Biology subjects

Tschaharganeh, D. F.

Publications and source records attributed to Tschaharganeh, D. F..

6 recordsLinked to original sources

bioRxiv2026

Cell-of-Origin, not Oncogenic Effect, Determines esmoplastic Immune Exclusion in KRAS-Driven Liver Cancer

Intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) are the two most common primary liver cancers and share common risk factors. Yet they exhibit distinct oncogenic driver landscapes and fundamentally different tumor microenvironments (TME), with iCCA characterised by dense desmoplastic stroma that limits therapeutic efficacy. Whether these differences reflect oncogenic context or the developmental lineage of the cancer cell has remained unresolved. Here, using syngeneic orthotopic murine models derived from CRISPR-engineered cholangiocyte and hepatocyte organoids each carrying Trp53 deletion and KrasG12D mutation, we show that cell-of-origin, not oncogenic pathway activation, is the dominant determinant of TME architecture. Spatial proteomics of [~]390,000 cells reveals that cholangiocyte-derived tumors develop a stromal barrier of peripherally enriched SMA+ cancer-associated fibroblasts (CAFs) that physically excludes immune cells and elevates PD-1/PD-L1 engagement, whereas hepatocyte derived tumors permit broader immune infiltration. Transcriptional variance partitioning confirms lineage as the primary source of gene expression divergence. Integrating murine and human transcriptomic and secretomic datasets, we identify LAMC2 and uPA as cholangiocyte lineage-specific secreted factors that trigger CAF activation. Genetic deletion of either factor markedly impairs iCCA formation in vivo. These findings establish that lineage-encoded secretory programmes create a desmoplastic and immune-excluded stroma and identify LAMC2 and uPA as functionally relevant modulators of TME in KRAS-driven iCCA.

cancer biology↗

bioRxiv2025

BAP1 modulates endoplasmic reticulum stress signaling and balances liver homeostasis and malignant progression

ObjectivePrimary liver cancer is a leading cause of cancer-related mortality and harbors recurrent mutations in chromatin regulators such as BRCA1-associated protein 1 (BAP1), yet their functional impact remains unclear. We investigated how BAP1 deficiency affects liver homeostasis and tumorigenesis to clarify its functional role. DesignWe employed inducible, liver-specific BAP1 knockdown in mice subjected to diet-induced metabolic stress (including rescue experiments), alongside autochthonous hydrodynamic CRISPR models, and profiled livers by RNA-seq, immunohistochemistry, and mass spectrometry-based lipidomics. Complementary mechanistic assays in liver cancer cells examined the unfolded protein response (UPR) under endoplasmic reticulum (ER) stress; findings were supported by immunohistochemical and transcriptomic analyses of BAP1-mutant patient samples. ResultsBAP1 safeguards liver homeostasis under diet-induced metabolic stress, as its loss triggers ER stress, hepatocyte death, and acute liver failure. Lipidomics revealed a shift toward ER-stress-associated dyslipidemia, and transcriptomics showed negative enrichment of fatty-acid metabolism and positive enrichment of UPR pathways. In contrast, BAP1 loss synergizes with oncogenic drivers to accelerate tumorigenesis in autochthonous liver cancer models, underscoring its context-dependent tumor suppressor function. Mechanistically, BAP1 directly regulates the ER stress mediator DDIT3 (CHOP) through chromatin remodeling, linking BAP1 loss to maladaptive stress responses. Consistently, elevated CHOP expression was observed in BAP1-mutant human liver cancers and other tumor types. ConclusionThese findings establish BAP1 as a key chromatin regulator that connects stress adaptation to both liver homeostasis and tumorigenesis, highlighting the BAP1-UPR axis for future translational assessment. What is already known on this topic?BAP1 is a recurrently mutated chromatin regulator across cancers, including primary liver cancer, but its functional role in liver biology and tumorigenesis has remained unclear. Metabolic dysfunction-associated liver disease is a growing driver of liver tumorigenesis and is characterized by lipid imbalance, ER stress, and activation of the unfolded protein response. What this study adds?We show that BAP1 is a key chromatin regulator that integrates metabolic and ER stress responses in the liver. Loss of BAP1 undermines cellular adaptation to metabolic challenge and cooperates with oncogenic signals to promote liver tumorigenesis via dysregulated DDIT3 (CHOP) expression, linking chromatin control to hepatic stress resilience and disease progression. How this study might affect research, practice or policy?Our findings position the UPR-CHOP axis as a candidate therapeutic vulnerability in BAP1-deficient liver cancers, particularly in the context of MASLD/MASH, and provide a conceptual framework for targeting stress adaptation pathways in precision oncology.

cancer biology↗

bioRxiv2025

Repurposing passenger amplifications as Trojan horses identifies MPZL1 as a potent target for solid cancers

Personalized cancer therapies focus mostly on targeting driver alterations, such as oncogenic point mutations or oncogenic driver events within large somatic copy number alterations. However, these alterations are often not actionable or only present in a small subset of patients. We hypothesized that passenger events, specifically in amplified regions, could be therapeutically exploited by providing actionable molecules on the cell surface, serving as Trojan horses for specific therapy delivery. Applying a multiomics in silico approach, we identified MPZL1 (Myelin protein zero-like 1), a glycosylated cell surface receptor located on chromosome 1q, as a promising candidate, which is amplified in up to 75% of cases in several solid cancers. Notably, immunohistochemistry of a wide range of human cancer tissues (n=2244 samples) as well as normal tissues revealed strong membranous MPZL1 expression in a majority of solid tumors (e.g. 48% of hepatocellular carcinomas or 89% of triple-negative breast cancers), whereas healthy tissues were mostly negative or just faintly positive for MPZL1. Next, we generated a highly specific monoclonal antibody directed to the extracellular domain of human MPZL1 protein and utilized this antibody to produce MPZL1 CAR-T cells. MPZL1 CAR-T cells showed high specificity as well as high sensitivity in targeting a multitude of human cancer cell lines (e.g. liver, breast, and lung cancer) with high MPZL1 expression in vitro. Finally, we demonstrate strong therapeutic efficiency of MPZL1 CAR-T cells not only in different human xenograft tumors in vivo but also in a unique autochthonous liver cancer mouse model. Our work provides a framework to target passenger events within large chromosomal amplifications, reveals MPZL1 as a new trojan horse entry point for therapies of 1q-amplified cancers, and as such opens a new avenue for innovative approaches in anti-cancer drug development.

cancer biology↗

bioRxiv2023

Phosphatidylinositol 4-kinase III alpha governs cytoskeletal organization for invasiveness of liver cancer cells

Background and AimsHigh expression of phosphatidylinositol 4-kinase III alpha (PI4KIII) correlates with poor survival rates in patients with hepatocellular carcinoma (HCC). In addition, Hepatitis C virus (HCV) infections activate PI4KIII and contribute to HCC progression. We aimed at mechanistically understanding the impact of PI4KIII on the progression of liver cancer and the potential contribution of HCV in this process. MethodsSeveral hepatic cell culture and mouse models were used to study functional importance of PI4KIII on liver pathogenesis. Antibody arrays, gene silencing and PI4KIII specific inhibitor were applied to identify the involved signaling pathways. The contribution of HCV was examined by using HCV infection or overexpression of its nonstructural protein. ResultsHigh PI4KIII expression and/or activity induced cytoskeletal rearrangements via increased-phosphorylation of paxillin and cofilin. This led to morphological alterations and higher migratory and invasive properties of liver cancer cells. We further identified the liver specific lipid kinase phosphatidylinositol 3-kinase C2 domain-containing subunit gamma (PIK3C2{gamma}) working downstream of PI4KIII in regulation of the cytoskeleton. PIK3C2{gamma} generates plasma membrane (PM) phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2]- enriched, invadopodia-like structures which regulate cytoskeletal reorganization by promoting Akt2 phosphorylation. ConclusionsPI4KIII regulates cytoskeleton organization via PIK3C2{gamma}/Akt2/paxillin-cofilin to favor migration and invasion of liver cancer cells. These findings provide mechanistic insight into the contribution of PI4KIII and HCV to progression of liver cancer and identify promising targets for therapeutic intervention. IMPACT AND IMPLICATIONSUnderstanding mechanistically how high PI4KIII expression are associated with poor clinical outcomes of liver cancer is important to develop pharmaceutical interventions. Our study sheds light on the importance of the two lipid kinases PI4KIII and PIK3C2{gamma} as well as the contribution of HCV on liver cancer progression, unraveling the signaling pathway governing this process. This preclinical study contributes to better understanding the complex connection of phospholipids, cytoskeleton and liver cancer and suggests strategies to improve therapeutic outcomes by targeting important signaling molecules. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/541742v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@16ba717org.highwire.dtl.DTLVardef@a6f681org.highwire.dtl.DTLVardef@181c3cdorg.highwire.dtl.DTLVardef@5df6aa_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2018

An optimized toolkit for precision base editing

CRISPR base editing is a potentially powerful technology that enables the creation of genetic mutations with single base pair resolution. By re-engineering both DNA and protein sequences, we developed a collection of constitutive and inducible base editing vector systems that dramatically improve the ease and efficiency by which single nucleotide variants can be created. This new toolkit is effective in a wide range of model systems, and provides a means for efficient in vivo somatic base editing.

bioengineering↗

bioRxiv2017

DNAJB1-PRKACA fusion kinase drives tumorigenesis and interacts with β-catenin and the liver regenerative response.

A segmental deletion resulting in DNAJB1-PRKACA gene fusion is now recognized as the signature genetic event of fibrolamellar hepatocellular carcinoma (FL-HCC), a rare but lethal liver cancer that primarily affects adolescents and young adults. Here, we implement CRISPR/Cas9 genome editing and transposon-mediated somatic gene transfer to demonstrate that expression of both the endogenous fusion protein or a chimeric cDNA leads to the formation of indolent liver tumors in mice that closely resemble human FL-HCC. Notably, overexpression of the wild type PRKACA was unable to fully recapitulate the oncogenic activity of DNAJB1-PRKACA, implying that FL-HCC does not simply result from enhanced PRKACA expression. Tumorigenesis was significantly enhanced by genetic activation of {beta}-catenin, an observation supported by evidence of recurrent Wnt pathway mutations in human FL-HCC, as well as treatment with hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), which causes tissue injury, inflammation and fibrosis. Our study validates the DNAJB1-PRKACA fusion kinase as an oncogenic driver and candidate drug target for FL-HCC and establishes a practical model for preclinical studies to identify strategies to treat this disease.\n\nSignificanceEfforts to understand and treat FL-HCC have been confounded by a lack of models that accurately reflect the genetics and biology of the disease. Here, we demonstrate that the Dnajb1-Prkaca gene fusion drives tumorigenesis in mice, and that fusion to DNAJB1 drives FL-HCC initiation more effectively than wild type PRKACA overexpression. The requirement of the PRKACA kinase domain in tumor initiation establishes the potential utility of kinase inhibitors targeting the fusion. By identifying genetic and environmental factors that can enhance the consistency and aggressiveness of disease progression, we reveal biological characteristics of the disease and advance a robust platform for future pre-clinical studies.

cancer biology↗