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Lung Mammary Metastases but Not Primary Tumors Induce Accumulation of Atypical Large Platelets and Their Chemokine Expression.

ABSTRACT: The tumor microenvironment (TME) at the metastatic site consists of multiple components with considerable cellular heterogeneity. To test whether endothelial cells (ECs) associated with lung metastases express a distinct gene expression program that promotes metastatic growth, we isolated CD31+/CD45- cells from lung mammary cancer metastases for RNA sequencing and found CD44 upregulation. Unexpectedly, the CD44+ subset did not comprise authentic ECs nor were they bone-marrow-derived CD45- endothelial progenitor cells. Instead, they were a population of large platelets that are distinct from regular small platelets. These CD44+ large platelets were enriched in lung metastases but not primary mammary tumors and upregulated myeloid cell-regulating chemokines indicative of potential regulation of metastasis via indirect mechanisms. Identification of this cellular player in the TME of metastasis suggests a role for the recently identified lung-resident megakaryocytes (MKs) and offers an unexplored route to discover novel mechanisms and an opportunity for therapeutic interventions.

SUBMITTER: Zheng W

PROVIDER: S-EPMC6919330 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Lung Mammary Metastases but Not Primary Tumors Induce Accumulation of Atypical Large Platelets and Their Chemokine Expression.

Zheng Wei W Zhang Hui H Zhao Dejian D Zhang Jinghang J Pollard Jeffrey W JW

Cell reports 20191101 7

The tumor microenvironment (TME) at the metastatic site consists of multiple components with considerable cellular heterogeneity. To test whether endothelial cells (ECs) associated with lung metastases express a distinct gene expression program that promotes metastatic growth, we isolated CD31+/CD45- cells from lung mammary cancer metastases for RNA sequencing and found CD44 upregulation. Unexpectedly, the CD44+ subset did not comprise authentic ECs nor were they ...[more]

PMID: 31722193

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Project description:The accumulation of mutations is a contributing factor in the initiation of premalignant mammary lesions and their progression to malignancy and metastasis. We have used a mouse model in which the carcinogen is the mouse mammary tumor virus (MMTV) which induces clonal premalignant mammary lesions and malignant mammary tumors by insertional mutagenesis. Identification of the genes and signaling pathways affected in MMTV-induced mouse mammary lesions provides a rationale for determining whether genetic alteration of the human orthologues of these genes/pathways may contribute to human breast carcinogenesis. A high-throughput platform for inverse PCR to identify MMTV-host junction fragments and their nucleotide sequences in a large panel of MMTV-induced lesions was developed. Validation of the genes affected by MMTV-insertion was carried out by microarray analysis. Common integration site (CIS) means that the gene was altered by an MMTV proviral insertion in at least two independent lesions arising in different hosts. Three of the new genes identified as CIS for MMTV were assayed for their capability to confer on HC11 mouse mammary epithelial cells the ability for invasion, anchorage independent growth and tumor development in nude mice. Analysis of MMTV induced mammary premalignant hyperplastic outgrowth (HOG) lines and mammary tumors led to the identification of CIS restricted to 35 loci. Within these loci members of the Wnt, Fgf and Rspo gene families plus two linked genes (Npm3 and Ddn) were frequently activated in tumors induced by MMTV. A second group of 15 CIS occur at a low frequency (2-5 observations) in mammary HOGs or tumors. In this latter group the expression of either Phf19 or Sdc2 was shown to increase HC11 cells invasion capability. Foxl1 expression conferred on HC11 cells the capability for anchorage-independent colony formation in soft agar and tumor development in nude mice. The published transcriptome and nucleotide sequence analysis of gene expression in primary human breast tumors was interrogated. Twenty of the human orthologues of MMTV CIS associated genes are deregulated and/or mutated in human breast tumors.

Project description:Rationale: Platelets are increasingly recognized as mediators of tumor growth and metastasis. Hypothesizing that activated platelets in the tumor microenvironment provide a targeting epitope for tumor-directed chemotherapy, we developed an antibody-drug conjugate (ADC), comprised of a single-chain antibody (scFv) against the platelet integrin GPIIb/IIIa (scFvGPIIb/IIIa) linked to the potent chemotherapeutic microtubule inhibitor, monomethyl auristatin E (MMAE). Methods: We developed an ADC comprised of three components: 1) A scFv which specifically binds to the high affinity, activated integrin GPIIb/IIIa on activated platelets. 2) A highly potent microtubule inhibitor, monomethyl auristatin E. 3) A drug activation/release mechanism using a linker cleavable by cathepsin B, which we demonstrate to be abundant in the tumor microenvironment. The scFvGPIIb/IIIa-MMAE was first conjugated with Cyanine7 for in vivo imaging. The therapeutic efficacy of the scFvGPIIb/IIIa-MMAE was then tested in a mouse metastasis model of triple negative breast cancer. Results: In vitro studies confirmed that this ADC specifically binds to activated GPIIb/IIIa, and cathepsin B-mediated drug release/activation resulted in tumor cytotoxicity. In vivo fluorescence imaging demonstrated that the newly generated ADC localized to primary tumors and metastases in a mouse xenograft model of triple negative breast cancer, a difficult to treat tumor for which a selective tumor-targeting therapy remains to be clinically established. Importantly, we demonstrated that the scFvGPIIb/IIIa-MMAE displays marked efficacy as an anti-cancer agent, reducing tumor growth and preventing metastatic disease, without any discernible toxic effects. Conclusion: Here, we demonstrate the utility of a novel ADC that targets a potent cytotoxic drug to activated platelets and specifically releases the cytotoxic agent within the confines of the tumor. This unique targeting mechanism, specific to the tumor microenvironment, holds promise as a novel therapeutic approach for the treatment of a broad range of primary tumors and metastatic disease, particularly for tumors that lack specific molecular epitopes for drug targeting.

Dataset Information

Lung Mammary Metastases but Not Primary Tumors Induce Accumulation of Atypical Large Platelets and Their Chemokine Expression.

Publications

Lung Mammary Metastases but Not Primary Tumors Induce Accumulation of Atypical Large Platelets and Their Chemokine Expression.

Similar Datasets

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