Imaging dynamic mTORC1 pathway activity in vivo reveals marked shifts that support time-specific inhibitor therapy in...

Area of Science:

• Oncology
• Molecular Biology
• Biomedical Imaging

Background:

• Acute myeloid leukemia (AML) is a fatal blood cancer with high relapse rates.
• Current mTORC1 inhibitors show limited efficacy in AML treatment.
• Understanding mTORC1 dynamics in vivo is crucial for developing effective therapies.

Purpose of the Study:

• To dynamically track mTORC1 activity, proliferation, and apoptosis in AML cells within the bone marrow microenvironment.
• To investigate the correlation between mTORC1 signaling, leukemia stemness, and response to chemotherapy.
• To evaluate the therapeutic potential of timed mTORC1 inhibition in AML.

Main Methods:

• Development of fluorescent probes for in vivo tracking of single AML cell dynamics.
• Quantification of mTORC1 activity, proliferation, and apoptosis in relation to microanatomical localization and heterogeneity.
• Cell barcoding to distinguish between induction and selection of mTORC1-high cells.
• Assessment of chemotherapy response and timed mTORC1 inhibition efficacy.

Main Results:

• Chemotherapy induced rapid, diffuse apoptosis in AML cells, irrespective of anatomical site.
• mTORC1 activity declined with AML progression but surged during maximal chemotherapy response, correlating with stemness.
• Cell barcoding demonstrated that chemotherapy induces, rather than selects for, high mTORC1 activity.
• Timed inhibition of mTORC1 significantly enhanced AML cell killing.

Conclusions:

• Real-time dynamics of AML and mTORC1 signaling are linked to disease progression and chemotherapy response.
• High mTORC1 signaling during chemotherapy correlates with leukemia stemness.
• Timed intervention with mTORC1 inhibitors can improve AML treatment outcomes.