Pursuing Cancer: 10x Genomics Customers Continue to Expand Our Knowledge of the Disease
"We always had cancer in mind when we thought about products from the earliest days. Cancer is one of the most complex genetic diseases, and I believed the tools we were building were going to let people understand cancer in a way they previously couldn't."
That’s Michael Schnall-Levin, SVP of R&D at 10x Genomics. He is a member of the early team of scientists and innovators, including founders CEO Serge Saxonov and CSO Ben Hindson, that came together in 2012 to take the dream that was 10x into the lab.
From its origins, 10x Genomics has sought to resolve complex biology and advance human health. This goal has manifested in many ways, including our efforts to create tools that can accelerate cancer research and drive discoveries that may, in turn, guide development of improved or novel therapeutics.
Recently, innovations in single cell and spatial gene expression analysis are providing insight into the study of cancer. Dr. Schnall-Levin comments on why cancer research needs these new capabilities: "Cancer is fundamentally a disease of heterogeneity. Tumor cells, infiltrating immune cells, and the surrounding environment all interact in highly complex ways. It's impossible to understand and ultimately defeat the disease without understanding how these cells differ, how they're spatially organized, and how they interact."
It was in the pursuit of this understanding of cancer that 10x Genomics researchers and collaborators produced our first cancer paper. The publication came out in 2016 in Nature Biotechnology, and presented a microfluidics-based, linked-read sequencing technology that could haplotype germline and cancer genomes with limited input DNA. The researchers used these Linked-Reads products to support genomic analysis of a primary colorectal cancer clinical tissue sample (1). Since then, the growing portfolio of 10x Genomics products, that include single cell and spatial profiling technologies, have been used in 100 oncology- or immuno-oncology-specific publications: this includes one paper in 2016, 12 in 2017, 35 in 2018, and now, a still growing 52 publications in 2019.
What discoveries are 10x Genomics products enabling today? This summer has been a particularly active publishing period, and we want to take the opportunity to highlight five papers from our customers. Their stories align along a common thread: that cancer is heterogeneous, and complex, yet thorough understanding of the disease, including how it originates and progresses, can be pursued via human ingenuity that leverages powerful tools.
Plasticity between cancer cell states makes glioblastoma harder to treat
The brain is one system in which researchers are pushing the boundaries of cancer research. Cyril Neftel and colleagues from Massachusetts General Hospital have performed "the most comprehensive scRNA-seq analysis of glioblastoma to date" (2). Single cell gene expression profiling of over 24,000 tumor cells helped them identify four unique cellular states that drive glioblastoma malignancy. These states are influenced by copy number amplifications or mutations in specific loci, including CDK4, EGFR, PDGFRA and NF1, and malignant cells exhibit significant plasticity between them (2). This single cell resolution offers a major advancement towards fully characterizing the heterogeneity of glioblastoma, known to be one of the main factors underlying therapeutic failure.
Cells that form childhood brain tumors originate early in embryonic development
To understand cancer, it is also important to trace the developmental origins of the disease. Maria Vladoiu and colleagues from the Hospital for Sick Children in Toronto, Canada sought to perform this kind of study on pediatric brain cancers, including medulloblastoma. They used scRNA-seq to compare the transcriptional profiles of normal mouse neural cells, gathered at different embryonic time points, with the transcriptomes of human childhood cerebellar tumours, and saw strong similarities between cancer cells and certain neural progenitor cells (3). This cancer cell atlas study shows that pediatric brain tumors appear much earlier than thought in utero. In addition, researchers anticipate that this study will help identify targetable developmental checkpoints that are defective in cerebellar tumours.
Unbiased census of bone marrow cells sheds light on leukemia
Cancer development and progression is heavily influenced by the tumor microenvironment. Cancer, in turn, has profound effects on its surroundings, coordinating and exploiting the cells, blood vessels, extracellular matrix and signaling pathways that make up its resident tissue. Ninib Baryawno and colleagues from Massachusetts General Hospital and the Broad Institute of Harvard sought to evaluate the influence of emerging acute myeloid leukemia (AML) on the bone marrow microenvironment. They used scRNA-seq to perform a comprehensive census of the mouse bone marrow stroma, observing that the presence of cancer cells led to impaired mesenchymal osteogenic differentiation and reduced regulatory molecules necessary for normal hematopoiesis (4). These findings suggest that cancer cells crosstalk with tissue stroma to impair normal tissue function and enable emergent cancer growth, and point to the possibility of developing stromal-targeted therapies in hematologic disease.
Immunotherapy recruits cancer-fighting T cells from outside the tumor
Part of this pursuit of cancer entails identifying novel therapeutic opportunities, improving existing therapies, and defining the molecular mechanisms underlying therapy success. Kathryn Yost and Ansuman Satpathy, along with their colleagues from the Stanford University School of Medicine and Parker Institute for Cancer Immunotherapy, performed single cell immune profiling on 79,046 T cells from basal and squamous cell carcinoma tumors following anti-PD1-therapy (5). They found that the clonal repertoire of exhausted CD8+ T cells was largely replaced by novel clones after immunotherapy treatment. This may suggest that pre-existing tumor-specific T cells have limited reinvigoration capacity, and that the T cell response to checkpoint blockade derives from T cell clones that may have just recently entered the tumor. This finding has important implications for the design of checkpoint blockade immunotherapies, in that improved therapeutic activity may hinge on the tumor microenvironment’s ability to attract new T cells.
New T cell receptor therapy prevents relapse in AML patients
These and other findings are paving the way for positive therapeutic outcomes for cancer patients, as Aude Chapuis and colleagues from the Fred Hutchinson Cancer Research Center in Seattle, Washington, demonstrate. They identified Wilms’ Tumor Antigen 1 (WT1) as a high-priority antigen target in AML, and subsequently introduced WT1-specific T cell receptors into donor T cells (6). They infused these new T cells into 12 poor-risk AML patients, hoping to reduce relapse in patients who have received hematopoietic cell transplantation (HCT) treatment. They observed 100% relapse-free survival at a median of 44 months following infusion, while a comparative group of 88 patients with similar risk AML had only 54% relapse-free survival (6). Subsequent scRNA-seq analysis helped them to assess the molecular qualities of these long-term persisting T cells, and thus the underlying reasons for therapy success.
New discoveries are being made—even in well studied areas—because of the novel perspective that solutions from 10x Genomics can provide. Studies like these allow us to see that cancer cell populations are far more dynamic and heterogeneous than expected, and that bulk population analysis has been inadequate to fully characterize hidden biological complexity. Thanks to high-resolution genomics, information that was previously out of reach is now helping cancer researchers to make discoveries more quickly.
See how other researchers are using 10x technology to address the biggest needs in cancer research:
Watch two videos to learn how to "Gain a Multidimensional View of Cancer" and "Resolve the Spectrum of Tumor Heterogeneity":
Learn more about our products:
- G.X. Zheng, B.T Lau, M. Schnall-Levin et al., Haplotyping germline and cancer genomes with high-throughput linked-read sequencing. Nature Biotechnology. 34, 3 (2016).
- C. Neftel, J. Laffy, M. G. Filbin et al., An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma. Cell. 178, 1–15 (2019).
- M. Vladoiu, I. El-Hamamy, L. Donovan, H. Farooq, B. Holgado et al., Childhood cerebellar tumours mirror conserved fetal transcriptional programs. Nature. 572, 7767 (2019).
- N. Baryawno, D. Przybylski, M. Kowalczyk et al., A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia. Cell. 177, 1–18 (2019).
- K. Yost, A. Satpathy, D. Wells et al., Clonal replacement of tumor-specific T cells following PD-1 blockade. Nature. 25, 8 (2019).
- A. Chapuis, D. Egan, M. Bar, T. Schmitt, M. McAfee et al., T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant. Nature Medicine. 25, 7 (2019).