Biology subjects

Hsieh, M.

Publications and source records attributed to Hsieh, M..

8 recordsLinked to original sources

bioRxiv2026

Transcriptional networks underlying tumour plasticity in small-cell lung cancer

Across human malignancies, the ability of cancer cells to switch states (plasticity) drives progression, metastasis, and therapy resistance 1-3. Here we investigated the transcriptional and epigenetic basis of plasticity in small-cell lung cancer (SCLC), an aggressive, treatment-refractory cancer 4, 5. SCLC tumours display plasticity along a neuroendocrine (NE) to nonNE axis; however, the trajectories of lineage transition and the gene regulatory network underlying it, remain poorly defined 6. Using single-cell multi-omics, we resolved distinct transcriptional SCLC cell states, including a previously unrecognised Intermediate state comprised of low-identity immunogenic SCLC cells that serve as an obligatory route in NE to nonNE lineage transition. Using single-cell gene expression and chromatin accessibility data, we next developed a Boolean Bayes model for transcription factor networks (BoBa-T) to predict regulators of SCLC cell states. We validated RORB as a novel gatekeeper of the NE state that represses the nonNE identity in SCLC. RORB inactivation drives NE cells into the Intermediate state, upregulates immunogenic programs, and inhibits tumour growth in immunocompetent hosts. Our work identifies a plastic, immunogenic waypoint for SCLC lineage switching and reveals strategies to target it therapeutically.

cancer biology↗

bioRxiv2025

Longitudinal study of liver disease progression in the PEX1-Gly844Asp mouse model of mild Zellweger Spectrum Disorder

IntroductionZellweger spectrum disorder (ZSD) is an autosomal recessive disorder caused by mutations in any of 13 PEX genes encoding proteins required for peroxisome assembly and function. Chronic liver disease is one of the major clinical manifestations in patients and impacts quality of life and survival. However, the pathophysiology of liver disease is ZSD remains largely unknown, and current interventions are limited. To further study the liver disease mechanism, we use the PEX1-Gly844Asp (G844D) mouse model for mild ZSD, which was previously shown to develop hepatomegaly and cholestasis, similar to ZSD patients. MethodsThe natural history of hepatopathy was broadly characterized in PEX1-G844D mice and littermate controls from 1 to 18 months of age using liver histology, electron microscopy, cultured hepatocytes and blood. Metabolite and mechanism analysis included liver functions, respiratory chain dynamics, lipidomics, peroxisome metabolites, gene and protein expression assays. ResultsPEX1-G844D mice featured liver disease progression from hepatomegaly (1 month) to cluster cell death (4 months), hepatosteatosis (6 months), inflammation (8 months), fibrosis, and hepatic cancer (12 and 15 months). Hepatocyte proliferation and reduced glycogen was observed across all ages. Measurement of peroxisomal functions showed defective peroxisomal import and secondary mitochondrial defects in cultured hepatocytes. In blood and liver, plasmalogens were decreased, and C26:0 lyso-phosphatidylcholine and C27 bile acid intermediates were elevated. In liver, we observed accumulation of triglycerides and cholesterol, and reduced membrane phospholipids and sphingolipids. In contrast, in serum we observed reduced triglycerides, cholesterol and membrane lipids. Gene expression profiles confirmed by immunoblotting supported reduced hepatic de novo lipogenesis, increased hepatic lipid uptake and oxidation, PPAR activation, and modulated glucose and glycogen metabolism. Liver X receptor agonist (T0901317) applied to cultured hepatocytes enhanced hepatic lipogenesis and lipid secretion, but aggravated steatosis. ConclusionTaken together, these results suggested the following mechanisms of hepatopathy progression. We propose that global peroxisome dysfunction (1) causes PPAR activation, leading to chronic hyperplasia and partially contributing to disrupted hepatic lipid homeostasis with hepatosteatosis, and (2) underlies chronic hypoglycemia, causing hypoinsulinemia and contributing to reduced hepatic lipogenesis and systemic lipid deficiency. Growth restriction in the mouse model and in ZSD patients could be attributable to systemic lipid deficiency. Our mechanistic delineation of the pathophysiology provides other additional novel potential therapeutic targets to halt liver disease in ZSD.

pathology↗

bioRxiv2021

Cancer drug discovery as a low rank tensor completion problem

The heterogeneity of cancer necessitates developing a multitude of targeted therapies. We propose the view that cancer drug discovery is a low rank tensor completion problem. We implement this vision by using heterogeneous public data to construct a tensor of drug-target-disease associations. We show the validity of this approach computationally by simulations, and experimentally by testing drug candidates. Specifically, we show that a novel drug candidate, SU11652, controls melanoma tumor growth, including BRAFWT melanoma. Independently, we show that another molecule, TC-E 5008, controls tumor proliferation on ex vivo ER+ human breast cancer. Most importantly, we identify these chemicals with only a few computationally selected experiments as opposed to brute-force screens. The efficiency of our approach enables use of ex vivo human tumor assays as a primary screening tool. We provide a web server, the Cancer Vulnerability Explorer (accessible at https://cavu.biohpc.swmed.edu), to facilitate the use of our methodology.

cancer biology↗

bioRxiv2020

A Newly Identified Role for IL-22 in Bladder Immunity

Bacterial and parasitic urinary tract infections(UTI) affect many, but our understanding of associated immunity remains poor. Prior work indicates interleukin-22(IL-22) is a key cytokine during infection of other epithelia. We hypothesized IL-22 is crucial during UTI. IL-22-null(KO) and wild-type(wt) mice underwent bladder wall injection with S. haematobium eggs or transurethral infection with uropathogenic E. coli UTI89. IL-22 and its soluble binding protein, IL-22BP, were increased in the bladder after S. haematobium egg injection. Genes typically induced by IL-22(CXCL2, REG3G[antimicrobial defense protein]], S100A8, S100A9, and Areg) were expressed at higher levels following S. haematobium egg injection. IL-22 stimulation of bladder tissue induced REG3B expression. IL-22 receptor alpha-1 expression was detectable in the urothelium by immunofluorescence and qPCR. Injection of S. haematobium eggs into IL-22-KO vs wt mice triggered differential expression of genes related to transferase activity(transferring alkyl or aryl groups) and epithelial cell development. Numerous uroplakin genes were downregulated in egg-injected, IL-22-KO mice versus their wt counterparts. These decreases in uroplakin expression suggest that, as in the gut, IL-22 is important for replenishing the epithelium during infection-related injury. Following transurethral infection with UTI89, IL-22-KO mice had lower bacterial counts in their urine, bladder, and kidneys. Giving stabilized IL-22 cytokine (IL-22-Fc) to UTI89-infected mice led to higher kidney bacterial counts and increased morbidity. Our data suggest that IL-22 is indeed important in urinary tract immunity, and may interfere with clearance of bacteria from the urinary tract, potentially through its role in maintenance of mature urothelium.

immunology↗

bioRxiv2020

IPSE, a Parasite-Derived, Host Immunomodulatory Infiltrin Protein, Alleviates Resiniferatoxin-Induced Bladder Pain

The transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor is an important mediator of nociception and its expression is enriched in nociceptive neurons. TRPV1 signaling has been implicated in bladder pain and is a potential analgesic target. Resiniferatoxin is the most potent known agonist of TRPV1. Acute exposure of the rat bladder to resiniferatoxin has been demonstrated to result in pain-related freezing and licking behaviors that are alleviated by virally encoded IL-4. The interleukin-4-inducing principle of Schistosoma mansoni eggs (IPSE) is a powerful inducer of IL-4 secretion, and is also known to alter host cell transcription through a nuclear localization sequence-dependent mechanism. We previously reported that IPSE ameliorates ifosfamide-induced bladder pain in an IL-4- and nuclear localization sequence-dependent manner. We hypothesized that pre-administration of IPSE to resiniferatoxin-challenged mice would dampen pain-related behaviors. IPSE indeed lessened resiniferatoxin-triggered freezing behaviors in mice. This was a nuclear localization sequence-dependent phenomenon, since administration of a nuclear localization sequence mutant version of IPSE abrogated IPSEs analgesic effect. In contrast, IPSEs analgesic effect did not seem IL-4-dependent, since use of anti-IL-4 antibody in mice given both IPSE and resiniferatoxin did not dramatically affect freezing behaviors. RNA-Seq analysis of resiniferatoxin- and IPSE-exposed bladders revealed differential expression of TNF/NF-{kappa}b-related signaling pathway genes. In vitro testing of IPSE uptake by urothelial cells and TRPV1-expressing neuronal cells showed uptake by both cell types. Thus, IPSEs nuclear localization sequence-dependent therapeutic effects on TRPV1-mediated bladder pain may act on TRPV1-expressing neurons and/or may rely upon urothelial mechanisms.

neuroscience↗

bioRxiv2019

Interleukin-4 signaling plays a major role in urogenital schistosomiasis-associated bladder pathogenesis

IL-4 is crucial in many helminth infections, but its role in urogenital schistosomiasis, infection with Schistosoma haematobium worms, remains poorly understood due to a historical lack of animal models. The bladder pathology of urogenital schistosomiasis is caused by immune responses to eggs deposited in the bladder wall. A range of pathology occurs, including urothelial hyperplasia and cancer, but associated mechanisms and links to IL-4 are largely unknown. We modeled urogenital schistosomiasis by injecting the bladder walls of IL-4 receptor-alpha knockout(Il4ra-/-) and wild type mice with S. haematobium eggs. Readouts included bladder histology and ex vivo assessments of urothelial proliferation, cell cycle and ploidy status. We also quantified the effects of exogenous IL-4 on urothelial cell proliferation in vitro, including cell cycle status and phosphorylation patterns of major downstream regulators in the IL-4 signaling pathway. There was a significant decrease in the intensity of granulomatous responses to bladder-wall injected S. haematobium eggs in Il4ra-/- versus wild type mice. S. haematobium egg injection triggered significant urothelial proliferation, including evidence of urothelial hyperdiploidy and cell cycle skewing in wild type but not Il4ra-/- mice. Urothelial exposure to IL-4 in vitro led to cell cycle polarization and increased phosphorylation of AKT. Our results show IL-4 signaling is required for key pathogenic features of urogenital schistosomiasis, and that particular aspects of this signaling pathway may exert these effects directly on the urothelium. These findings point to potential mechanisms by which urogenital schistosomiasis promotes bladder carcinogenesis.

immunology↗

bioRxiv2018

IPSE, a parasite-derived host immunomodulatory protein, is a promising therapeutic for hemorrhagic cystitis

Chemotherapy-induced hemorrhagic cystitis is characterized by bladder pain and voiding dysfunction caused by hemorrhage and inflammation. Of currently available therapies, prophylactic 2-mercaptoethanesulfonic acid (MESNA) has limited efficacy and cannot treat pre-existing lesions. Therefore, novel therapeutic options to treat hemorrhagic cystitis are needed. We previously reported that systemic administration of the Schistosomiasis haematobium-derived protein H-IPSEH06 (IL-4-inducing principle from Schistosoma mansoni eggs), is superior to 3 doses of MESNA in alleviating hemorrhagic cystitis. Based on prior reports by others on S. mansoni IPSE and additional work by our group, we reasoned that H-IPSEH06 mediates its effects on hemorrhagic cystitis by binding IgE on basophils and inducing IL-4 expression, promoting urothelial proliferation, and translocating to the nucleus to modulate expression of genes implicated in relieving bladder dysfunction. We speculated that local bladder injection of the S. haematobium IPSE ortholog IPSEH03, hereafter called H-IPSEH03, might be more efficacious in preventing hemorrhagic cystitis compared to systemic administration of IPSEH06. We demonstrate herein that H-IPSEH03 is a promising therapeutic for the treatment of voiding dysfunction and bladder pain in hemorrhagic cystitis. Namely, it attenuates ifosfamide-induced increases in bladder wet weight in an IL-4-dependent fashion. H-IPSEH03 relieves hemorrhagic cystitis-associated allodynia. Finally, H-IPSEH03 drives increased urothelial cell proliferation. This indicates that IPSE induces bladder healing mechanisms, which suggests that it may be a novel non-opioid analgesic to treat bladder pain syndromes.

immunology↗

bioRxiv2018

IPSE, a urogenital parasite-derived immunomodulatory protein, ameliorates ifosfamide-induced hemorrhagic cystitis through downregulation of pro-inflammatory pathways

Ifosfamide and other oxazaphosphorines can result in hemorrhagic cystitis, a constellation of complications caused by acrolein metabolites. We previously showed that a single dose of IPSE, a schistosome-derived host modulatory protein, can ameliorate ifosfamide-related cystitis; however, the exact mechanisms underlying this urotoxic effect and its prevention are not fully understood. To provide insights into IPSEs protective mechanism, we undertook transcriptional profiling of bladders from ifosfamide-treated mice, with or without IPSE pretreatment. Following ifosfamide challenge, there was upregulation of a range of pro-inflammatory genes. The pro-inflammatory pathway involving the IL-1{beta}, TNF and IL-6 triad via NF{kappa}B and STAT3 signaling pathways was identified as the key driver of inflammation. The NRF2-mediated oxidative stress response pathway, which regulates both Hmox1-mediated heme homoeostasis and expression of antioxidant enzymes, was highly activated. Anti-inflammatory and cellular proliferation cascades implicated in tissue repair, namely Wnt, Hedgehog and PPAR pathways, were downregulated. IPSE administration before ifosfamide injection resulted in significant downregulation of major proinflammatory pathways including the triad of IL-1{beta}, TNF and IL-6 pathways, the interferon signaling pathway, and less apparent reduction in oxidative stress responses. Taken together, we have identified signatures of acute phase inflammation and oxidative stress responses in the ifosfamide-injured bladder, which are reversed by pretreatment with IPSE, a parasite derived anti-inflammatory molecule. In addition to providing new insights into the underlying mechanism of IPSEs therapeutic effects, this work has revealed several pathways that could be therapeutically targeted to prevent and treat ifosfamide-induced hemorrhagic cystitis.

immunology↗