Biology subjects

Wen, H.-J.

Publications and source records attributed to Wen, H.-J..

8 recordsLinked to original sources

bioRxiv2025

Genomic Evidence for Males of Exceptional Reproductive Output (ERO) in Apes and Humans

It is widely suspected that a small percentage of males have exceptional reproductive output (ERO) but progeny numbers of males are rarely measurable, even in humans. If we define the variance ratio of reproductive-output in males and females as = VM/VF, the ERO hypothesis would predict >>1. Since autosomal, X, and Y chromosomes are found in males 1/2, 1/3, and 100% of the time, their DNA diversities can inform about . For example, autosomal and Y-linked diversities are governed, respectively, by (VM+VF)/2 and VM. When comparing the chromosomal diversities, appears to be near 20 for chimpanzees and orangutans, and 1-10 for gorillas. The exception is bonobos with < 1. In humans, the extensive genomic data are coupled to a theory, developed herein, that can filter out selection influences on Y-linked diversities. Hence, the estimation of is rigorous, yielding values near or above 20, depending on the population. When >10, the presence of ERO males is very likely. These analyses can be applied more generally to species with XY sex determination.

evolutionary biology↗

bioRxiv2024

The theory of massively repeated evolution and full identifications of Cancer Driving Nucleotides (CDNs)

Tumorigenesis, like most complex genetic traits, is driven by the joint actions of many mutations. At the nucleotide level, such mutations are Cancer Driving Nucleotides (CDNs). The full sets of CDNs are necessary, and perhaps even sufficient, for the understanding and treatment of each cancer patient. Currently, only a small fraction of CDNs is known as most mutations accrued in tumors are not drivers. We now develop the theory of CDNs on the basis that cancer evolution is massively repeated in millions of individuals. Hence, any advantageous mutation should recur frequently and, conversely, any mutation that does not is either a passenger or deleterious mutation. In the TCGA cancer database (sample size n = 300 - 1000), point mutations may recur in i out of n patients. This study explores a wide range of mutation characteristics to determine the limit of recurrences (i*) driven solely by neutral evolution. Since no neutral mutation can reach i* = 3, all mutations recurring at i [≥] 3 are CDNs. The theory shows the feasibility of identifying almost all CDNs if n increases to 100,000 for each cancer type. At present, only < 10% of CDNs have been identified. When the full sets of CDNs are identified, the evolutionary mechanism of tumorigenesis in each case can be known and, importantly, gene targeted therapy will be far more effective in treatment and robust against drug resistance.

evolutionary biology↗

bioRxiv2024

On the discovered Cancer Driving Nucleotides (CDNs)-Distributions across genes, cancer types and patients

A central goal of cancer genomics is to identify, in each patient, all the cancer driving mutations. Among them, point mutations are referred to as Cancer Driving Nucleotides (CDNs), which recur in cancers. The companion study shows that the probability of i recurrent hits in n patients would decrease exponentially with i; hence, any mutation with i [≥] 3 hits in the TCGA database is a high-probability CDN. This study characterizes the 50[~]150 CDNs identifiable for each cancer type of TCGA (while anticipating 10 times more undiscovered ones) as follows: i) CDNs tend to code for amino acids of divergent chemical properties. ii) At the genic level, far more CDNs (>5-fold) fall on non-canonical than canonical cancer driving genes (CDGs). Most undiscovered CDNs are expected to be on unknown CDGs. iii) CDNs tend to be more widely shared among cancer types than canonical CDGs, mainly because of the higher resolution at the nucleotide than the whole-gene level. iv) Most important, among the 50[~]100 coding region mutations carried by a cancer patient, 5[~]8 CDNs are expected but only 0[~]2 CDNs have been identified at present. This low level of identification has hampered functional test and gene targeted therapy. We show that, by expanding the sample size to 105, most CDNs can be identified. Full CDN identification will then facilitate the design of patient-specific targeting against multiple CDN-harboring genes.

evolutionary biology↗

bioRxiv2024

Metaplastic tuft cells transdifferentiate to neural-like progenitor cells in the progression of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) is partly initiated through the transdifferentiation of acinar cells to metaplastic ducts that act as precursors of neoplasia and cancer. Tuft cells are solitary chemosensory cells not found in the normal pancreas but arise in metaplasia and neoplasia, diminishing as neoplastic lesions progress to carcinoma. Metaplastic tuft cells (mTCs) function to suppress tumor progression through communication with the tumor microenvironment, but their fate during progression is unknown. To determine the fate of mTCs during PDA progression, we have created a lineage tracing model that uses a tamoxifen-inducible tuft-cell specific Pou2f3CreERT/+ driver to induce transgene expression, including the lineage tracer tdTomato or the oncogene Myc. mTC lineage trace models of pancreatic neoplasia and carcinoma were used to follow mTC fate. We found that mTCs, in the carcinoma model, transdifferentiate into neural-like progenitor cells (NRPs), a cell type associated with poor survival in PDA patients. Using conditional knock-out and overexpression systems, we found that Myc activity in mTCs is necessary and sufficient to induce this Tuft-to-Neuroendocrine-Transition (TNT).

cancer biology↗

bioRxiv2023

ROR2 regulates cellular plasticity in pancreatic neoplasia and adenocarcinoma

Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells into precancerous lesions to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We discovered that normal acinar cell differentiation, maintained by the transcription factor Pdx1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in mouse and human. We have identified the receptor tyrosine kinase Ror2 as marker of a gastric metaplasia (SPEM)-like identity in the pancreas. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to the classical subtype of PDAC. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition. SignificanceWe discovered the receptor tyrosine kinase ROR2 as an important regulator of cellular identity in pancreatic precancerous lesions and pancreatic cancer. ROR2 drives an aggressive PDAC phenotype and confers resistance to Kras inhibitors, suggesting that targeting ROR2 will enhance sensitivity to this new generation of targeted therapies.

cancer biology↗

bioRxiv2022

Gene expression as phenotype - Many small-step changes leading to little long-term phenotypic evolution

Unlike in genotypic evolution, there are few general rules governing phenotypic evolution with one of them being the small-step evolution. More specifically, natural selection tends to favor mutations of smaller phenotypic effects than of larger ones. This postulate can be viewed as a logical extension of Fishers Geometric Model (FGM). Testing this FGM postulate, however, is challenging as the test would require a large number of phenotypes, each with a clear genetic basis. For such a test, we treat the expression level of each gene as a phenotype. Furthermore, a mechanism of small-step expression evolution exists, namely via the control by microRNAs (miRNAs). Each miRNA in metazoans is known to weakly repress the expression of tens or hundreds of target genes. In our analysis of mammalian and Drosophila expression data, small step evolution via miRNA regulation happens frequently in long-term evolution. However, such small-step evolution does not lead to long-term phenotypic changes which would take too many such steps to accomplish. Furthermore, target site changes often cancel themselves out by continual gains and losses. The results suggest that the FGM postulate may be most appropriate for phenotypic fine-tuning near the expression optimum. In contrast, longterm expression evolution may occasionally take large steps (e.g., mutations in transcription factors) when big environmental shift happens. In another study (Lu et al. 2021), we further show how the small-step evolution of expression phenotypes is a manifestation of miRNAs role in developmental canalization. In conclusion, the rules of phenotypic evolution may depend crucially on the genetics of the phenotype, rather than its metric properties.

evolutionary biology↗

bioRxiv2021

Homo-harringtonine (HHT) - A highly effective drug against coronaviruses and the potential for large-scale clinical applications

In the search for treatment schemes of COVID-19, we start by examining the general weakness of coronaviruses and then identify approved drugs attacking that weakness. The approach, if successful, should identify drugs with a specific mechanism that is at least as effective as the best drugs proposed and are ready for clinical trials. All coronaviruses translate their non-structural proteins ([~]16) in concatenation, resulting in a very large super-protein. Homo-harringtonine (HHT), which has been approved for the treatment of leukemia, blocks protein elongation very effectively. Hence, HHT can repress the replication of many coronaviruses at the nano-molar concentration. In two mouse models, HHT clears SARS-CoV-2 in 3 days, especially by nasal dripping of 40 ug per day. We also use dogs to confirm the safety of HHT delivered by nebulization. The nebulization scheme could be ready for large-scale applications at the onset of the next epidemics. For the current COVID-19, a clinical trial has been approved by the Ditan hospital of Beijing but could not be implemented for want of patients. The protocol is available to qualified medical facilities.

microbiology↗

bioRxiv2020

The Pancreatic Tumor Microenvironment Buffers Redox Imbalance Imposed by Disrupted Mitochondrial Metabolism

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) restricts vascularization and, consequently, access to blood-derived nutrients and oxygen, which impacts tumor growth. Intracellular redox imbalance is another restraint on cellular proliferation, yet it is unknown if the TME contributes to the maintenance of redox homeostasis in PDA cells. Here, we demonstrate that the loss of mitochondrial glutamate-oxaloacetate transaminase 2 (GOT2), a component in the malate-aspartate shuttle, disturbs redox homeostasis and halts proliferation of PDA cells in vitro. In contrast, GOT2 inhibition has no effect on in vivo tumor growth or tumorigenesis in an autochthonous model. We propose that this discrepancy is explained by heterocellular pyruvate exchange from the TME, including from cancer associated fibroblasts. More broadly, pyruvate similarly confers resistance to inhibitors of mitochondrial respiration. Genetic or pharmacologic inhibition of pyruvate uptake or metabolism abrogated pyruvate-mediated alleviation of reductive stress from NADH buildup. In sum, this work describes a potential resistance mechanism mediated by metabolic crosstalk within the pancreatic TME. These findings have important implications for metabolic treatment strategies since several mitochondrial inhibitors are currently in clinical trials for PDA and other cancers.

cancer biology↗