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A synthetic lethal strategy to target chromosome 8p deleted cancers

ABSTRACT: This project aimed to identify a specific target for chromosome 8p deletions. Using large-scale functional-genomic screening data of over 527 well-characterized cancer cell lines. We were able to identify the dependency of SLC25A28 (Mitoferrin-2, MFRN2), a mitochondrial iron transporter, in chromosome 8p deleted cancer cell lines. Interestingly, we found that SLC25A37 (Mitoferrin-1, MFRN1), the paralog of MFRN2, resides on chromosome 8p and is frequently deleted in liver cancer. We found a strong correlation between the cellular dependency on MFRN2 and the MFRN1 expression levels, possibly explaining why MFRN2 is a synthetic lethal target for 8p deletions. Our study discovered MFRN2 as a target for a therapeutic strategy in chromosome 8p deleted cancer specimens. Further, it revealed MFRN1 as a biomarker that predicts the response to MFRN2-directed therapy.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte, Snu-387 Cell

DISEASE(S): Hepatocellular Carcinoma

SUBMITTER: Darjus Tschaharganeh

LAB HEAD: Darjus Tschaharganeh

PROVIDER: PXD044780 | Pride | 2024-06-03

REPOSITORIES: Pride

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Project description:Viswanathan SR, Nogueira MF, Buss CG, Krill-Burger JM, Wawer MJ, Malolepsza E, Choi PS, Berger A, Shih J, Tanenbaum B, Strathdee CA, Tamayo P, Pedamallu CS, Vazquez F, Lage K, Carr SA, Schenone M, Bhatia SN, Cherniack AD, Tsherniak A, Hahn WC, Meyerson M. Nature Genetics 2018. Chromosome arm-level deletion events are highly prevalent across cancer types. The targeting of functionally redundant paralog genes required for cell viability has been proposed as a potential therapeutic strategy to selectively kill cancer cells with chromosome arm deletions. Here, we identify MAGOHB as a novel therapeutic target for chromosome 1p deleted cancer through an analysis of paralog dependencies emerging from genome-wide shRNA screening of cancer cell lines. MAGOHB and its functionally redundant paralog, MAGOH, are core members of the exon-junction complex (EJC), a multi-protein complex that is deposited at exon-exon junctions after mRNA splicing and that has important roles in regulating pre-mRNA splicing, mRNA transport, and nonsense-mediated decay (NMD) MAGOHB is the top differential dependency in cells with hemizygous loss of MAGOH, a pervasive passenger genetic event across multiple tumor types that frequently occurs in the context of chromosome 1p loss. Inhibition of MAGOHB in cells with deletion of MAGOH compromises viability by globally perturbing alternative splicing and RNA surveillance, resulting in an accumulation of premature-termination codon-containing transcripts. We further identify IPO13, a bidirectional karyopherin that mediates nuclear import of the MAGOH/B-Y14 heterodimer as a potentially druggable target whose dependency is highly correlated to both MAGOH and MAGOHB dependency, suggesting a rationale for inhibiting MAGOH/MAGOHB function by interfering with EJC recycling. Finally, we validate MAGOHB as a target in vivo through delivery of a tumor-penetrating peptide-siRNA nanocomplex. Our results define MAGOH and MAGOHB as reciprocal paralog dependencies across cancer types and identify the MAGOHB-IPO13 axis as an potential therapeutic target in MAGOH-deleted cancers and in cancers with chromosome 1p deletion.

Project description:Eukaryotic DNA replication initiates from multiple sites on each chromosome called replication origins. In the budding yeast Saccharomyces cerevisiae, origins are defined at discrete sites. Regular spacing and diverse firing characteristics of origins are thought to be required for efficient completion of replication, especially in the presence of replication stress. However, a S. cerevisiae chromosome III harboring multiple origin deletions has been reported to replicate relatively normally, and yet how an origin-deficient chromosome could accomplish successful replication remains unkown. To address this issue, we deleted seven well-characterized origins from chromosome VI, and found that thsese deletions do not cause gross growth defects even in the presence of replication inhibitors. We demonstrated that the origin deletions do cause a strong decrease in the binding of the origin recognition complex. Unexpectedly, replication profiling of this chromosome showed that DNA replication initiates from non-canonical loci around deleted origins in yeast. These results suggest that replication initiation can be unexpectedly flexible in this organism. In this study, we aimed to establish an independent system to investigate how an origin-deficient chromosome is replicated. To this end, we systematically deleted seven well-characterized origins on the left arm of S. cerevisiae chromosome VI and analyzed (1) Orc2 localization during G2/M arrest and (2) BrdU incorporation during synchronous release from G1 arrest into S-phase, and compared the results to wild-type cell signals. For Orc2 ChIP-Chip experiments, Orc-bound DNA was isolated from Orc2-2Xlinker-3XFlag epitope-tagged cells arrested in G2/M using antibodies against Flag. For BrdU ChIP-Chip experiments, actively replicating DNA was isolated from cells harboring a single integrated BrdU incorporation vector released synchronously into 200mM HU using antibodies against BrdU. Immunoprecipitated and input (Orc2) or G1 (BrdU) DNA was then amplified and competitively hybridized to high-resolution strand-specific microarrays covering chromosomes III, VI, and XII.

Project description:To model the effect of Pten loss on breast cancer, we deleted Pten using a floxed allele and the deleter lines MMTV-Cre(NLST), which targets stem/bi-potent progenitor cells, and WAP-Cre, which targets CD24-positive, pregnancy-identified stem cells/alveolar progenitors. Mammary tumors were detected in WAP-Cre:Ptenf/f females with a latency of 15.2 months. By 18 months, nearly all mice had succumbed to cancer. MMTV-Cre:Ptenf/f mice developed mammary tumors after a longer latency of 26.4 months and reduced penetrance (70%) compared to WAP-Cre:Ptenf/f mice. Tumors from both models were heterogeneous, consisting primarily of differentiated adenocarcinoma (adenomyoepithelioma; ~70%) and adenosquamous carcinoma (20-25%). In addition, a small fraction of tumors was classified as acinar and poorly differentiated adenocarcinoma (4-7%) and adenosarcoma (3-4%). To test the consequences of combined Pten and p53 gene mutation on breast cancer, we deleted both genes via MMTV-Cre or WAP-Cre. Kaplan-Meier tumor free survival curves revealed that WAP-Cre:Ptenf/f:p53f/f and MMTV-Cre:Ptenf/f:p53f/f females developed tumors with reduced latency of 11.3 and 9.8 months, compared with 15.2, 26.4, and 16.9 months for single-mutant WAP-Cre:Ptenf/f, MMTV-Cre:Ptenf/f or MMTV-Cre:p53f/f mice, respectively. In contrast to the heterogeneity of Pten tumors and small percentage of adenosarcomas in these mice, ~70% of Pten:p53 lesions were histologically classified as adeno-sacrcomatoid-like or mesenchymal-like breast cancer, with the rest exhibiting mixed mesenchymal plus adenocarcinomas and differentiated adenocarcinomas. The adeno-sacrcomatoid-like tumors expressed the mesenchymal markers vimentin, K5, SMA, N-cadherin and desmin but not ER, as well as islands of luminal-like K18 expressing cells surrounded by a layer of K14-positive cells. We used microarrays to detect differentially expressed genes in the Pten:p53 double-knock-out vs Pten or p53 single deletions Total RNA was extracted from tumors developed by double Trizol method and hybridized on Affymetrix microarrays.

			Action	DRS
	UP000005640_9606.fasta	Fasta
	oecf3-SK0383-01.raw	Raw
	oecf3-SK0383-02.raw	Raw
	oecf3-SK0383-03.raw	Raw
	oecf3-SK0383-04.raw	Raw

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A synthetic lethal strategy to target chromosome 8p deleted cancers

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