Measuring kinetics and metastatic propensity of CTCs by blood exchange between mice

Bashar Hamza; Alex B Miller; Lara Meier; Max Stockslager; Sheng Rong Ng; Emily M King; Lin Lin; Kelsey L DeGouveia; Nolawit Mulugeta; Nicholas L Calistri; Haley Strouf; Christina Bray; Felicia Rodriguez; William A Freed-Pastor; Christopher R Chin; Grissel C Jaramillo; Megan L Burger; Robert A Weinberg; Alex K Shalek; Tyler Jacks; Scott R Manalis

doi:10.1038/s41467-021-25917-5

Measuring kinetics and metastatic propensity of CTCs by blood exchange between mice

Nat Commun. 2021 Sep 28;12(1):5680. doi: 10.1038/s41467-021-25917-5.

Authors

Bashar Hamza^#^{1

2}, Alex B Miller^#^{2

3}, Lara Meier^{2

4

5}, Max Stockslager^{2

6}, Sheng Rong Ng^{2

7}, Emily M King², Lin Lin², Kelsey L DeGouveia^{2

8}, Nolawit Mulugeta², Nicholas L Calistri², Haley Strouf², Christina Bray², Felicia Rodriguez^{2

9}, William A Freed-Pastor^{2

10}, Christopher R Chin², Grissel C Jaramillo^{2

7}, Megan L Burger², Robert A Weinberg^{2

7

11}, Alex K Shalek^{2

3

12

13

14

15

16}, Tyler Jacks^{2

7}, Scott R Manalis^{17

18

19

20

21}

Affiliations

¹ Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
² David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Harvard-MIT Department of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany.
⁵ Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁶ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁷ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁸ Department of Biomedical Engineering, Wentworth Institute of Technology, Boston, MA, USA.
⁹ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹¹ Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
¹² Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹³ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁵ Ragon Institute of MGH, MIT and Harvard University, Cambridge, MA, USA.
¹⁶ Department of Immunology, Massachusetts General Hospital, Boston, MA, USA.
¹⁷ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. srm@mit.edu.
¹⁸ Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. srm@mit.edu.
¹⁹ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. srm@mit.edu.
²⁰ Broad Institute of MIT and Harvard, Cambridge, MA, USA. srm@mit.edu.
²¹ Ludwig Center at MIT's Koch Institute for Integrative Cancer Research, Cambridge, MA, USA. srm@mit.edu.

^# Contributed equally.

Abstract

Existing preclinical methods for acquiring dissemination kinetics of rare circulating tumor cells (CTCs) en route to forming metastases have not been capable of providing a direct measure of CTC intravasation rate and subsequent half-life in the circulation. Here, we demonstrate an approach for measuring endogenous CTC kinetics by continuously exchanging CTC-containing blood over several hours between un-anesthetized, tumor-bearing mice and healthy, tumor-free counterparts. By tracking CTC transfer rates, we extrapolated half-life times in the circulation of between 40 and 260 s and intravasation rates between 60 and 107,000 CTCs/hour in mouse models of small-cell lung cancer (SCLC), pancreatic ductal adenocarcinoma (PDAC), and non-small cell lung cancer (NSCLC). Additionally, direct transfer of only 1-2% of daily-shed CTCs using our blood-exchange technique from late-stage, SCLC-bearing mice generated macrometastases in healthy recipient mice. We envision that our technique will help further elucidate the role of CTCs and the rate-limiting steps in metastasis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood Transfusion / methods
Carcinoma, Non-Small-Cell Lung / blood
Carcinoma, Non-Small-Cell Lung / pathology*
Carcinoma, Pancreatic Ductal / blood
Carcinoma, Pancreatic Ductal / pathology*
Cell Line, Tumor
Humans
Kinetics
Lung Neoplasms / blood
Lung Neoplasms / pathology*
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Neoplasm Metastasis
Neoplastic Cells, Circulating / pathology*
Pancreatic Neoplasms / blood
Pancreatic Neoplasms / pathology*
Propensity Score
RNA-Seq / methods
Single-Cell Analysis / methods
Small Cell Lung Carcinoma / blood
Small Cell Lung Carcinoma / pathology*

Abstract

Publication types

MeSH terms

Grants and funding