Novel Reporter Genes Enable In Vivo Ultrasound Imaging of Tumors

Real-time visualization of tumor progression within living organisms can provide important insight into cancer biology, but even the most advanced optical techniques often have limited imaging depth due the scattering and absorption of light by tissue. Ultrasound offers an advantage by enabling deep tissue imaging via the transmission of high-frequency sound waves that travel in different detectable patterns depending on the tissue’s density and compressibility, and genetically encodable reporters for ultrasound have recently been developed to enhance the ultrasound contrast of target cell types. To advance this technique, Hurt, Buss, Duan, and colleagues generated acoustic reporter genes (ARG) capable of robust and stable heterologous expression in bacterial and mammalian cells. These ARGs were derived from clusters of genes found in aquatic bacteria and archaea that encode gas vesicles (GV), air-filled nanostructures that aid in flotation and possess low density and high compressibility. GV gene clusters were cloned from diverse bacterial species, inducibly expressed in Escherichia coli, and screened for strong ultrasound signal following a nondestructive pulse sequence, revealing favorable performance of GVs adapted from organisms including Serratia sp. 39006 and Anabaena flos-aquae. An optimized bacterial ARG (bARG_Ser) was created through the deletion of nonessential sequences of the Serratia cluster and placement within an L-arabinose–inducible plasmid, and expression of bARG_Ser in a probiotic E. coli strain facilitated the ultrasound detection of bacterial colonization within tumors in live mice with high contrast and sensitivity. Similarly, a doxycycline-inducible mammalian ARG (mARG_Ana) was derived from a modified A. flos-aquae GV cluster and expressed in human breast cancer cells following orthotopic injection into mice. Not only could mARG_Ana imaging of tumors provide spatial information beyond what was possible with optical methods, but mARG_Ana also enabled the ultrasound-guided biopsy of specific regions within genetically chimeric subcutaneous tumors at a high success rate. Overall, these advances in ultrasound contrast have broadened the ability to visualize tumor biology in vivo.

Hurt RC, Buss MT, Duan M, Wong K, You MY, Sawyer DP, et al. Genomically mined acoustic reporter genes for real-time in vivo monitoring of tumors and tumor-homing bacteria. Nat Biotechnol 2023 Jan 2 [Epub ahead of print].

Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.