Visualizing intratumoral heterogeneity: a dream come true!

DIPCO, a novel diagnostic pipeline for in-depth characterization of phenotypes in formalin-fixed paraffin-embedded tumor samples
Visualizing intratumoral heterogeneity: a dream come true!

The paper in Nature Biomedical Engineering is here:

Ever since I started as a grad student in the Karolinska University Hospital in Stockholm, Sweden, I have been fascinated by visualizing biological and medical phenomenon with light microscopy. About the same time as I began my research career in the 1990s, the microscopy field started a rapid development with many new fluorescent probes and new microscopy techniques, a fact that is proven by the two Nobel prizes for GFP in 2008 and for STED (stimulated emission depletion) microscopy and PALM (photoactivated localization microscopy) in 2014.

Through a long-lasting collaboration with surgeon Ayako Miyakawa at the Karolinska University Hospital in Stockholm, Sweden I have learned about that many pitfalls when diagnosing and treating patients with cancer. In 2015, Nobuyuki Tanaka from Keio University, Tokyo, Japan was recruited as a postdoc in my laboratory. He was a clinician and urologist with a quest to learn more about intratumoural heterogeneity. At that time, another postdoc in my group, Shigeaki Kanatani, had setup the tissue clearing technique in our laboratory. We also recently got a light-sheet microscope in our microscopy facility, custom built by Raju Tomer from, at that time, Karl Deisseroth’s laboratory in Stanford University, CA, US. Together we sought out to explore the possibilities to develop a pipeline to characterize intratumoural heterogeneity in formalin-fixed paraffin-embedded (FFPE) human tumour samples. 

Intratumoural heterogeneity is central to the natural selection that drives the processes of carcinogenesis, metastasis and acquired resistance to therapeutic interventions (Fig. 1). Solid tumours are three dimensional bodies that consist of structures and landscapes that need to be visualized in three dimensions in order to fully understand their nature. Today’s diagnostic methods applied in hospitals only use two dimensions, creating an information gap. Thus, shedding light on this problem could contribute significantly to our general understanding of how tumours are formed and further the development of new treatment strategies.

Figure 1. Cancer genetic heterogeneity occurs at multiple levels: between patients, between primary and metastatic tumours in a single patient, and between the individual cells of a tumour. Reproduced from Fox, E. J. & Loeb, L. A. Cancer: One cell at a time. Nature 512, 143–144 doi:10.1038/nature13650. Macmillan Publishers.

Our recent paper published in Nature Biomedical Engineering describes a new pipeline named DIPCO (diagnosing immunolabelled paraffin-embedded cleared organs) to phenotypically characterize FFPE tumour samples. This approach can be used to examine both new and old FFPE tumours and then return samples to the biobank for future needs (Fig. 2). We believe these technologies could be implemented quite easily in the clinic through collaborations with basic scientists, and could help pathologists to diagnose tough samples to stage. This project taught us that it is of uttermost importance to initiate and develop collaborations between clinicians working at hospitals and basic scientist working in academia to significantly improve treatment of patients.

Figure 2. The DIPCO pipeline consists of three steps (clearing, imaging and re-embedding), and enables sample reuse.

Our paper: Tanaka, N. et al. Whole-tissue biopsy phenotyping of three-dimensional tumours reveals patterns of cancer heterogeneity. Nat. Biomed. Eng. (2017) doi:10.1038/s41551-017-0139-0.

Banner credits: Fox, E. J. & Loeb, L. A. Cancer: One cell at a time. Nature 512, 143–144 doi:10.1038/nature13650. Macmillan Publishers.