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All Publications


  • PTPN1 Deficiency Modulates BMPR2 Signaling and Induces Endothelial Dysfunction in Pulmonary Arterial Hypertension. Cells Ali, M. K., Tian, X., Zhao, L., Schimmel, K., Rhodes, C. J., Wilkins, M. R., Nicolls, M. R., Spiekerkoetter, E. F. 2023; 12 (2)

    Abstract

    Bone morphogenic protein receptor 2 (BMPR2) expression and signaling are impaired in pulmonary arterial hypertension (PAH). How BMPR2 signaling is decreased in PAH is poorly understood. Protein tyrosine phosphatases (PTPs) play important roles in vascular remodeling in PAH. To identify whether PTPs modify BMPR2 signaling, we used a siRNA-mediated high-throughput screening of 22,124 murine genes in mouse myoblastoma reporter cells using ID1 expression as readout for BMPR2 signaling. We further experimentally validated the top hit, PTPN1 (PTP1B), in healthy human pulmonary arterial endothelial cells (PAECs) either silenced by siRNA or exposed to hypoxia and confirmed its relevance to PAH by measuring PTPN1 levels in blood and PAECs collected from PAH patients. We identified PTPN1 as a novel regulator of BMPR2 signaling in PAECs, which is downregulated in the blood of PAH patients, and documented that downregulation of PTPN1 is linked to endothelial dysfunction in PAECs. These findings point to a potential involvement for PTPN1 in PAH and will aid in our understanding of the molecular mechanisms involved in the disease.

    View details for DOI 10.3390/cells12020316

    View details for PubMedID 36672250

  • The Human Respiratory Microbiome: Current Understandings and Future Directions. American journal of respiratory cell and molecular biology Zhao, L., Luo, J. L., Ali, M. K., Spiekerkoetter, E., Nicolls, M. R. 2022

    Abstract

    Microorganisms colonizing the human body. The lungs and respiratory tract, previously thought to be sterile, harbor diverse microbial communities and the genomes of bacteria (bacteriome), viruses (virome), and fungi (mycobiome). Recent advances in amplicon and shotgun metagenomic sequencing technologies, and data analyzing methods have greatly aided the identification and characterization of microbial populations from airways. The respiratory microbiome has been shown to play roles in human health and disease and is an area of rapidly emerging interest in pulmonary medicine. In this review we provide updated information in the field by focusing on four lung conditions including asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and idiopathic pulmonary fibrosis (IPF). We evaluate gut, oral, and upper airway microbiomes, and how they contribute to lower airway flora. The discussion is followed by a systematic review of the lower airway microbiome in health and disease. We conclude with promising research avenues and implications for evolving therapeutics.

    View details for DOI 10.1165/rcmb.2022-0208TR

    View details for PubMedID 36476129

  • Exploratory genomic analysis of high grade neuroendocrine neoplasms across diverse primary sites. Endocrine-related cancer Sun, T. Y., Zhao, L., Van Hummelen, P., Martin, B., Hornbacker, K., Lee, H., Xia, L. C., Padda, S. K., Ji, H. P., Kunz, P. 2022

    Abstract

    High grade (grade 3) neuroendocrine neoplasms (G3 NENs) have poor survival outcomes. From a clinical standpoint, G3 NENs are usually grouped regardless of primary site and treated similarly. Little is known regarding the underlying genomics of these rare tumors, especially when compared across different primary sites. We performed whole transcriptome (n = 46), whole exome (n = 40) and gene copy number (n = 43) sequencing on G3 NEN FFPE samples from diverse organs (in total 17 were lung, 16 were gastroenteropancreatic, 13 other). G3 NENs despite arising from diverse primary sites did not have gene expression profiles that were easily segregated by organ of origin. Across all G3 NENs, TP53, APC, RB1 and CDKN2A were significantly mutated. The CDK4/6 cell cycling pathway was mutated in 95% of cases, with upregulation of oncogenes within this pathway. G3 NENs had high tumor mutation burden (mean 7.09 mutations/MB), with 20% having >10 mutations/MB. Two somatic copy number alterations were significantly associated with worse prognosis across tissue types: focal deletion 22q13.31 (HR, 7.82; p = 0.034) and arm amplification 19q (HR, 4.82; p = 0.032). This study is among the most diverse genomic study of high-grade neuroendocrine neoplasms. We uncovered genomic features previously unrecognized for this rapidly fatal and rare cancer type that could have potential prognostic and therapeutic implications.

    View details for DOI 10.1530/ERC-22-0015

    View details for PubMedID 36165930

  • The role of circular RNAs in pulmonary hypertension. The European respiratory journal Ali, M. K., Schimmel, K., Zhao, L., Chen, C. K., Dua, K., Nicolls, M. R., Spiekerkoetter, E. 2022

    Abstract

    Circular RNAs (CircRNAs) are endogenous, covalently circularized, non-protein-coding RNAs generated from back splicing. Most circRNAs are very stable, highly conserved, and expressed in a tissue-, cell- and developmental stage-specific manner. CircRNAs play a significant role in various biological processes, such as regulation of gene expression and protein translation via sponging of microRNAs and binding with RNA binding proteins. CircRNAs have become a topic of great interest in research due to their close link with the development of various diseases. Their high stability, conservation, and abundance in body fluids make them promising biomarkers for many diseases. A growing body of evidence suggests that aberrant expression of circRNAs and their targets plays a crucial role in pulmonary vascular remodeling and Group 1 pulmonary arterial hypertension (PAH) as well as other forms of pulmonary hypertension (PH) (Group 3 and 4). Here we discuss the roles and molecular mechanisms of circRNAs in the pathogenesis of pulmonary vascular remodeling and PH. We also highlight the therapeutic and biomarker potential of circRNAs in PH.

    View details for DOI 10.1183/13993003.00012-2022

    View details for PubMedID 35680145

  • Exploring disease interrelationships in patients with lymphatic disorders: A single center retrospective experience. Clinical and translational medicine Rockson, S. G., Zhou, X., Zhao, L., Hosseini, D. K., Jiang, X., Sweatt, A. J., Kim, D., Tian, W., Snyder, M. P., Nicolls, M. R. 2022; 12 (4): e760

    Abstract

    The lymphatic contribution to the circulation is of paramount importance in regulating fluid homeostasis, immune cell trafficking/activation and lipid metabolism. In comparison to the blood vasculature, the impact of the lymphatics has been underappreciated, both in health and disease, likely due to a less well-delineated anatomy and function. Emerging data suggest that lymphatic dysfunction can be pivotal in the initiation and development of a variety of diseases across broad organ systems. Understanding the clinical associations between lymphatic dysfunction and non-lymphatic morbidity provides valuable evidence for future investigations and may foster the discovery of novel biomarkers and therapies.We retrospectively analysed the electronic medical records of 724 patients referred to the Stanford Center for Lymphatic and Venous Disorders. Patients with an established lymphatic diagnosis were assigned to groups of secondary lymphoedema, lipoedema or primary lymphovascular disease. Individuals found to have no lymphatic disorder were served as the non-lymphatic controls. The prevalence of comorbid conditions was enumerated. Pairwise co-occurrence pattern analyses, validated by Jaccard similarity tests, was utilised to investigate disease-disease interrelationships.Comorbidity analyses underscored the expected relationship between the presence of secondary lymphoedema and those diseases that damage the lymphatics. Cardiovascular conditions were common in all lymphatic subgroups. Additionally, statistically significant alteration of disease-disease interrelationships was noted in all three lymphatic categories when compared to the control population.The presence or absence of a lymphatic disease significantly influences disease interrelationships in the study cohorts. As a physiologic substrate, the lymphatic circulation may be an underappreciated participant in disease pathogenesis. These relationships warrant further, prospective scrutiny and study.

    View details for DOI 10.1002/ctm2.760

    View details for PubMedID 35452183

  • SSCS: A Stage Supervised Subtyping System for Colorectal Cancer. Biomedicines Zhao, L., Pan, Y. 1800; 9 (12)

    Abstract

    Colorectal cancer (CRC) is heterogeneous and deadly, and the exact cause of the disease is unknown. Recent progress indicated that CRC is not a single disease, but a group of diseases with significant heterogeneity. Three previous CRC subtyping systems: microsatellite instability (MSI), consensus molecular subtypes (CMS), and tumor-node-metastases (TNM) stage were evaluated for their molecular and clinical implications. Results suggested that the MSI and CMS systems are prognostic and predictive mostly in early-stage CRC. As the stage remains an influential factor for CRC subtype analysis, we developed a new subtyping system named stage supervised CRC subtypes (SSCS), in order to better stratify CRC biologically and clinically. Our subtyping system can be used to classify CRC patients into five subtypes (SSCS1-5). SSCS1 was found to have the highest frequency of MSI-H cases compared to the remaining four subtypes. SSCS2 had the most favorable prognosis, whereas the worst prognosis was seen in SSCS4. SSCS3 had cell cycle and metabolism-related gene sets upregulation, and SSCS5 subtype was enriched with amplicon-associated gene sets. Moreover, tumor-infiltrating fibroblast was found to be predictive for poor disease-free survival (DFS) only within the SSCS4 subtype. Conventional dendritic cells (cDC), on the contrary, were associated with favorable DFS in the SSCS3 subtype. Our study provides a new subtyping system SSCS, which can be used for better stratify CRC patients compared to current standards. Further exploration of the subtype-specific cell types has the potential to be novel therapies for CRC.

    View details for DOI 10.3390/biomedicines9121815

    View details for PubMedID 34944631

  • Characterization of the consensus mucosal microbiome of colorectal cancer. NAR cancer Zhao, L., Grimes, S. M., Greer, S. U., Kubit, M., Lee, H., Nadauld, L. D., Ji, H. P. 1800; 3 (4): zcab049

    Abstract

    Dysbioisis is an imbalance of an organ's microbiome and plays a role in colorectal cancer pathogenesis. Characterizing the bacteria in the microenvironment of a cancer through genome sequencing has advantages compared to culture-based profiling. However, there are notable technical and analytical challenges in characterizing universal features of tumor microbiomes. Colorectal tumors demonstrate microbiome variation among different studies and across individual patients. To address these issues, we conducted a computational study to determine a consensus microbiome for colorectal cancer, analyzing 924 tumors from eight independent RNA-Seq data sets. A standardized meta-transcriptomic analysis pipeline was established with quality control metrics. Microbiome profiles across different cohorts were compared and recurrently altered microbial shifts specific to colorectal cancer were determined. We identified cancer-specific set of 114 microbial species associated with tumors that were found among all investigated studies. Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria were among the four most abundant phyla for the colorectal cancer microbiome. Member species of Clostridia were depleted and Fusobacterium nucleatum was one of the most enriched bacterial species in tumors. Associations between the consensus species and specific immune cell types were noted. Our results are available as a web data resource for other researchers to explore (https://crc-microbiome.stanford.edu).

    View details for DOI 10.1093/narcan/zcab049

    View details for PubMedID 34988460

  • Colorectal Cancer-Associated Microbiome Patterns and Signatures. Frontiers in genetics Zhao, L., Cho, W. C., Nicolls, M. R. 1800; 12: 787176

    Abstract

    The gut microbiome is dynamic and shaped by diet, age, geography, and environment. The disruption of normal gut microbiota (dysbiosis) is closely related to colorectal cancer (CRC) risk and progression. To better identify and characterize CRC-associated dysbiosis, we collected six independent cohorts with matched normal pairs (when available) for comparison and exploration of the microbiota and their interactions with the host. Comparing the microbial community compositions between cancerous and adjacent noncancerous tissues, we found that more microbes were depleted than enriched in tumors. Despite taxonomic variations among cohorts, consistent depletion of normal microbiota (members of Clostridia and Bacteroidia) and significant enrichment of oral-originated pathogens (such as Fusobacterium nucleatum and Parvimonas micra) were observed in CRC compared to normal tissues. Sets of hub and hub-connecting microbes were subsequently identified to infer microbe-microbe interaction networks in CRC. Furthermore, biclustering was used for identifying coherent patterns between patients and microbes. Two patient-microbe interaction patterns, named P0 and P1, can be consistently identified among the investigated six CRC cohorts. Characterization of the microbial community composition of the two patterns revealed that patients in P0 and P1 differed significantly in microbial alpha and beta diversity, and CRC-associated microbiota changes consist of continuous populations of widespread taxa rather than discrete enterotypes. In contrast to the P0, the patients in P1 have reduced microbial alpha diversity compared to the adjacent normal tissues, and P1 possesses more oral-related pathogens than P0 and controls. Collectively, our study investigated the CRC-associated microbiome changes, and identified reproducible microbial signatures across multiple independent cohorts. More importantly, we revealed that the CRC heterogeneity can be partially attributed to the variety and compositional differences of microbes and their interactions to humans.

    View details for DOI 10.3389/fgene.2021.787176

    View details for PubMedID 35003221