Dataset Information

Organ specific fibroblast-derived matrix as a tool for understanding breast cancer metastasis

ABSTRACT: Triple negative breast cancer has an extremely poor prognosis due to lack of available targeted treatments, especially for metastasis. Metastatic sites frequently include the lymph nodes and the lungs, and during the metastatic process, breast cancer cells must come into contact with the extracellular matrix (ECM) at every step. The ECM provides both structural support and biochemical cues, and cell-ECM interactions can lead to changes in to drug response. Here, we used fibroblast-derived ECM to perform high throughput drug screening of 4T1 breast cancer cells on metastatic organ ECM (lung) and we see that drug response differs to drug inhibition on plastic. The FDM that we are able to produce from different metastatic organs is abundant in, and contains a complex mixture of ECM proteins. We also show differences in ECM composition between the primary site and metastatic sites. Furthermore, we show that global kinase signalling of 4T1 cells on the ECM is relatively unchanged between organs, however we show large changes in signalling compared to plastic. Our study highlights the importance of context when testing drug response in vitro, showing that the consideration of the ECM is critically important.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Fibroblast

SUBMITTER: Erwin Schoof

LAB HEAD: Janine Erler

PROVIDER: PXD025786 | Pride | 2022-02-17

REPOSITORIES: Pride

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Publications

Organ-Specific, Fibroblast-Derived Matrix as a Tool for Studying Breast Cancer Metastasis.

Jensen Adina R D ARD Horton Edward R ER Blicher Lene H LH Pietras Elin J EJ Steinhauer Cornelia C Reuten Raphael R Schoof Erwin M EM Erler Janine T JT

Cancers 20210702 13

During the metastatic process, breast cancer cells must come into contact with the extra-cellular matrix (ECM) at every step. The ECM provides both structural support and biochemical cues, and cell-ECM interactions can lead to changes in drug response. Here, we used fibroblast-derived ECM (FDM) to perform high throughput drug screening of 4T1 breast cancer cells on metastatic organ ECM (lung), and we see that drug response differs from treatment on plastic. The FDMs that we can produce from diff ...[more]

PMID: 34283050

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Project description:Background:Breast cancer is the second most frequent type of cancer affecting women. We are increasingly aware that changes in mRNA splicing are associated with various characteristics of cancer. The most deadly aspect of cancer is metastasis, the process by which cancer spreads from the primary tumor to distant organs. However, little is known specifically about the involvement of alternative splicing in the formation of macroscopic metastases. Our study investigates transcript isoform changes that characterize tumors of different abilities to form growing metastases. Results:To identify alternative splicing events (ASEs) that are associated with the fully metastatic phenotype in breast cancer, we used Affymetrix Exon Microarrays to profile mRNA isoform variations genome-wide in weakly metastatic (168FARN and 4T07) and highly metastatic (4T1) mammary carcinomas. Statistical analysis identified significant expression changes in 7606 out of 155,994 (4%) exons and in 1725 out of 189,460 (1%) intronic regions, which affect 2623 out of 16,654 (16%) genes. These changes correspond to putative alternative isoforms - several of which are novel - that are differentially expressed between tumors of varying metastatic phenotypes. Gene pathway analysis showed that 1224 of genes expressing alternative isoforms were involved in cell growth, cell interactions, cell proliferation, cell migration and cell death and have been previously linked to cancers and genetic disorders. We chose ten predicted splice variants for RT-PCR validation, eight of which were successfully confirmed (MED24, MFI2, SRRT, CD44, CLK1 and HNRNPH1). These include three novel intron retentions in CD44, a gene in which isoform variations have been previously associated with the metastasis of several cancers. Conclusions:Our findings reveal that various genes are differently spliced and/or expressed in association with the metastatic phenotype of tumor cells. Identification of metastasis-specific isoforms may contribute to the development of improved breast cancer stage identification and targeted therapies. Keywords: Seek pre-mRNA changes associated with the fully metastatic phenotype in breast cancer We used RNA tumor tissues derived from three murine mammary carcinoma cell lines (168FARN, 4T07 and 4T1); four biological replicates of 168FARN, four biological replicates of 4T07, and four biological replicates of 4T1 were hybridized independently at McGill university site.

Dataset Information

Organ specific fibroblast-derived matrix as a tool for understanding breast cancer metastasis

Publications

Organ-Specific, Fibroblast-Derived Matrix as a Tool for Studying Breast Cancer Metastasis.

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