Biology subjects

Dhar, S. S.

Publications and source records attributed to Dhar, S. S..

5 recordsLinked to original sources

bioRxiv2026

TIM3+ Tumor Associated M2 Macrophages Impair Antitumor T Cell Immunity and Promote Gastric Cancer Progression and Peritoneal Metastasis

Peritoneal metastases (PM) are the leading cause of cancer-related death in gastric cancer (GC) patients with survival typically < 9 months. Here, we demonstrate that TIM3 and its ligands are increased along the GC continuum and associated with poor survival. Integrated omics analyses and functional studies revealed highly enriched TIM3 in CD163+ tumor associated M2 immunosuppressive macrophages significantly promote tumor cell invasion and tumor growth in vivo, while TIM3 depletion in macrophages reduced tumor cell malignant attributes and increased T cell immunity from PBMCs or CD45+ immune cells of malignant ascites in co-culture system. By cytokine and kinase arrays, we discovered that depletion of TIM3 in macrophages reduced the production of notable secretome of cytokines/chemokines from M2 macrophages; and the protumor function of TIM3+ macrophages rely on the p90RSK1/2/CCL20 axis. Finally, we reveal that TIM3 blockage or genetic KO had superior antitumor activity in combination with anti-PD1 immunotherapy and mitomycin C (MMC) chemotherapy. Together, this study uncovers an important role for TIM3 in tumor associated M2 macrophages and underscores the potential of TIM3 blockage in GC patients with PM. Statement of significanceIn this study, we show TIM3 increases along GC continuum, and highly enriched on tumor associated M2 macrophages that fuel tumor growth; and suppress T cell function via p90RSK1/2/CCL20 axis. TIM3 depletion restores T-cell immunity and curbs tumor growth. TIM3 blockade combined with anti-PD1 and mitomycin C provide a novel therapeutic strategy for GC patients with PM.

immunology↗

bioRxiv2025

YAP1 Depletion Enhances TAZ and its Complexation with TEAD4 and AP-1 Heterodimer C-JUN/FOSB to Promote Gastric Cancer Progression and Metastases

BackgroundDysregulation of the Hippo signaling pathway, characterized by aberrant activation of the transcriptional coactivators YAP1 and TAZ, drives tumour progression, immunosuppression and metastasis. Hippo pathway components are emerging therapeutic targets in several solid tumours, however, the expression profiles of Hippo coactivators YAP1, TAZ and their transcriptional factors TEAD1-4 in gastric cancer peritoneal metastases (GCPMs) and their therapeutic value are unknown. ObjectiveTo determine expression status of YAP1, TAZ and TEAD1-4 in GCPMs; and to evaluate whether dual targeting of YAP1 and TAZ provides superior antitumour activity compared with inhibition of either coactivator alone. DesignExpression of YAP1, TAZ and TEAD1-4 was examined in GCPMs by single-cell RNA sequencing and co-immunofluorescent staining. Functional studies using genetic knockout and antisense oligonucleotide (ASO) inhibition of YAP1 or TAZ were performed to assess antineoplastic effects in vitro and in vivo. Co-immunoprecipitation and luciferase reporter assays were used to characterize YAP1/TAZ interactions with TEADs and AP-1 components (JUN and FOSB) and to quantify transcriptional activity. Antitumour efficacy was validated in patient-derived xenograft (PDX) and KP-Luc2 syngeneic models. ResultsYAP1, TAZ, and TEADs1- 4 were highly coexpressed in GCPMs and correlated with poor survival. YAP1 inhibition alone elicited compensatory upregulation of TAZ, while combined inhibition of both coactivators maximally repressed cell proliferation and invasion in vitro, and tumor growth in vivo. Increased TAZ complexation with TEAD4 and AP-1 (c-JUN and FOSB) heterodimer was observed following YAP1 knockdown or pharmacological ASO inhibition. Dual inhibition of YAP1 and TAZ was required to maximally suppress YAP1/TAZ expression and reduce their nuclear accumulation, transactivation of TEAD, and activation of downstream genes. ConclusionsThese findings show that combined YAP1 and TAZ inhibition holds promise for the treatment of GCPMs, a highly lethal disease with an urgent need for novel treatment options. WHAT IS ALREADY KNOWN ON THIS TOPICO_LIGastric cancer with peritoneal metastasis (GCPM), occurring in > 45% of gastric cancer (GC) patients, is a highly lethal malignancy with limited therapeutic options. C_LIO_LIThe Hippo pathway mediator Yes-associated protein 1 (YAP1) is intimately involved in chemoresistance, cancer stemness properties, and the epithelial-to-mesenchymal transition in gastric and other cancers. C_LIO_LIWhile YAP1 represents a promising therapeutic target, clinical trial of YAP1 antisense oligonucleotides has been disappointing. C_LI WHAT THIS STUDY ADDSO_LIHippo coactivators YAP1, TAZ and their main transcription factors TEAD1-4 are markedly upregulated in GCPMs and associated with poor prognosis. C_LIO_LIAntisense targeting of YAP1 results in compensatory upregulation of its paralog TAZ. C_LIO_LIUpon YAP1 depletion, TAZ forms transcriptional complexes with TEAD4 and the AP-1 heterodimer (JUN and FOSB). C_LIO_LIDual targeting of YAP1 and TAZ, by oligonucleotides, achieves maximal suppression of tumour growth in vitro and in vivo. C_LI HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYO_LIThese findings provide a strong mechanistic rationale for co-targeting YAP1 and TAZ as a therapeutic approach in metastatic gastric cancer. C_LIO_LIDual Hippo coactivator inhibition could inform the design of future clinical trials aimed at improving outcomes for patients with GCPMs. C_LI

cancer biology↗

bioRxiv2023

Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of lysine demethylation and oxidative phosphorylation

The histone H3 lysine 4 (H3K4) methyltransferase KMT2D (also called MLL4) is one of the most frequently mutated epigenetic modifiers in medulloblastoma (MB) and many other types of cancer. Notably, heterozygous loss of KMT2D is prevalent in MB and other cancer types. However, what role heterozygous KMT2D loss plays in tumorigenesis has not been well characterized. Here, we show that heterozygous Kmt2d loss highly promotes MB driven by heterozygous loss of the MB suppressor gene Ptch in mice. Heterozygous Kmt2d loss upregulated tumor-promoting programs, including oxidative phosphorylation and G-protein-coupled receptor signaling, in Ptch+/--driven MB genesis. Mechanistically, both downregulation of the transcription-repressive tumor suppressor gene NCOR2 by heterozygous Kmt2d loss and upregulation of the oncogene MycN by heterozygous Ptch loss increased the expression of tumor-promoting genes. Moreover, heterozygous Kmt2d loss extensively diminished enhancer signals (e.g., H3K27ac) and H3K4me3 signature, including those for tumor suppressor genes (e.g., Ncor2). Combinatory pharmacological inhibition of oxidative phosphorylation and the enhancer-decommissioning H3K4 demethylase LSD1 drastically reduced tumorigenicity of MB cells bearing heterozygous Kmt2d loss. These findings reveal the mechanistic basis underlying the MB-promoting effect of heterozygous KMT2D loss, provide a rationale for a therapeutic strategy for treatment of KMT2D-deficient MB, and have mechanistic implications for the molecular pathogenesis of other types of cancer bearing heterozygous KMT2D loss.

cancer biology↗

bioRxiv2021

GIVE Statistic for Goodness of Fit in Instrumental Variables Models with Application to COVID Data

Since COVID-19 outbreak, scientists have been interested to know whether there is any impact of the Bacillus Calmette-Guerin (BCG) vaccine against COVID-19 mortality or not. It becomes more relevant as a large population in the world may have latent tuberculosis infection (LTBI), for which a person may not have active tuberculosis but persistent immune responses stimulated by Mycobacterium tuberculosis antigens, and that means, both LTBI and BCG generate immunity against COVID-19. In order to understand the relationship between LTBI and COVID-19 mortality, this article proposes a measure of goodness of fit, viz., Goodness of Instrumental Variable Estimates (GIVE) statistic, of a model obtained by Instrumental Variables estimation. The GIVE helps in finding the appropriate choice of instruments, which provides a better fitted model. In the course of study, the large sample properties of the GIVE statistic are investigated. As indicated before, the COVID-19 data is analysed using the GIVE statistic, and moreover, simulation studies are also conducted to show the usefulness of the GIVE statistic.

bioinformatics↗

bioRxiv2018

Super-enhancer impairment is a link between MLL4 inactivated lung tumors and their vulnerability to glycolysis pathway inhibition

Epigenetic modifiers often harbor loss-of-function mutations in lung cancer, but their tumor-suppressive roles are poorly characterized. Here we show that lung-specific loss of the gene encoding the histone methyltransferase MLL4 (alias KMT2D; a COMPASS-like enzyme), which is ranked the most highly inactivated epigenetic modifier in lung cancer, strongly promotes lung adenocarcinoma in mice. Mll4 loss upregulated tumor-promoting programs, including glycolysis. The pharmacological inhibition of glycolysis preferentially impeded tumorigenic growth of human lung cancer cells bearing MLL4-inactivating mutations. Mll4 loss widely impaired epigenomic signals for super-enhancers and enhancers, including the super-enhancer for the circadian rhythm repressor gene Per2, and decreased Per2 expression. Per2 downregulated several glycolytic pathway genes. These findings uncover a distinct tumor-suppressive epigenetic mechanism in which MLL4 enhances Per2-mediated repression of pro-tumorigenic glycolytic genes via super-enhancer activation to suppress lung adenocarcinoma tumorigenesis and also implicate a glycolysis-targeting strategy as a therapeutic intervention for the treatment of MLL4- mutant lung cancer.

cancer biology↗