Microfluidics-based genomics analysis

Microfluidics technologies facilitate rapid, high-throughput, and reproducible capture and analysis of individual cells

Systems-level reconstruction of the disease state

Global gene expression analysis of individual cells comprising normal or cancer tissues facilitate reconstruction of how the system functions in toto

Stem cells in development and disease

Understanding the role of stem cells and developmental programs in cancer initiation and metastasis

 

Patient-derived xenograft (PDX) models are generated by transplanting human patient tumor samples into mice. PDX mice can subsequently serve as patient ‘avatars’ to authentically study many aspects of tumor progression and metastasis.

The metastatic spread of tumor cells to other tissues in the body is the cause of nearly all mortality for breast cancer patients. Our work focuses on identifying new strategies to prevent or control metastasis, as we believe this is the most promising approach to improving patient outcomes

Tumors behave much like normal tissues, which are hierarchically organized with stem-like cells at the apex that give rise to more differentiated progeny. We study the role of stem cells and cellular differentiation in cancer progression and metastasis using in vitro, in vivo, and genomic approaches.

The fundamental unit of all tissues is the single cell. We use diverse single-cell technologies and bioinformatic approaches to understand cellular diversity and its impact on cancer progression and metastasis.

Featured publication

Transcriptional diversity and bioenergetic shift in human breast cancer metastasis revealed by single-cell RNA sequencing
Davis RT et al., Nature Cell Biology, 2020

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 the identification of global transcriptomic changes in rare metastatic cells during seeding using single-cell RNA sequencing and patient-derived-xenograft models of breast cancer. We find that both primary tumours and micrometastases display transcriptional heterogeneity but micrometastases harbour a distinct transcriptome program conserved across patient-derived-xenograft models that is highly predictive of poor survival of patients. Pathway analysis revealed mitochondrial oxidative phosphorylation 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 oxidative phosphorylation dramatically attenuated metastatic seeding in the lungs, which demonstrates the functional importance of oxidative phosphorylation in metastasis and highlights its potential as a therapeutic target to prevent metastatic spread in patients with breast cancer.

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