A Biobank of Circulating Tumour Cell (CTC)-derived explant models (CDX) from SCLC Patients to advance research

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The majority of patients with SCLC die within a year of diagnosis. Acquiring tumour biopsies for research is challenging, with repeat biopsies rarely obtained limiting our understanding of this aggressive disease. In 2014, we exploited a unique feature of SCLC, the relative abundance of CTCs. From a tube of blood, we enriched CTCs and grew them in immunocompromised mice, forming patient faithful preclinical models, CDX1. SCLC evolves remarkably quickly from a chemosensitive to chemoresistant disease. We noted that a key advantage of CDX is the ability to generate models before a patient’s chemotherapy and again post-chemotherapy at inevitable disease relapse. Studying SCLC biology after first line treatment is essential, as this is when new therapeutics are tested. At the time, we felt the CDX approach was a ‘game-changer’ for SCLC researchers and were delighted when CDX subsequently caught on with the research community2,3.

in vivo team members Melanie Galvin and Stewart Brown who helped generate the CDX models

Encouraged by our CDX success and realising that only large panel of models would accommodate the phenotypic diversity of SCLC, we embarked on a journey to establish a comprehensive biobank of CDX models. However, life sometimes takes an unexpected turn and in 2017 a devastating fire destroyed the building where the Cancer Research UK Manchester Institute was based. Thankfully, no-one was hurt and theCDX models we had derived were safely banked down.  But our CDX journey was halted for 18 months until our research was up and running again in our temporary home at Alderley Park. CDX model generation recommenced with adjustments required due to the 14 mile separation from Professor Fiona Blackhall’s thoracic oncology clinics at the Christie NHS Foundation Trust. We are now especially proud to present our characterisation of 38 CDX models including 6 pre and post chemotherapy pairs as a Nature Cancer Resource4.

Dual Expression of Neuroendocrine Transcriptional Master Regulators ASCL1 and NEUROD1 in SCLC CDX

As predicted, SCLC phenotypic heterogeneity and its consequences are being revealed as SCLC enters its “second golden age”5. Large panels of CDX models, such as that described here, will help to drive the field onwards, complementing alternative approaches including Patient derived models from tissue biopsies (PDX), human cell lines and genetically engineeredmouse models (GEMMs). We are exploiting our CDX models to probe mechanism(s) of chemo-resistance, to better understand early dissemination and metastatic behaviour (including vasculogenic mimicry and tissue tropism) and to discover new druggable targets. The phenotypic diversity we see amongst the CDX models presents opportunities for patient stratification requiring biomarker development with ‘line of sight’ to the clinic where liquid biopsies6,7 have a major roles to play in the design of future clinical trials for personalised therapy of SCLC. As the 3rd anniversary of the fire approaches, we are now looking forward to watching a state- of-the-art research building rise from the ashes and moving back where we belong, next to the Christie Hospital and patients with SCLC who so graciously and altruistically provided their clinical samples for CDX research.

 

 

References:

  1. Hodgkinson CL, Morrow CJ, Li Y, Metcalf RL, Rothwell DG, Trapani F, et al. Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Nat Med. 2014;20(8):897-903.
  2. Drapkin BJ, George J, Christensen CL, Mino-Kenudson M, Dries R, Sundaresan T, et al. Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts.  Cancer Discov. 2018; 8(5):600-615
  3. Allison Stewart C, Gay CM, Xi Y, Sivajothi S, Sivakamasundari V, Fujimoto J, et al. Single-cell analyses reveal increased intratumoral heterogenieity after the onset of therapy resistance in small-cell lung cancer. Nat. Cancer, 2020 https://doi.org/10.1038/s43018... 
  4. Simpson KL, Stoney R, Frese KK, Simms N, Rowe W, Pearce S, et al. (2020) A Biobank of Small Cell Lung Cancer CDX Models Elucidates Inter- and Intra-tumoural Phenotypic Heterogeneity. Nature Cancer. https://doi.org/10.1038/s43018...
  5. Rudin CM, Poirier JT, Byers LA, Dive C, Dowlati A, George J, et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer. 2019;19(5):289-297.
  6. Hou JM, Krebs MG, Lancashire L, Sloane R, Swain R, Backen A, Priest L, Greystoke A, Zhou C, Morris K, Ward T, Blackhall F, Dive C. (2012). Clinical Significance and Molecular Characteristics of Circulating Tumor Cells and Circulating Tumor Microemboli in Patients with Small Cell Lung Cancer. J. Clin. Oncol., 30:525-32.
  7. Mohan, S., Foy, V., Ayub, M., Leong, H.S., Schofield, P., Sahoo, S., Descamps, T., Kilerci, B., Smith, N.K., Carter, M. et al. (2020) Profiling of Circulating Free DNA Using Targeted and Genome-wide Sequencing in Patients with SCLC. J Thorac Oncol. 15(2):216-230.
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Caroline Dive

Professor, Cancer Research UK Manchester Institute, The University of Manchester

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