Modulating cell-free DNA biology as the next frontier in liquid biopsies

Shervin Tabrizi¹, Carmen Martin-Alonso², Kan Xiong³, Sangeeta N Bhatia⁴, Viktor A Adalsteinsson³, J Christopher Love⁵

Affiliations

¹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Radiation Oncology, Mass General Brigham, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: shervin@broadinstitute.org.
² Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Wyss Institute at Harvard University, Boston, MA, USA; Howard Hughes Medical Institute, Cambridge, MA, USA.
⁵ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

PMID: 39730275
PMCID: PMC12145268 (available on 2026-06-01)
DOI: 10.1016/j.tcb.2024.11.007

Review

Modulating cell-free DNA biology as the next frontier in liquid biopsies

Shervin Tabrizi et al. Trends Cell Biol. 2025 Jun.

. 2025 Jun;35(6):459-469.

doi: 10.1016/j.tcb.2024.11.007. Epub 2024 Dec 26.

Authors

Shervin Tabrizi¹, Carmen Martin-Alonso², Kan Xiong³, Sangeeta N Bhatia⁴, Viktor A Adalsteinsson³, J Christopher Love⁵

Affiliations

¹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Radiation Oncology, Mass General Brigham, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: shervin@broadinstitute.org.
² Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Wyss Institute at Harvard University, Boston, MA, USA; Howard Hughes Medical Institute, Cambridge, MA, USA.
⁵ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

PMID: 39730275
PMCID: PMC12145268 (available on 2026-06-01)
DOI: 10.1016/j.tcb.2024.11.007

Abstract

Technical advances over the past two decades have enabled robust detection of cell-free DNA (cfDNA) in biological samples. Yet, higher clinical sensitivity is required to realize the full potential of liquid biopsies. This opinion article argues that to overcome current limitations, the abundance of informative cfDNA molecules - such as circulating tumor DNA (ctDNA) - collected in a sample needs to increase. To accomplish this, new methods to modulate the biological processes that govern cfDNA production, trafficking, and clearance in the body are needed, informed by a deeper understanding of cfDNA biology. Successful development of such methods could enable a major leap in the performance of liquid biopsies and vastly expand their utility across the spectrum of clinical care.

Keywords: biomarkers; cfDNA clearance; cfDNA shedding; ctDNA.

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Conflict of interest statement

Declaration of interests The authors are listed as inventors on a patent related to improving cfDNA recovery (PCT/US2022/013769). J.C.L., V.A.A., and S.N.B. are cofounders of Amplifyer Bio. C.M.A. is an employee of Amplifyer Bio. J.C.L. has interests in Sunflower Therapeutics PBC, Honeycomb Biotechnologies, OneCyte Biotechnologies, QuantumCyte, and Repligen, which were not involved in this work. V.A.A. is a coinventor on a patent application (US 2023/0203568, pending) licensed to Exact Sciences and receives research funding from Exact Sciences. S.N.B. reports consulting roles and/or equity in Sunbird Bio, Satellite Bio, Catalio Capital, Port Therapeutics, Matrisome Bio, Xilio Therapeutics, Ochre Bio, Vertex Pharmaceuticals, Ropirio Therapeutics, Danaher, and Owlstone Medical, which were not involved in this work. J.C.L.’s and S.N.B.’s interests were reviewed and managed under MIT’s policies for potential conflicts of interest.

References

1. Moding EJ et al. (2021) Detecting Liquid Remnants of Solid Tumors: Circulating Tumor DNA Minimal Residual Disease. Cancer Discov 11, 2968–2986 - PMC - PubMed
1. Heitzer E et al. (2019) Current and future perspectives of liquid biopsies in genomics-driven oncology. Nature Reviews Genetics 20, 71–88 - PubMed
1. Cescon DW et al. (2020) Circulating tumor DNA and liquid biopsy in oncology. Nat Cancer 1, 276–290 - PubMed
1. Kurtz DM et al. (2021) Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA. Nat Biotechnol 39, 1537–1547 - PMC - PubMed
1. Schmitt MW et al. (2012) Detection of ultra-rare mutations by next-generation sequencing. Proc Natl Acad Sci U S A 109, 14508–14513 - PMC - PubMed

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Modulating cell-free DNA biology as the next frontier in liquid biopsies

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Modulating cell-free DNA biology as the next frontier in liquid biopsies

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