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Delayed-type drug hypersensitivity reactions are major causes of morbidity and mortality. The origin, phenotype and function of pathogenic T cells across the spectrum of severity requires investigation. We leveraged recent technical advancements to study skin-resident memory T cells (TRM) versus recruited T cell subsets in the pathogenesis of severe systemic forms of disease, SJS/TEN and DRESS, and skin-limited disease, morbilliform drug eruption (MDE). Microscopy, bulk transcriptional profiling and scRNAseq + CITEseq + TCRseq supported in SJS/TEN clonal expansion and recruitment of cytotoxic CD8+ T cells from circulation into skin, along with expanded and non-expanded cytotoxic CD8+ skin TRM. Comparatively, MDE displayed a cytotoxic T cell profile in skin without appreciable expansion and recruitment of cytotoxic CD8+ T cells from circulation, implicating TRM as potential protagonists in skin-limited disease. Mechanistic interrogation in patients unable to recruit T cells from circulation into skin and in a parallel mouse model supported that skin TRM were sufficient to mediate MDE. Concomitantly, SJS/TEN displayed a reduced regulatory T cell (Treg) signature compared to MDE. DRESS demonstrated recruitment of cytotoxic CD8+ T cells into skin like SJS/TEN, yet a pro-Treg signature like MDE. These findings have important implications for fundamental skin immunology and clinical care.
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Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we have developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are highest in liver tissue, which is also a hub for lipid production. While the loss of GSH does not cause liver failure, it decreases lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we find that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver's balance of redox buffering and triglyceride production.
Assuntos
Glutamato-Cisteína Ligase , Glutationa , Fígado , Fator 2 Relacionado a NF-E2 , Triglicerídeos , Animais , Glutationa/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fígado/metabolismo , Glutamato-Cisteína Ligase/metabolismo , Glutamato-Cisteína Ligase/genética , Camundongos , Triglicerídeos/metabolismo , Estresse Oxidativo , Masculino , Metabolismo dos Lipídeos , Camundongos Knockout , Camundongos Endogâmicos C57BL , Oxirredução , Lipogênese/genéticaRESUMO
Implanted biomaterials and devices face compromised functionality and efficacy in the long term owing to foreign body reactions and subsequent formation of fibrous capsules at the implant-tissue interfaces1-4. Here we demonstrate that an adhesive implant-tissue interface can mitigate fibrous capsule formation in diverse animal models, including rats, mice, humanized mice and pigs, by reducing the level of infiltration of inflammatory cells into the adhesive implant-tissue interface compared to the non-adhesive implant-tissue interface. Histological analysis shows that the adhesive implant-tissue interface does not form observable fibrous capsules on diverse organs, including the abdominal wall, colon, stomach, lung and heart, over 12 weeks in vivo. In vitro protein adsorption, multiplex Luminex assays, quantitative PCR, immunofluorescence analysis and RNA sequencing are additionally carried out to validate the hypothesis. We further demonstrate long-term bidirectional electrical communication enabled by implantable electrodes with an adhesive interface over 12 weeks in a rat model in vivo. These findings may offer a promising strategy for long-term anti-fibrotic implant-tissue interfaces.
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Materiais Biocompatíveis , Fibrose , Reação a Corpo Estranho , Próteses e Implantes , Adesivos Teciduais , Animais , Feminino , Humanos , Masculino , Camundongos , Ratos , Parede Abdominal , Adsorção , Materiais Biocompatíveis/química , Colo , Eletrodos Implantados , Fibrose/patologia , Fibrose/prevenção & controle , Reação a Corpo Estranho/prevenção & controle , Reação a Corpo Estranho/patologia , Coração , Pulmão , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Reação em Cadeia da Polimerase , Ratos Sprague-Dawley , Estômago , Suínos , Fatores de Tempo , Adesivos Teciduais/química , Imunofluorescência , Reprodutibilidade dos Testes , Análise de Sequência de RNARESUMO
Acute injury in the airways or the lung activates local progenitors and stimulates changes in cell-cell interactions to restore homeostasis, but it is not appreciated how more distant niches are impacted. We utilized mouse models of airway-specific epithelial injury to examine secondary tissue-wide alveolar, immune, and mesenchymal responses. Single-cell transcriptomics and in vivo validation revealed transient, tissue-wide proliferation of alveolar type 2 (AT2) progenitor cells after club cell-specific ablation. The AT2 cell proliferative response was reliant on alveolar macrophages (AMs) via upregulation of Spp1 which encodes the secreted factor Osteopontin. A previously uncharacterized mesenchymal population we termed Mesenchymal Airway/Adventitial Niche Cell 2 (MANC2) also exhibited dynamic changes in abundance and a pro-fibrotic transcriptional signature after club cell ablation in an AM-dependent manner. Overall, these results demonstrate that acute airway damage can trigger distal lung responses including altered cell-cell interactions that may contribute to potential vulnerabilities for further dysregulation and disease.
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Objective: Epidemiological studies suggest that consumption of fruits and vegetables (FV) is negatively associated with the incidence of certain cancers and mortality. However, a causal relationship has not been demonstrated. Thus, we investigated the effect of life-long consumption of high level of FV on median lifespan, key biological functions, and pathologies in mice fed low-fat (LF) or high-fat (HF) diets and the underlying mechanisms. Methods: Using a 2 × 2 factorial design, 5 weeks-old male C57BL/6J mice were randomly assigned to one of four groups (n = 60/group): LF (LF-C, 10% kcal fat), HF (HF-C, 45% kcal fat) or each supplemented with 15% (w/w) of a unique FV mixture (LF + FV and HF + FV, respectively). Mice were euthanized when one group reached 50% mortality. Body weight and composition, tumor incidence, and death were monitored. Blood levels of lipids and pro-inflammatory cytokines were assessed. Results: After 21 months of feeding, HF-C group reached 50% mortality, at which time mice in all groups were terminated. HF-C had higher mortality (50.0%) compared to the LF-C group (18.3%, p = 0.0008). Notably, HF-FV had lower mortality (23.3%) compared to HF-C group (p = 0.008); there was no significant difference in mortality between HF-FV and LF-C groups. Tumors were found in all groups, and were predominantly present in the liver, followed by those of lung, intestine, and seminal vesicle. Tumor incidence in the HF-C group (73.3%) was higher than that in LF-C group (30.0%, p < 0.0001). HF + FV group had 23.3% lower tumor incidence compared to the HF-C group (p = 0.014). No significant difference in tumor incidence between the LF-C and LF + FV groups was observed. Long-term FV supplementation reduced systemic inflammation and blood lipids. Conclusion: We provide the first causal evidence that life-long intake of a diet, containing a high level and large variety of FV, decreases tumor incidence and extends median lifespan in mice fed a western-style high-fat diet. These effects of FV are at least in part due to reduced blood levels of pro-inflammatory cytokines and improved dyslipidemia.
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Wnt signaling pathways are transmitted via 10 homologous frizzled receptors (FZD1-10) in humans. Reagents broadly inhibiting Wnt signaling pathways reduce growth and metastasis of many tumors, but their therapeutic development has been hampered by the side effect. Inhibitors targeting specific Wnt-FZD pair(s) enriched in cancer cells may reduce side effect, but the therapeutic effect of narrow-spectrum Wnt-FZD inhibitors remains to be established in vivo. Here, we developed a fragment of C. difficile toxin B (TcdBFBD), which recognizes and inhibits a subclass of FZDs, FZD1/2/7, and examined whether targeting this FZD subgroup may offer therapeutic benefits for treating breast cancer models in mice. Utilizing 2 basal-like and 1 luminal-like breast cancer models, we found that TcdBFBD reduces tumor-initiating cells and attenuates growth of basal-like mammary tumor organoids and xenografted tumors, without damaging Wnt-sensitive tissues such as bones in vivo. Furthermore, FZD1/2/7-positive cells are enriched in chemotherapy-resistant cells in both basal-like and luminal mammary tumors treated with cisplatin, and TcdBFBD synergizes strongly with cisplatin in inhibiting both tumor types. These data demonstrate the therapeutic value of narrow-spectrum Wnt signaling inhibitor in treating breast cancers.
Assuntos
Toxinas Bacterianas , Neoplasias da Mama , Clostridioides difficile , Neoplasias Mamárias Animais , Humanos , Animais , Camundongos , Feminino , Via de Sinalização Wnt , Neoplasias da Mama/metabolismo , Toxinas Bacterianas/metabolismo , Clostridioides difficile/metabolismo , CisplatinoRESUMO
Despite small cell lung cancers (SCLCs) having a high mutational burden, programmed death-ligand 1 (PD-L1) immunotherapy only modestly increases survival. A subset of SCLCs that lose their ASCL1 neuroendocrine phenotype and restore innate immune signaling (termed the "inflammatory" subtype) have durable responses to PD-L1. Some SCLCs are highly sensitive to Aurora kinase inhibitors, but early-phase trials show short-lived responses, suggesting effective therapeutic combinations are needed to increase their durability. Using immunocompetent SCLC genetically engineered mouse models (GEMMs) and syngeneic xenografts, we show durable efficacy with the combination of a highly specific Aurora A kinase inhibitor (LSN3321213) and PD-L1. LSN3321213 causes accumulation of tumor cells in mitosis with lower ASCL1 expression and higher expression of interferon target genes and antigen-presentation genes mimicking the inflammatory subtype in a cell-cycle-dependent manner. These data demonstrate that inflammatory gene expression is restored in mitosis in SCLC, which can be exploited by Aurora A kinase inhibition.
Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Camundongos , Animais , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Antígeno B7-H1/genética , Aurora Quinase A/genética , Aurora Quinase A/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Mitose , Interferons/genéticaRESUMO
The lung contains multiple progenitor cell types, but how their responses are choreographed during injury repair and whether this changes with age is poorly understood. We report that histone H3 lysine 9 di-methylation (H3K9me2), mediated by the methyltransferase G9a, regulates the dynamics of distal lung epithelial progenitor cells and that this regulation deteriorates with age. In aged mouse lungs, H3K9me2 loss coincided with fewer alveolar type 2 (AT2) cell progenitors and reduced alveolar regeneration but increased the frequency and activity of multipotent bronchioalveolar stem cells (BASCs) and bronchiolar progenitor club cells. H3K9me2 depletion in young mice decreased AT2 progenitor activity and impaired alveolar injury repair. Conversely, H3K9me2 depletion increased chromatin accessibility of bronchiolar cell genes, increased BASC frequency, and accelerated bronchiolar cell injury repair. These findings indicate that during aging, the epigenetic regulation that coordinates lung progenitor cells' regenerative responses becomes dysregulated, aiding our understanding of age-related susceptibility to lung disease.
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Epigênese Genética , Pulmão , Camundongos , Animais , Pulmão/metabolismo , Cromatina/metabolismo , Metilação , Processamento de Proteína Pós-TraducionalRESUMO
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Although cSCC contributes to substantial morbidity and mortality in high-risk individuals, deployment of otherwise effective chemoprevention of cSCC is limited by toxicities. Our systematic computational drug repurposing screen predicted that selumetinib, a MAPK (mitogen-activated protein kinase) kinase inhibitor (MEKi), would reverse transcriptional signatures associated with cSCC development, consistent with our genomic analysis implicating MEK as a chemoprevention target. Although systemic MEKi suppresses the formation of cSCC in mice, systemic MEKi can cause severe adverse effects. Here, we report the development of a metabolically labile MEKi, NFX-179, designed to potently and selectively suppress the MAPK pathway in the skin before rapid metabolism in the systemic circulation. NFX-179 was identified on the basis of its biochemical and cellular potency, selectivity, and rapid metabolism upon systemic absorption. In our ultraviolet-induced cSCC mouse model, topical application of NFX-179 gel reduced the formation of new cSCCs by an average of 60% at doses of 0.1% and greater at 28 days. We further confirmed the localized nature of these effects in an additional split-mouse randomized controlled study where suppression of cSCC was observed only in drug-treated areas. No toxicities were observed. NFX-179 inhibits the growth of human SCC cell lines in a dose-dependent manner, and topical NFX-179 application penetrates human skin and inhibits MAPK signaling in human cSCC explants. Together, our data provide a compelling rationale for using topical MEK inhibition through the application of NFX-179 gel as an effective strategy for cSCC chemoprevention.
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Carcinoma de Células Escamosas , Neoplasias Cutâneas , Animais , Humanos , Camundongos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Proliferação de Células , Quimioprevenção , Quinases de Proteína Quinase Ativadas por Mitógeno , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/prevenção & controle , Neoplasias Cutâneas/genéticaRESUMO
DNA mismatch repair deficiency (MMRd) is associated with a high tumor mutational burden (TMB) and sensitivity to immune checkpoint blockade (ICB) therapy. Nevertheless, most MMRd tumors do not durably respond to ICB and critical questions remain about immunosurveillance and TMB in these tumors. In the present study, we developed autochthonous mouse models of MMRd lung and colon cancer. Surprisingly, these models did not display increased T cell infiltration or ICB response, which we showed to be the result of substantial intratumor heterogeneity of mutations. Furthermore, we found that immunosurveillance shapes the clonal architecture but not the overall burden of neoantigens, and T cell responses against subclonal neoantigens are blunted. Finally, we showed that clonal, but not subclonal, neoantigen burden predicts ICB response in clinical trials of MMRd gastric and colorectal cancer. These results provide important context for understanding immune evasion in cancers with a high TMB and have major implications for therapies aimed at increasing TMB.
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Neoplasias Encefálicas , Neoplasias Colorretais , Síndromes Neoplásicas Hereditárias , Animais , Camundongos , Neoplasias Colorretais/genética , Antígenos de Neoplasias/genética , Mutação , Reparo de Erro de Pareamento de DNA/genética , Biomarcadores Tumorais/genéticaRESUMO
Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1, POU2F3 and Inflammatory. Initially, SCLC subtypes were thought to be mutually exclusive, but recent evidence shows intra-tumoural subtype heterogeneity and plasticity between subtypes. Here, using a CRISPR-based autochthonous SCLC genetically engineered mouse model to study the consequences of KDM6A/UTX inactivation, we show that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumours that express both ASCL1 and NEUROD1. Mechanistically, KDM6A normally maintains an active chromatin state that favours the ASCL1 subtype with its loss decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes leading to a cell state that is primed for ASCL1-to-NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides an autochthonous SCLC genetically engineered mouse model to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Animais , Camundongos , Carcinoma de Pequenas Células do Pulmão/genética , Histona Desmetilases/genética , Cromatina , Epigenômica , Neoplasias Pulmonares/genéticaRESUMO
Oxidative stress is associated with cardiovascular and neurodegenerative diseases. Here we report studies of neurovascular oxidative stress in chemogenetic transgenic mouse lines expressing yeast D-amino acid oxidase (DAAO) in neurons and vascular endothelium. When these transgenic mice are fed D-amino acids, DAAO generates hydrogen peroxide in target tissues. DAAO-TGCdh5 transgenic mice express DAAO under control of the putatively endothelial-specific Cdh5 promoter. When we provide these mice with D-alanine, they rapidly develop sensory ataxia caused by oxidative stress and mitochondrial dysfunction in neurons within dorsal root ganglia and nodose ganglia innervating the heart. DAAO-TGCdh5 mice also develop cardiac hypertrophy after chronic chemogenetic oxidative stress. This combination of ataxia, mitochondrial dysfunction, and cardiac hypertrophy is similar to findings in patients with Friedreich's ataxia. Our observations indicate that neurovascular oxidative stress is sufficient to cause sensory ataxia and cardiac hypertrophy. Studies of DAAO-TGCdh5 mice could provide mechanistic insights into Friedreich's ataxia.
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Ataxia de Friedreich , Camundongos , Animais , Camundongos Transgênicos , Cardiomegalia , Estresse Oxidativo , Ataxia/complicaçõesRESUMO
Alveolar type 2 (AT2) cells, the epithelial progenitor cells of the distal lung, are known to be the prominent cell of origin for lung adenocarcinoma. The regulatory programs that control chromatin and gene expression in AT2 cells during the early stages of tumor initiation are not well understood. Here, we dissected the response of AT2 cells to Kras activation and p53 loss (KP) using combined single cell RNA and ATAC sequencing in an established tumor organoid system. Multi-omic analysis showed that KP tumor organoid cells exhibit two major cellular states: one more closely resembling AT2 cells (SPC-high) and another with loss of AT2 identity (hereafter, Hmga2-high). These cell states are characterized by unique transcription factor (TF) networks, with SPC-high states associated with TFs known to regulate AT2 cell fate during development and homeostasis, and distinct TFs associated with the Hmga2-high state. CD44 was identified as a marker of the Hmga2-high state, and was used to separate organoid cultures for functional comparison of these two cell states. Organoid assays and orthotopic transplantation studies indicated that SPC-high cells have higher tumorigenic capacity in the lung microenvironment compared to Hmga2-high cells. These findings highlight the utility of understanding chromatin regulation in the early oncogenic versions of epithelial cells, which may reveal more effective means to intervene the progression of Kras-driven lung cancer.
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Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are reported to be highest in liver tissue, which is also a hub for lipid production. While the loss of GSH did not cause liver failure, it decreased lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we found that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver's balance of redox buffering and triglyceride production.
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The endoplasmic reticulum (ER)-resident protein fat storage-inducing transmembrane protein 2 (FIT2) catalyzes acyl-CoA cleavage in vitro and is required for ER homeostasis and normal lipid storage in cells. The gene encoding FIT2 is essential for the viability of mice and worms. Whether FIT2 acts as an acyl-CoA diphosphatase in vivo and how this activity affects the liver, where the protein was discovered, are unknown. Here, we report that hepatocyte-specific Fitm2 knockout (FIT2-LKO) mice fed a chow diet exhibited elevated acyl-CoA levels, ER stress, and signs of liver injury. These mice also had more triglycerides in their livers than control littermates due, in part, to impaired secretion of triglyceride-rich lipoproteins and reduced capacity for fatty acid oxidation. We found that challenging FIT2-LKO mice with a high-fat diet worsened hepatic ER stress and liver injury but unexpectedly reversed the steatosis phenotype, similar to what is observed in FIT2-deficient cells loaded with fatty acids. Our findings support the model that FIT2 acts as an acyl-CoA diphosphatase in vivo and is crucial for normal hepatocyte function and ER homeostasis in the murine liver.
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Fígado Gorduroso , Fígado , Animais , Camundongos , Fígado/metabolismo , Triglicerídeos/metabolismo , Fígado Gorduroso/metabolismo , Hepatócitos/metabolismo , Retículo Endoplasmático/metabolismo , Camundongos Knockout , Homeostase , Proteínas de Membrana/metabolismoRESUMO
Human movement is accomplished through muscle contraction, yet there does not exist a portable system capable of monitoring muscle length changes in real time. To address this limitation, we previously introduced magnetomicrometry, a minimally-invasive tracking technique comprising two implanted magnetic beads in muscle and a magnetic field sensor array positioned on the body's surface adjacent the implanted beads. The implant system comprises a pair of spherical magnetic beads, each with a first coating of nickel-copper-nickel and an outer coating of Parylene C. In parallel work, we demonstrate submillimeter accuracy of magnetic bead tracking for muscle contractions in an untethered freely-roaming avian model. Here, we address the clinical viability of magnetomicrometry. Using a specialized device to insert magnetic beads into muscle in avian and lagomorph models, we collect data to assess gait metrics, bead migration, and bead biocompatibility. For these animal models, we find no gait differences post-versus pre-implantation, and bead migration towards one another within muscle does not occur for initial bead separation distances greater than 3 cm. Further, using extensive biocompatibility testing, the implants are shown to be non-irritant, non-cytotoxic, non-allergenic, and non-irritating. Our cumulative results lend support for the viability of these magnetic bead implants for implantation in human muscle. We thus anticipate their imminent use in human-machine interfaces, such as in control of prostheses and exoskeletons and in closed-loop neuroprosthetics to aid recovery from neurological disorders.
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SIGNIFICANCE: Differential expression of PKM1 and PKM2 impacts prostate tumorigenesis and suggests a potential therapeutic vulnerability in prostate cancer.
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Adenocarcinoma , Neoplasias da Próstata , Adenocarcinoma/genética , Carcinogênese , Humanos , Masculino , Próstata/metabolismo , Neoplasias da Próstata/genética , Piruvato Quinase/metabolismoRESUMO
Lung progenitor cells are crucial for regeneration following injury, yet it is unclear whether lung progenitor cells can be functionally engrafted after transplantation. We transplanted organoid cells derived from alveolar type II (AT2) cells enriched by SCA1-negative status (SNO) or multipotent SCA1-positive progenitor cells (SPO) into injured mouse lungs. Transplanted SNO cells are retained in the alveolar regions, whereas SPO cells incorporate into airway and alveolar regions. Single-cell transcriptomics demonstrate that transplanted SNO cells are comparable to native AT2 cells. Transplanted SPO cells exhibit transcriptional hallmarks of alveolar and airway cells, as well as transitional cell states identified in disease. Transplanted cells proliferate after re-injury of recipient mice and retain organoid-forming capacity. Thus, lung epithelial organoid cells exhibit progenitor cell functions after reintroduction to the lung. This study reveals methods to interrogate lung progenitor cell potential and model transitional cell states relevant to pathogenic features of lung disease in vivo.
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Organoides , Ataxias Espinocerebelares , Animais , Diferenciação Celular , Células Epiteliais , Pulmão , Camundongos , Células-TroncoRESUMO
Ovarian and uterine cancers are the most prevalent types of gynecological malignancies originating from mesothelial and/or Müllerian-derived epithelial cells. Recent genomic studies have identified common mutations in them that affect signaling pathways such as p53, PTEN/PI3K, RAS, and WNT pathways. However, how these mutations and their corresponding deregulated pathways affect gynecological cancer development from their cells-of-origin remains largely elusive. To address this, we performed the intrabursal injection of Cre-expressing adenovirus under the control of Krt8 promoter (Ad-K8-Cre) to mice carrying combinations of various conditional alleles for cancer genes. We found that Ad-K8-Cre specifically targeted mesothelial cells, including ovarian surface epithelial (OSE) cells (mainly the LGR5+ subset of OSE cells) and mesothelial cells lining the fallopian tube (FT) serosa; the injected Ad-K8-Cre also targeted Müllerian-derived epithelial cells, including FT epithelial cells and uterine endometrial epithelial cells. The loss of p53 may preferentially affect Müllerian-derived epithelial cells, leading to the development of uterine and ovarian malignancies, whereas PTEN-loss may preferentially affect mesothelial cells, leading to the development of ovarian endometrioid malignancies (upon KRAS-activation or APC-loss) or adenoma on the FT surface (upon DICER-loss). Overall, our data suggest that different Krt8+ mesothelial and epithelial cell types in the female reproductive system may have different sensitivities toward oncogenic mutations and, as a result, oncogenic events may dominantly determine the locations and types of the gynecological malignancies developed from them.