Biology subjects

Schischlik, F.

Publications and source records attributed to Schischlik, F..

8 recordsLinked to original sources

bioRxiv2023

Charting the transcriptomic landscape of primary and metastatic cancers in relation to their origin and target normal tissues

Metastasis is a leading cause of cancer-related deaths, yet understanding how metastatic tumors adapt from their origin to target tissues is challenging. To address this, we assessed whether primary and metastatic tumors resemble their tissue of origin or target tissue in terms of gene expression. We analyzed gene expression profiles from various cancer types, including single-cell and bulk RNA-seq data, in both paired and unpaired primary and metastatic patient cohorts. We quantified the transcriptomic distances between tumor samples and their normal tissues, revealing that primary tumors are more similar to their tissue of origin, while metastases shift towards the target tissue. Pathway-level analysis highlighted critical transcriptomic changes during metastasis. Notably, primary cancers exhibited higher activity in cancer hallmarks, including Activating Invasion and Metastasis, compared to metastatic cancers. This comprehensive landscape analysis provides insight into how cancer tumors adapt to their metastatic environments, providing a transcriptome-wide view of the processes involved.

cancer biology↗

bioRxiv2023

Predicting tumor immune microenvironment and checkpoint therapy response of head & neck cancer patients from blood immune single-cell transcriptomics

The immune state of tumor microenvironment is crucial for determining immunotherapy response but is not readily accessible. Here we investigate if we can infer the tumor immune state from the blood and further predict immunotherapy response. First, we analyze a dataset of head and neck squamous cell carcinoma (HNSCC) patients with matched scRNA-Seq of peripheral blood mononuclear cells (PBMCs) and tumor tissues. We find that the tumor immune cell fractions of different immune cell types and many of the genes they express can be inferred from the matched PBMC scRNA-Seq. Second, analyzing another HNSCC dataset with PBMC scRNA-Seq and immunotherapy response, we find that the inferred ratio between tumor memory B and regulatory T cell fractions is predictive of immunotherapy response and is superior to the well-established cytolytic and exhausted T-cell signatures. Overall, these results showcase the potential of scRNA-Seq liquid biopsies in cancer immunotherapy, calling for their larger-scale testing. SignificanceThis head and neck cancer study demonstrates the potential of using blood single-cell transcriptomics to (1) infer the tumor immune status and (2) predict immunotherapy response from the tumor immune status inferred from blood. These results showcase the potential of single-cell transcriptomics liquid biopsies for further advancing personalized cancer immunotherapy.

bioinformatics↗

bioRxiv2022

High Density Domain-Focused CRISPR Screens Reveal Epigenetic Regulators of HOX/MEIS Gene Expression in Acute Myeloid Leukemia

Aberrant expression of stem-cell-associated genes is a common feature in acute myeloid leukemia (AML) and is linked to leukemic self-renewal and therapy resistance. Using AF10-rearranged leukemia as a prototypical example displaying a recurrent "stemness" network activated in AML, we screened for chromatin regulators that sustain aberrant activation of these networks. We deployed a CRISPR-Cas9 screen with a bespoke domain-focused library and identified several novel chromatin-modifying complexes as regulators of the TALE domain transcription factor MEIS1, a key leukemia stem cell (LSC)-associated gene. CRISPR droplet sequencing revealed that many of these MEIS1 regulators coordinately controlled the transcription of several AML oncogenes. In particular, we identified a novel role for the Tudor-domain containing chromatin reader protein SGF29 in the transcription of key AML oncogenes. Furthermore, SGF29 deletion impaired leukemogenesis in models representative of multiple AML subtypes. Our studies reveal a novel role for SGF29 as a non-oncogenic dependency in AML and identify the SGF29 Tudor domain as an attractive target for drug discovery.

cancer biology↗

bioRxiv2021

Synthetic lethality-based prediction of anti-SARS-CoV-2 targets

Novel strategies are needed to identify drug targets and treatments for the COVID-19 pandemic. The altered gene expression of virus-infected host cells provides an opportunity to specifically inhibit viral propagation via targeting the synthetic lethal (SL) partners of such altered host genes. Pursuing this antiviral strategy, here we comprehensively analyzed multiple in vitro and in vivo bulk and single-cell RNA-sequencing datasets of SARS-CoV-2 infection to predict clinically relevant candidate antiviral targets that are SL with altered host genes. The predicted SL-based targets are highly enriched for infected cell inhibiting genes reported in four SARS-CoV-2 CRISPR-Cas9 genome-wide genetic screens. Integrating our predictions with the results of these screens, we further selected a focused subset of 26 genes that we experimentally tested in a targeted siRNA screen using human Caco-2 cells. Notably, as predicted, knocking down these targets reduced viral replication and cell viability only under the infected condition without harming non-infected cells. Our results are made publicly available, to facilitate their in vivo testing and further validation.

systems biology↗

bioRxiv2021

Deconvolving clinically relevant cellular immune crosstalk from bulk gene expression using CODEFACS and LIRICS

The tumor microenvironment (TME) is a complex mixture of cell types whose interactions affect tumor growth and clinical outcome. To discover such interactions, we developed CODEFACS (COnfident DEconvolution For All Cell Subsets), a tool deconvolving cell-type-specific gene expression in each sample from bulk expression, and LIRICS (LIgand Receptor Interactions between Cell Subsets), a statistical framework prioritizing clinically relevant ligand-receptor interactions between cell types from the deconvolved data. We first demonstrate the superiority of CODEFACS versus the state-of-the-art deconvolution method, CIBERSORTx. Second, analyzing the TCGA, we uncover cell-type-specific interactions of mismatch-repair-deficient tumors that are associated with their higher anti-PD1 response rates, including specific T-cell co-stimulating interactions that enhance immunotherapy response independently of the tumors mutation burden levels. Finally, we identify a subset of ligand-receptor interactions in the melanoma TME that predict patient response to anti-PD1 therapy better than recently published transcriptomics-based methods.

bioinformatics↗

bioRxiv2020

Identifying the Landscape of Intratumoral Microbes via a Single Cell Transcriptomic Analysis

The study of the tumor microbiome has been garnering increased attention. We developed a computational pipeline (CSI-Microbes) for identifying microbial reads from single-cell RNA sequencing (scRNA-seq) data. Using a series of controlled experiments and analyses, we performed the first systematic evaluation of the efficacy of recovering microbial UMIs by multiple scRNA-seq technologies, which identified the newer 10x chemistries (3 v3 and 5) as the best suited approach. Based on these findings, we analyzed patient esophageal and colorectal carcinomas and found that reads from distinct genera tend to co-occur in the same host cells, testifying to possible intracellular polymicrobial interactions. Microbial reads are disproportionately abundant within myeloid cells that upregulate proinflammatory cytokines like IL1B and CXCL8 and downregulate antigen processing and presentation (APP) pathways. The latter, however, are markedly upregulated in infected tumor cells. These results testify that intracellular bacteria predominately reside within co-opted myeloid cells, which inflame the tumor microenvironment and may influence immunotherapy response. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/096230v3_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@16399a5org.highwire.dtl.DTLVardef@1fc464dorg.highwire.dtl.DTLVardef@16ba6c5org.highwire.dtl.DTLVardef@91fa4c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2018

MTHFD1 is a genetic interactor of BRD4 and links folate metabolism to transcriptional regulation

The histone acetyl-reader BRD4 is an important regulator of chromatin structure and transcription, yet factors modulating its activity have remained elusive. Here we describe two complementary screens for genetic and physical interactors of BRD4, which converge on the folate pathway enzyme MTHFD1. We show that a fraction of MTHFD1 resides in the nucleus, where it is recruited to distinct genomic loci by direct interaction with BRD4. Inhibition of either BRD4 or MTHFD1 results in similar changes in nuclear metabolite composition and gene expression, and pharmacologic inhibitors of the two pathways synergize to impair cancer cell viability in vitro and in vivo. Our finding that MTHFD1 and other metabolic enzymes are chromatin-associated suggests a direct role for nuclear metabolism in the control of gene expression.

cancer biology↗

bioRxiv2018

Systematic genetic mapping of necroptosis identifies SLC39A7 as modulator of death receptor trafficking

Regulation of cell and tissue homeostasis by programmed cell death is a fundamental process with wide physiological and pathological implications. The advent of scalable somatic cell genetic technologies creates the opportunity to functionally map these essential pathways, thereby identifying potential disease-relevant components. We investigated the genetic basis underlying necroptotic cell death by performing a complementary set of loss- and gain-of-function genetic screens. To this end, we established FADD-deficient haploid human KBM7 cells, which specifically and efficiently undergo necroptosis after a single treatment with either TNF or the SMAC mimetic compound birinapant. A series of unbiased gene-trap screens identified key signaling mediators, such as TNFR1, RIPK1, RIPK3, and MLKL. Among the novel components, we focused on the zinc transporter SLC39A7, whose knock-out led to necroptosis resistance by affecting TNF receptor trafficking and ER homeostasis. Orthogonal, solute carrier (SLC)-focused CRISPR/Cas9-based genetic screens revealed the exquisite specificity of SLC39A7, among ~ 400 SLC genes, for TNFR1- and FAS-but not TRAIL-R1-mediated responses. The newly established cellular model also allowed genome-wide gain-of-function screening for genes conferring resistance to necroptosis via the CRISPR/Cas9 synergistic activation mediator approach. Among these, we found cIAP1 and cIAP2, and characterized the role of TNIP1 (TNFAIP3-interacting protein 1), which prevented pathway activation in a ubiquitin-binding dependent manner. Altogether, the gain- and loss-of-function screens described here provide a global genetic chart of the molecular factors involved in necroptosis and death receptor signaling, prompting investigation of their individual contribution and potential role in pathological conditions.

cell biology↗