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Transcriptional diversity and bioenergetic shift in human breast cancer metastasis revealed by single-cell RNA sequencing

ABSTRACT: Although metastasis remains the cause of most cancer-related mortality, mechanisms governing seeding in distal tissues are poorly understood. Here we establish a robust method for identification of global transcriptomic changes in rare metastatic cells during seeding using single-cell RNA-sequencing and patient-derived xenograft (PDX) models of breast cancer. We find that both primary tumours and micrometastases display transcriptional heterogeneity, but micrometastases harbor a distinct transcriptome program conserved across PDX models that is highly predictive of poor survival in patients. Pathway analysis revealed mitochondrial oxidative phosphorylation (OXPHOS) as the top pathway upregulated in micrometastases, in contrast to higher levels of glycolytic enzymes in primary tumour cells, which we corroborated by flow cytometric and metabolomic analyses. Pharmacological inhibition of OXPHOS dramatically attenuated metastatic seeding in the lungs, which demonstrates the functional importance of OXPHOS in seeding and highlights its potential as a therapeutic target to prevent metastatic spread in breast cancer patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE123837 | GEO | 2020/02/20

REPOSITORIES: GEO

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Project description:Breast cancer is a heterogeneous collection of disease arising from the breast with distinct molecular and phenotypic features. Certain subsets of patients have tumors that are particularly difficult-to-treat, which include triple-negative breast cancer (TNBC), metastatic/recurrent disease and rare histological variants. To delineate the underlying biology and identify therapeutic candidates for these patients, a series of 37 breast cancer patient-derived xenografts (PDX) from both chemo-naïve and pre-treated specimens was generated from 81 transplant attempts. Whole-genome and transcriptome sequencing revealed marked fidelity of the molecular landscape for the majority of PDXs in comparison to parental tumors. Reverse-phase protein array analysis of PDXs further identified potential therapeutic targets. Metastatic potential varied between PDXs, where low-penetrance lung micrometastases was the most common pattern of dissemination and observed in 34.5% of models. Three PDXs recapitulated the metastatic localization seen in the corresponding patients, including two lines with high-frequency metastases to multiple vital organ systems, while another PDX displayed tropism to the skull-base. Chemosensitivity profiling was performed in vivo with standard-of-care agents (doxorubicin, cisplatin, gemcitabine or paclitaxel), where multi-drug chemoresistance was found in 60.0% of PDXs and 64.7% of responses were concordant with pre-engraftment responses observed in the patient. Consolidating chemogenomic data identified potentially actionable features in 97.2% of PDXs, and marked regressions were seen in vivo when a subset of these underwent proof-of-concept functional studies. This included FGFR inhibitor sensitivity in a FGFR1-amplified lobular carcinoma, mTOR inhibitor sensitivity in a recurrent neuroendocrine breast cancer with proteomic evidence of mTOR/PI3K activation, and platinum sensitivity in a TNBC with BRCA1 germline mutation predicted as benign. Together, this clinically-annotated PDX library with comprehensive molecular and phenotypic profiling serves as a resource for both discovery and validation preclinical studies on difficult-to-treat breast tumors.

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Transcriptional diversity and bioenergetic shift in human breast cancer metastasis revealed by single-cell RNA sequencing

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