Biology subjects

Rupji, M.

Publications and source records attributed to Rupji, M..

4 recordsLinked to original sources

bioRxiv2023

Loss of the endocytic tumor suppressor HD-PTP phenocopies LKB1 and promotes RAS-driven oncogenesis.

Abstract/SummaryOncogenic RAS mutations drive aggressive cancers that are difficult to treat in the clinic, and while direct inhibition of the most common KRAS variant in lung adenocarcinoma (G12C) is undergoing clinical evaluation, a wide spectrum of oncogenic RAS variants together make up a large percentage of untargetable lung and GI cancers. Here we report that loss-of-function alterations (mutations and deep deletions) in the gene that encodes HD-PTP (PTPN23) occur in up to 14% of lung cancers in the ORIEN Avatar lung cancer cohort, associate with adenosquamous histology, and occur alongside an altered spectrum of KRAS alleles. Furthermore, we show that in publicly available early-stage NSCLC studies loss of HD-PTP is mutually exclusive with loss of LKB1, which suggests they restrict a common oncogenic pathway in early lung tumorigenesis. In support of this, knockdown of HD-PTP in RAS-transformed lung cancer cells is sufficient to promote FAK-dependent invasion. Lastly, knockdown of the Drosophila homolog of HD-PTP (dHD-PTP/Myopic) synergizes to promote RAS-dependent neoplastic progression. Our findings highlight a novel tumor suppressor that can restrict RAS-driven lung cancer oncogenesis and identify a targetable pathway for personalized therapeutic approaches for adenosquamous lung cancer.

cancer biology↗

bioRxiv2022

Targeting TRIP13 in Wilms Tumor with Nuclear Export Inhibitors

Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies in a systematic manner remains challenging in part due to the lack of faithful preclinical in vitro models. We established ten short-term patient-derived WT cell lines and characterized these models using low-coverage whole genome sequencing, whole exome sequencing and RNA-sequencing, which demonstrated that these ex-vivo models faithfully recapitulate WT biology. We then performed targeted RNAi and CRISPR-Cas9 loss-of-function screens and identified the nuclear export genes (XPO1 and KPNB1) as strong vulnerabilities. We observed that these models are sensitive to nuclear export inhibition using the FDA approved therapeutic agent, selinexor (KPT-330). Selinexor treatment of FHWT suppressed TRIP13 expression, which was required for survival. We further identified in vitro and in vivo synergy between selinexor and doxorubicin, a chemotherapy used in high risk FHWT. Taken together, we identified XPO1 inhibition with selinexor as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.

cancer biology↗

bioRxiv2020

The level of oncogenic Ras controls the malignant transformation of Lkb1 mutant tissue in vivo.

The genetic and metabolic heterogeneity of RAS-driven cancers has confounded therapeutic strategies in the clinic. To address this, rapid and genetically tractable animal models are needed that recapitulate the heterogeneity of RAS-driven cancers in vivo. Here, we generate a Drosophila melanogaster model of Ras/Lkb1mutant carcinoma. We show that low-level expression of oncogenic Ras (RasLo) promotes the survival of Lkb1 mutant tissue, but results in autonomous cell cycle arrest and non-autonomous overgrowth of wild-type tissue. In contrast, high-level expression of oncogenic Ras (RasHi) transforms Lkb1 mutant tissue resulting in lethal malignant tumors. Using simultaneous multiview light-sheet microcopy, we have characterized invasion phenotypes of Ras/Lkb1 tumors in living larvae. Our molecular analysis reveals sustained activation of the AMPK pathway in malignant Ras/Lkb1 tumors, and demonstrate the genetic and pharmacologic dependence of these tumors on CaMK-activated Ampk. We further show that LKB1 mutant human lung adenocarcinoma patients with high levels of oncogenic KRAS exhibit worse overall survival and increased AMPK activation. Our results suggest that high levels of oncogenic KRAS is a driving event in the malignant transformation of LKB1 mutant tissue, and uncover a novel vulnerability that may be used to target this aggressive genetic subset of RAS-driven tumors. One Sentence SummaryA multivariable Ras-driven Drosophila model reveals a novel LKB1 mutant lung adenocarcinoma patient subpopulation and targetable effector pathway.

cancer biology↗

bioRxiv2018

NOJAH: Not Just Another Heatmap for Genome-Wide Cluster Analysis

Since their inception, several tools have been developed for cluster analysis and heatmap construction. The application of such tools to the number and types of genome-wide data available from next generation sequencing (NGS) technologies requires the adaptation of statistical concepts, such as in defining a most variable gene set, and more intricate cluster analyses method to address multiple omic data types. Additionally, the growing number of publicly available datasets has created the desire to estimate the statistical significance of a gene signature derived from one dataset to similarly group samples based on another dataset. The currently available number of tools and their combined use for generating heatmaps, along with the several adaptations of statistical concepts for addressing the higher dimensionality of genome-wide NGS-derived data, has created a further challenge in the ability to replicate heatmap results. We introduce NOJAH (NOt Just Another Heatmap), an interactive tool that defines and implements a workflow for genome-wide cluster analysis and heatmap construction by creating and combining several tools into a single user interface. NOJAH includes several newly developed scripts for techniques that though frequently applied are not sufficiently documented to allow for replicability of results. These techniques include: defining a most variable gene set (a.k.a., core genes), estimating the statistical significance of a gene signature to separate samples into clusters, and performing a result merging integrated cluster analysis. With only a user uploaded dataset, NOJAH provides as output, among other things, the minimum documentation required for replicating heatmap results. Additionally, NOJAH contains five different existing R packages that are connected in the interface by their functionality as part of a defined workflow for genome-wide cluster analysis. The NOJAH application tool is available at http://bbisr.shinyapps.winship.emory.edu/NOJAH/ with corresponding source code available at https://github.com/bbisr-shinyapps/NOJAH/.

bioinformatics↗