Single Cell Sequencing: The Future of Cancer Care
Imagine that you have recently been diagnosed with cancer and have discussed treatment options with your oncologist. Twenty years ago, there would only be a limited number of unattractive treatment options from which to choose, depending on tumor progression. A standard of care combining surgical excision of the tumor with chemotherapy measurably increased five-year survival but tumor relapse and chemotherapy side effects, worse in many ways than the disease itself, has slowed progress.
The advent of oncology therapies acting against molecular targets in pathways inhibiting carcinogenesis has opened new treatment options with greatly reduced toxicities. A recent example is the blocking of the epidermal growth factor (EGF) signaling pathway by the binding of a monoclonal antibody to the EGF receptor (Erbitux, Vectibix) or the inhibition of tyrosine kinase activity in the EGF pathway (Tarceva, Iressa, Tykerb). Despite these advances, a distressingly high percentage of tumors still relapse after the first treatment, leading all too often to early patient death despite aggressive treatment with second- and third-line therapies. Indeed, tumor recurrence is responsible for more than half of the US$126 billion annual direct costs in the United States in the care of patients with cancer  and remains critical.
What do we know about the mechanisms driving tumor relapse? Recent research shows genetic heterogeneity from cell-to-cell in a tumor and from patient-to-patient for the same tumor type . The cellular heterogeneity has been categorized according to different characteristics by which tumor cells become resistant to a drug therapy. The first category are tumor cells with innate resistance that gives them a pre-existing resistance to the drug; a second group comprises cells that have acquired resistance from a de novo mutation(s); and a third population consists of stem-like cells that differentiate to escape the selective pressure imposed by the drug . Drivers of tumor relapse are not only genetic in nature but also epigenetic as shown in a recent study by Knoechel et al. on epigenetic mechanisms of relapse in T-cell lymphoblastic leukemia .
How were these insights into tumor relapse revealed? By sequencing and comparing nucleic acid sequences (DNA, RNA, and chromatin DNA) from single cells in tumors from different patients. Despite the significant investments made toward higher throughput, lower cost sequencing, the ability to reliably sequence the millions of cells in a typical tissue biopsy remains elusive. Nanopore-based sequencing as described by Rosenstein in the July 2014 issue of IEEE Pulse  is a promising path forward that could yield significant clinical benefit. The combination of a simple yet powerful method to quickly obtain sequence information from many thousands of cells in a tumor clearly will change in a fundamental way our understanding of complex, heterogeneous diseases like cancer. Treatment selection and therapeutic options based on a single-cell tumor profile will be done in the near future. With this emergent capability, cancer may become not the life-threatening condition it is today with high mortality but a treatable chronic disease.
- A. Mariotto, K. R. Yabroff, Y. Shao, E. Feuer, and M. Brown, “Projections of the cost of cancer care in the United States: 2010–2020,” J. Natl. Cancer Inst., vol. 103, no. 2, pp. 117–128, 2011.
- R. Burrell, N. McGranahan, J. Bartek, and C. Swanton, Nature, pp. 338–345, 2013.
- C. Meacham and S. Morrison, Nature, vol. 501, pp. 328–438, 2013.
- B. Knoechel et al., Nat. Genet., vol. 46, pp. 364–370, Apr. 2014.
- [Online]. Available: http://www.genomeweb.com/sequencing/nih-awards-145-million-fund-new-sequencing-technologies
- J. Rosenstein, “The promise of nanopore technology,” IEEE Pulse, vol. 5, no. 4,
pp. 52–54, July 2014.