Biology subjects

Wu, J. X.

Publications and source records attributed to Wu, J. X..

4 recordsLinked to original sources

bioRxiv2025

Patient-derived organoids reveal hypoxia-driven plasticity and therapeutic vulnerabilities in pheochromocytomas and paragangliomas

Pheochromocytomas and paragangliomas (PPGLs) are rare chromaffin cell-derived neuroendocrine tumors of sympathetic (catecholamine-producing) or parasympathetic (nonsecretory) origin, frequently driven by dysregulation of hypoxia-inducible factor (HIF) signaling, particularly HIF-2. Although often benign, PPGLs can metastasize unpredictably, with limited therapeutic options once disseminated. Progress has been hindered by the lack of robust preclinical models, especially those that capture their molecular complexity and microenvironmental influences. To address this gap, we established patient-derived tumor organoids (PDOs) from 35 PPGLs, encompassing a broad spectrum of clinical and molecular phenotypes. The organoids retained key immunohistochemical, genomic, transcriptomic, and catecholamine-secretory features of their parental tumors. PPGL organoids cultured under hypoxic conditions generally exhibited enhanced viability, supporting hypoxia as a driver of cell survival. Hypoxia activated HIF-1 and expanded ASCL1+ cell populations, suggesting a lineage shift toward an immature chromaffin state. In contrast, long-term normoxic cultures activated hypoxia inducible factor 2 (HIF-2) and acquired a hybrid sympathoblast-mesenchymal identity in subpopulations with upregulation of extracellular matrix and cell cycle markers, independent of genotype. These features resemble high-risk neuroblastoma subtypes and establish a molecular parallel suggestive of shared lineage plasticity and pathogenic programs, detectable in primary PPGLs. Drug screening across a library of up to 51 drugs and combinations revealed both shared and unique vulnerabilities, with response rates to approved therapies matching clinical observations. The CDK4/6 inhibitor abemaciclib, previously unexplored in PPGLs, elicited the strongest activity. Abemaciclib-responsive PDOs and their matched tumors, including a metastatic sample, exhibited epithelial mesenchyme transition enrichment, nominating potential biomarkers for patient stratification. Our results establish PDOs as a novel platform for modeling neuroendocrine tumor biology, reveal microenvironment-driven plasticity in PPGLs, with potential translational relevance, and identify actionable vulnerabilities in a disease with few effective systemic therapies. Main findingsO_LIPDOs can be successfully generated from PPGLs of various genetic backgrounds and reflect parental tumor properties C_LIO_LIPDO cultures grown in hypoxia retain main molecular features of parental tumors, have increased viability and a more immature developmental/biosynthetic profile C_LIO_LILong term PDOs grown for 4 weeks in normoxia activate HIF2, drift toward a hybrid sympathoblast-mesenchymal-like identity resembling relapsed/therapy resistant neuroblastomas, features that can be detected in primary tumors C_LIO_LIA subset of PDOs respond to Abemaciclib, a drug class not previously used therapeutically in PPGLs C_LI

cancer biology↗

bioRxiv2023

Where, who, and what counts under area-based conservation targets: A framework for identifying opportunities that benefit biodiversity, climate mitigation, and human communities

O_LIArea-based conservation targets, such as 30-30, if strategically applied, can increase resiliency to climate change and provide co-benefits to people and biodiversity. However, protected areas historically were not designated within the context of global change, and human communities at highest risk are often overlooked in conservation planning. C_LIO_LITo inform 30-30 conservation planning in the United States (i.e., America the Beautiful; ATB), we evaluated where US conservation opportunities exist by identifying habitats that can simultaneously benefit climate change mitigation and bird populations, as well as who lives in these areas and how conservation actions could both improve human well-being or potentially be at odds with local communities. To inform the equitable implementation of area-based conservation targets, we integrated maps of critical habitat for birds now and under a changing climate with carbon stocks and sinks and developed a prioritization framework to investigate the spatial alignment of these locations with areas identified as important for both human well-being and land-dependent human communities. C_LIO_LIAlthough nearly 30% of US lands have some level of protection, only 6% of US lands (143 million acres) are managed for biodiversity and align with Bird and Carbon (BC) priorities, and <3% of protected US lands (59 million acres) align with priorities for Birds, Carbon, and Human well-being (BCH). C_LIO_LIOf the 312 million acres of BCH priorities identified, 71% lack known protection or formal conservation plans (14% of US lands) and should be considered conservation opportunities that could simultaneously address the biodiversity and climate crises, and social inequities. Targeting these BCH areas for conservation action would contribute to more equitable benefits to marginalized communities, and could fulfill the Justice 40 commitment, which aims to allocate 40% of federal investments in climate benefits to marginalized communities (which, for the 30% goal under ATB equates to 12% of US lands). C_LIO_LIAt least 80% of all BCH priorities co-occur with Indigenous peoples and local communities (IPLCs) who have strong cultural and socioeconomic ties to the land, making it imperative to work with local communities to define what counts as conservation actions towards the 30% goal and what successful conservation outcomes that benefit biodiversity, climate change mitigation, and human communities look like. C_LI

ecology↗

bioRxiv2022

What is an urban bird? Trait-based predictions of urban tolerance for the world's birds are modulated by latitude and human population density

As human density increases, biodiversity must increasingly co-exist with urbanization or face local extinction. Tolerance of urban areas has been linked to numerous functional traits, yet few globally-consistent patterns have emerged to explain variation in urban tolerance, which stymies attempts at a generalizable predictive framework. Here, we calculate an Urban Association Index (UAI) for 3768 bird species in 137 cities across all permanently inhabited continents. We then assess how UAI varies as a function of ten species-specific traits and further test whether the strength of trait relationships vary as a function of three city-specific variables. Of the ten species traits, nine were significantly associated with urban tolerance. Urban-associated species tend to be smaller, less territorial, have greater dispersal ability, broader dietary and habitat niches, larger clutch sizes, greater longevity, and have lower elevational limits. Only bill shape showed no global association with urban tolerance. Additionally, the strength of several trait relationships varied across cities as a function of latitude and/or human population density. For example, the effects of body mass and diet breadth are more pronounced at higher latitudes, while the effects of territoriality and longevity were reduced in cities with higher population density. Thus, the importance of trait filters in birds varies predictably across cities, indicating biogeographic variation in selection for urban tolerance that could explain prior challenges in the search for global patterns. A globally-informed framework that predicts urban tolerance will be integral to conservation as increasing proportions of the worlds biodiversity are impacted by urbanization.

ecology↗

bioRxiv2020

A Recombinant Protein Biomarker DDA Library Increases DIA Coverage of Low Abundance Plasma Proteins

Credible detection and quantification of low abundance proteins from human blood plasma is a major challenge in precision medicine biomarker discovery when using mass spectrometry (MS). Here, we employed a mixture of recombinant proteins in DDA libraries to subsequently detect cancer-associated low abundance plasma proteins using SWATH/DIA. The exemplar DDA recombinant protein spectral library (rPSL) was derived from tryptic digestion of 36 human recombinant proteins that had been previously implicated as possible cancer biomarkers in both our own and other studies. The rPSL was then used to identify proteins from non-depleted colorectal cancer (CRC) plasmas by SWATH-MS. Most (32/36) of the proteins in the rPSL were reliably identified in plasma samples, including 8 proteins (BTC, CXCL10, IL1B, IL6, ITGB6, TGF, TNF, TP53) not previously detected using high-stringency MS in human plasmas according to PeptideAtlas. The rPSL SWATH-MS protocol was compared to DDA-MS using MARS-depleted and post-digestion peptide fractionated plasmas (here referred to as a human plasma DDA library). Of the 32 proteins identified using rPSL SWATH, only 12 were identified using DDA-MS. The 20 additional proteins exclusively identified by using the rPSL approach with SWATH were mostly lower abundance (i.e., <10ng/ml) plasma proteins. To mitigate FDR concerns, and replicating a more typical approach, the DDA rPSL was also merged into a human plasma DDA library. When SWATH identification was repeated using this merged library, the majority (33/36) of low abundance plasma proteins from the rPSL could still be identified using high-stringency HPP Guidelines v3.0 protein inference criteria.

biochemistry↗