved. We generated a near-telomere-to-telomere (T2T) diploid assembly of a donor paired with deep short- and long-read sequencing of their melanoma. This revealed that 16% of somatic variants occur in sequences absent from GRCh38, with satellite repeats acting as hotspots for UV-induced damage due to sequence-intrinsic mutability and inefficient repair. Centromere kinetochore domains emerged as focal sites of structural, genetic, and epigenetic variation, leading to remodeling of centromere kinetochore binding domains during tumor evolution. Single-molecule telomere reconstructions uncovered cycles of attrition, deletion, and telomerase-mediated extension that shape cancer telomeres. Finally, diploid chromatin maps exposed that copy number alterations and epimutations, rather than point mutations, predominate in rewiring cancer regulatory programs. These findings define the full landscape of a cancers somatic variation and their functional impact, establishing a blueprint for T2T studies of mosaicism.

genomics↗

bioRxiv2025

A simple liquid 3D cell culture paradigm models oxidative mitochondrial metabolism of epithelial breast cancer cells with relevance for lung metastases.

Three-dimensional (3D) cell culture systems have emerged as powerful tools for modeling tumor biology in ex vivo settings. However, the diverse array of available 3D culture methods presents challenges in selecting the most appropriate model for specific research questions. This study provides a comparative analysis of breast cancer cells (SUM149, IBC-3, and MDA-MB-468) in the mammosphere culture (SphC) model or an "emboli" culture (EmC) model, which enrich for cancer stem cells and epithelial features, respectively. The EmC model, designed originally for inflammatory breast cancer, is characterized by media viscosity and mechanical rocking of the culture vessel. Notably, cells in EmC showed a distinct and durable reduction in cell proliferation ex vivo while demonstrating increased capacity to establish experimental lung metastases in vivo. Ultrastructural quantitative analysis of electron microscopy images suggested that cells in EmC acquire nuclear and mitochondrial features that resemble those of tumor tissue. Proteomics, single-cell transcriptomics, and metabolic flux analyses showed that cells in EmC and SphC favor mitochondrial oxidative metabolism (OXPHOS) and glycolysis, respectively. EmC rendered cells hypersensitive to OXPHOS inhibition, but more resistant to oxidative stress. Several genes associated with lung metastasis, including ID1, were specifically enriched in EmC. Given the emerging role of OXPHOS in cancer cell survival during dissemination and as established metastases, we propose that the EmC paradigm is a suitable ex vivo model to study signaling pathways relevant for tumor tissue and to assess drug sensitivities and resistance mechanisms of metastatic breast cancer cells ex vivo. SIGNIFICANCEThis study provides an in-depth characterization of a resource-efficient yet powerful 3D culture paradigm to improve the physiological relevance of ex vivo approaches. Applicable to epithelial cancers, this model offers a platform to accelerate the discovery of physiologically relevant signaling pathways and specific cancer cell vulnerabilities.

cancer biology↗

bioRxiv2024

Hematological phenotypes in GATA2 deficiency syndrome arise from secondary injuries and maladaptation to proliferation

The GATA2 transcription factor is a pivotal regulator of hematopoiesis. Disruptions in the GATA2 gene drive severe hematologic abnormalities and are associated with an increased risk of myelodysplastic syndromes and acute myeloid leukemia; however, the mechanisms underlying the pathophysiology of GATA2 deficiency remain still unclear. We developed two different mouse models that are based on serial and limiting donor cell transplantation of (aged) GATA2 haploinsufficient cells and mirror the symptoms of GATA2 deficiency. Similar to what has been observed in patients, our models show that GATA2 haploinsufficiency leads to B lymphopenia, monocytopenia, lethal bone marrow failure (BMF), myelodysplasia and leukemia. Leukemia arises exclusively as a result of BMF, driven by somatic aberrations and accompanied by increased Myc target expression and genomic instability. These findings were confirmed in human GATA2+/- K562 cell lines showing defects in cytokinesis and are in line with the fact that monosomy 7 and trisomy 8 are frequent events in patients with MDS. Key pointsO_LIIn a mouse model for GATA2 deficiency, leukemia emerges from bone marrow failure C_LIO_LIMaladaptation to proliferative signals and chromosomal segregation defects contribute to the hematological phenotypes in GATA2 deficiency C_LI

cell biology↗

bioRxiv2024

Restraint of melanoma progression by cells in the local skin environment

Keratinocytes, the dominant cell type in the melanoma microenvironment during tumor initiation, exhibit diverse effects on melanoma progression. Using a zebrafish model of melanoma and human cell co-cultures, we observed that keratinocytes undergo an EMT-like transformation in the presence of melanoma, reminiscent of their behavior during wound healing. Surprisingly, overexpression of the EMT transcription factor Twist in keratinocytes led to improved overall survival in zebrafish melanoma models, despite no change in tumor initiation rates. This survival benefit was attributed to reduced melanoma invasion, as confirmed by human cell co-culture assays. Single-cell RNA-sequencing revealed a unique melanoma cell cluster in the Twist-overexpressing condition, exhibiting a more differentiated, less invasive phenotype. Further analysis nominated homotypic jam3b-jam3b and pgrn-sort1a interactions between Twist-overexpressing keratinocytes and melanoma cells as potential mediators of the invasive restraint. Our findings suggest that EMT in the tumor microenvironment may paradoxically limit melanoma invasion through altered cell-cell interactions.

cancer biology↗

bioRxiv2023

Biomimetic multi-channel microstimulation of somatosensory cortex conveys high resolution force feedback for bionic hands

AO_SCPLOWBSTRACTC_SCPLOWManual interactions with objects are supported by tactile signals from the hand. This tactile feedback can be restored in brain-controlled bionic hands via intracortical microstimulation (ICMS) of somatosensory cortex (S1). In ICMS-based tactile feedback, contact force can be signaled by modulating the stimulation intensity based on the output of force sensors on the bionic hand, which in turn modulates the perceived magnitude of the sensation. In the present study, we gauged the dynamic range and precision of ICMS-based force feedback in three human participants implanted with arrays of microelectrodes in S1. To this end, we measured the increases in sensation magnitude resulting from increases in ICMS amplitude and participants ability to distinguish between different intensity levels. We then assessed whether we could improve the fidelity of this feedback by implementing "biomimetic" ICMS-trains, designed to evoke patterns of neuronal activity that more closely mimic those in natural touch, and by delivering ICMS through multiple channels at once. We found that multi-channel biomimetic ICMS gives rise to stronger and more distinguishable sensations than does its single-channel counterpart. Finally, we implemented biomimetic multi-channel feedback in a bionic hand and had the participant perform a compliance discrimination task. We found that biomimetic multi-channel tactile feedback yielded improved discrimination over its single-channel linear counterpart. We conclude that multi-channel biomimetic ICMS conveys finely graded force feedback that more closely approximates the sensitivity conferred by natural touch.

neuroscience↗

bioRxiv2022

Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimers disease

Accumulation of hyperphosphorylated tau in the locus coeruleus (LC) is a ubiquitous feature of prodromal Alzheimers disease (AD), and LC neurons degenerate as AD progresses. Tau-mediated LC dysfunction may contribute to early neuropsychiatric symptoms, while loss of LC integrity is associated with conversion to cognitive impairment. Hyperphosphorylated tau alters firing rates in other brain regions, but its effects on LC neurons have not been described. The purpose of this study was to characterize changes in firing properties of LC neurons when they are the only cells containing hyperphosphorylated tau, as well as later in disease when {beta}-amyloid (A{beta}) and tau pathology is abundant in the forebrain. Single unit LC activity was recorded from anesthetized wild-type (WT) and TgF344-AD rats, which carry the APP/PS1 transgene. Similar to human AD, these rats develop hyperphosphorylated tau in the LC (at 6 months) prior to A{beta} or tau pathology in forebrain regions (at 12-15 months). At baseline, LC neurons from TgF344-AD rats were hypoactive at both ages compared to WT littermates, but showed elevated spontaneous bursting properties, particularly in younger animals. Differences in footshock-evoked LC firing depended on age, with 6-month TgF344-AD rats demonstrating aspects of hyperactivity, and aged transgenic rats showing hypoactivity relative to WT. Tau-induced alterations in LC firing rates may contribute to the pathophysiology of AD, with early hyperactivity associated with prodromal symptoms, followed by hypoactivity contributing to cognitive impairment. These results support further investigation into disease stage-dependent noradrenergic interventions for AD. HighlightsO_LIRecorded locus coeruleus (LC) neurons in a rat model of Alzheimers disease (AD) C_LIO_LITgF344-AD rats develop early endogenous LC tau pathology akin to human AD C_LIO_LI6- and 15-month TgF344-AD rats had reduced tonic LC firing C_LIO_LILC neurons from 6-month TgF344-AD rats were hyperactive in response to footshock C_LIO_LILC neuron dysfunction may contribute to AD symptoms C_LI

neuroscience↗

bioRxiv2020

Anatomic position determines oncogenic specificity in melanoma

Oncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programs in the cell of origin. Here, we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet, or under the nails3. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma but CRKL amplifications in acral melanoma. We modeled these changes in transgenic zebrafish models and found that CRKL-driven tumors predominantly formed in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin/limb melanocytes, compared to body melanocytes, revealed a positional identity gene program typified by posterior HOX13 genes. This positional gene program synergized with CRKL to drive tumors at acral sites. Abrogation of this CRKL-driven program eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.

cancer biology↗

bioRxiv2020

Spatial transcriptomics reveals the architecture of the tumor/microenvironment interface

During tumor progression, cancer cells come into contact with novel non-tumor cell types, but it is unclear how tumors adapt to these new environments. Here, we integrate spatially resolved transcriptomics, single-cell RNA-seq, and single-nucleus RNA-seq to characterize tumor-microenvironment interactions at the tumor boundary. Using a zebrafish model of melanoma, we identify a distinct "interface" cell state where the tumor contacts neighboring tissues. This interface is composed of specialized tumor and microenvironment cells that upregulate a common set of cilia genes, and cilia proteins are enriched only where the tumor contacts the microenvironment. Cilia gene expression is regulated by ETS-family transcription factors, which normally act to suppress cilia genes outside of the interface. An ETS-driven interface is conserved in human patient samples, suggesting it is a conserved feature of human melanoma. Our results demonstrate the power of spatially resolved transcriptomics in uncovering mechanisms that allow tumors to adapt to new environments.

cancer biology↗

bioRxiv2020

Perceptual responses to microstimulation frequency are spatially organized in human somatosensory cortex

Microstimulation in the somatosensory cortex can evoke artificial tactile percepts and can be incorporated into bidirectional brain-computer interfaces (BCIs) to restore function after injury or disease. However, little is known about how stimulation parameters themselves affect perception. Here, we stimulated through microelectrode arrays implanted in the somatosensory cortex of a human participant with a cervical spinal cord injury and varied the stimulus amplitude, duration, and frequency. Increasing the amplitude and duration increased the perceived intensity on all tested electrodes. Surprisingly, we found that increasing the frequency evoked more intense percepts on some electrodes but evoked less intense percepts on most electrodes. Electrodes divided into three groups which evoked distinct perceptual qualities that depended on the stimulus frequency and were spatially organized in cortex. These results contribute to our growing understanding of the structure and function of the somatosensory cortex and will facilitate principled development of stimulation strategies for bidirectional BCIs.

neuroscience↗

bioRxiv2020

Developmental chromatin programs determine oncogenic competence in melanoma

Oncogenes are only transforming in certain cellular contexts, a phenomenon called oncogenic competence. The mechanisms regulating this competence remain poorly understood. Here, using a combination of a novel human pluripotent stem cell (hPSC)-based cancer model along with zebrafish transgenesis, we demonstrate that the transforming ability of BRAFV600E depends upon the intrinsic transcriptional program present in the cell of origin. Remarkably, in both systems, melanocytes (MC) are largely resistant to BRAF. In contrast, both neural crest (NC) and melanoblast (MB) populations are readily transformed. Molecular profiling reveals that NC/MB cells have markedly higher expression of chromatin modifying enzymes, and we discovered that the chromatin remodeler ATAD2 is required for response to BRAF and tumor initiation. ATAD2 forms a complex with SOX10, allowing for expression of downstream oncogenic programs. These data suggest that oncogenic competence is mediated by developmental regulation of chromatin factors, which then allow for proper response to those oncogenes.

cancer biology↗

bioRxiv2019

Restored tactile sensation improves neuroprosthetic arm control

Summary paragraphThe sense of touch is critical for skillful hand control1-3, but is largely missing for people who use prosthetic devices. Instead, prosthesis users rely heavily on visual feedback, even though state transitions that are necessary to skillfully interact with objects, such as object contact, are relayed more precisely through tactile feedback4-6. Here we show that restoring tactile sensory feedback, through intracortical microstimulation of the somatosensory cortex7, enables a person with a bidirectional intracortical brain-computer interface to improve their performance on functional object transport tasks completed with a neurally-controlled prosthetic limb. The participant had full visual feedback and had practiced the task for approximately two years prior to these experiments. Nevertheless, successful trial times on a commonly used clinical upper limb assessment task were reduced from a median time of 20.9 s (13.1 - 40.5 s interquartile range) to 10.2 s (5.4 - 18.1 s interquartile range) when vision was supplemented with microstimulation-evoked cutaneous percepts that were referred to different fingers and were graded in intensity based on real-time prosthesis contact forces. Faster completion times were primarily due to a reduction in the amount of time spent attempting to grasp objects. These results demonstrate the importance of tactile sensations in upper-limb control and the utility of creating bidirectional brain-computer interfaces to restore this stream of information using intracortical microstimulation.

clinical trials↗

bioRxiv2018

TGFβ blocks STING-induced IFNα/ β release and tumor rejection in spontaneous mammary tumors

Type I interferons (IFN) are being rediscovered as potent anti-tumoral agents. Activation of the STimulator of INterferon Genes (STING) by DMXAA can induce a strong production of IFN/{beta} and the rejection of transplanted primary tumors. In the present study, we addressed whether targeting STING with DMXAA also leads to the regression of spontaneous MMTV-PyMT mammary tumors. We show that these tumors are refractory to DMXAA-induced regression. This is due to a blockade in the phosphorylation of IRF3 and the ensuing IFN/{beta} production. Mechanistically, we identified TGF{beta} abundant in spontaneous tumors, as a key molecule limiting this IFN-induced-tumor regression by DMXAA. Finally, blocking TGF{beta} restores the production of IFN by activated MHCII+ tumor-associated macrophages, and enables tumor regression induced by STING activation. On the basis of these findings, we propose that type I IFN-dependent cancer therapies could be greatly improved by combinations including the blockade of TGF{beta}.

cancer biology↗