Biology subjects

Guenther, L. M.

Publications and source records attributed to Guenther, L. M..

4 recordsLinked to original sources

bioRxiv2026

Chemokine-Dependent Natural Killer Cells Prevent Pulmonary Metastasis in a Newly Established Mouse Osteosarcoma Model

Rampant genomic instability of osteosarcoma (OS) and associated inter- and intratumoral heterogeneity convey a high risk of metastasis despite contemporary multimodal therapy. A mouse primary OS tumor model, originating from Myc-overexpressing Trp53-null mesenchymal progenitor cells, closely mimics cardinal genetic features and gene expression patterns of human OS samples. Subcutaneous injection of OS cells into immunocompromised NSG mice produced extensive metastases, whereas many fewer metastases occurred in T cell-deficient nude mice, suggesting a principal role for innate immunity in controlling OS dissemination. Depletion of natural killer (NK) cells in nude mice facilitated OS metastasis. OS cells released a suite of chemokines, with CCL2 the most prominent. A genome-wide CRISPR/Cas9 screen in OS cells identified 11 genes, including Ccl2, whose loss facilitated pulmonary metastasis in nude mice. Disruption of CCL2 in OS cells partially phenocopied the effects of antibody-dependent NK cell depletion, underscoring a plausible OS-NK signaling pathway that limits OS metastasis. SignificanceOsteosarcoma exhibits complex genomic instability and a propensity for pulmonary metastasis that limit chemotherapeutic response and patient survival. Despite the plethora of heterogeneous genetic alterations that connote poor prognosis, a novel preclinical in vivo model for studying metastasis highlights potentially targetable signaling between osteosarcoma cell-derived chemokines and pulmonary NK cells.

cancer biology↗

bioRxiv2026

Tabular foundation model predicts alternative lengthening of telomeres (ALT) and identifies SMARCAL1 as a target in ALT-driven cancers

Alternative lengthening of telomeres (ALT) is a telomerase-independent pathway used by aggressive cancers to maintain their replicative immortality. Because ALT is absent from normal human cells, it is an appealing target for cancer therapy, but the lack of ability to determine ALT status at scale has hindered discovery. Here, we developed ALTitude, a machine learning method from a tabular foundation model that infers ALT from cell line whole genome sequencing data, without need for paired germline analysis. We deployed ALTitude across the DepMap, doubling the number of known ALT+ cancer models. Systematic integration of ALTitude with CRISPR-Cas9 screens yielded the selective dependency on SMARCAL1 in ALT+ cell lines, where we show it stabilizes the ALT phenotype. Acute depletion of SMARCAL1 leads to G2/M arrest, mitotic catastrophe, and cell death. These data provide a valuable resource for studying ALT-related genomic features and present SMARCAL1 as a therapeutic target for ALT+ malignancies.

cancer biology↗

bioRxiv2023

A compendium of Amplification-Related Gain Of Sensitivity (ARGOS) genes in human cancer

Chromosomal gains are among the most frequent somatic genetic alterations occurring in cancer. While the effect of sustained oncogene expression has been characterized, the impact of copy-number gains affecting collaterally-amplified "bystander" genes on cellular fitness remains less understood. To investigate this, we built a comprehensive map of dosage compensations across human cancers by integrating expression and copy number profiles from over 8,000 TCGA tumors and CCLE cell lines. Further, we analyzed the effect of gene overexpression across 17 human cancer ORF screens to provide an overview of genes that prove toxic to cancer cells when overexpressed. Combining these two independent approaches we propose a class of Amplification-Related Gain Of Sensitivity (ARGOS) genes. These genes are located in commonly amplified regions of the genome, have lower expression levels than expected by their copy-number status, and are toxic to cancer cells when overexpressed. We experimentally validated CDKN1A and RBM14 as high-confidence pan-cancer ARGOS genes in lung and breast cancer cell line models. We additionally suggest that RBM14s mechanism of toxicity involves altered DNA damage response and innate immune signaling processes following gene overexpression. Finally, we provide a comprehensive catalog of compensated, toxic, and ARGOS genes as a community resource.

cancer biology↗

bioRxiv2021

Mitochondrial Dysfunction is a Driver for SP-2509 Drug Resistance in Ewing Sarcoma

Expression of the fusion oncoprotein EWS/FLI causes Ewing sarcoma, an aggressive pediatric tumor characterized by widespread epigenetic deregulation. These epigenetic changes are targeted by novel lysine specific demethylase-1 (LSD1) inhibitors, which are currently in early phase clinical trials. Single agent targeted therapy often induces resistance, and successful clinical development requires knowledge of resistance mechanisms, enabling the design of effective combination strategies. Here, we used a genome-scale CRISPR-Cas9 loss-of-function screen to identify genes whose knockout (KO) conferred resistance to the LSD1 inhibitor SP- 2509 in Ewing sarcoma cell lines. Multiple genes required for mitochondrial electron transport chain (ETC) complexes III and IV function were hits in our screen. We validated this finding using genetic and chemical approaches including CRISPR KO, ETC inhibitors, and mitochondrial depletion. Further global transcriptional profiling revealed that altered complex III/IV function disrupted the oncogenic program mediated by EWS/FLI and LSD1 and blunted the transcriptomic response to SP-2509. These findings demonstrate that mitochondrial dysfunction modulates SP-2509 efficacy and suggest that new therapeutic strategies combining LSD1 with agents which prevent mitochondrial dysfunction may benefit patients with this aggressive malignancy.

cancer biology↗