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Updated: Jul 24, 2025
Modeling Osteosarcoma Using Li-Fraumeni Syndrome Patient-derived Induced Pluripotent Stem Cells
Published on: June 13, 2018
Suppression of osteosarcoma progression by engineered lymphocyte-derived proteomes
Kexin Li1,2, Xun Sun1,2, Hudie Li1,2
1Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, China.
Abstract:
Cancer cells tend to develop resistance to chemotherapy and enhance aggressiveness. A counterintuitive approach is to tame aggressiveness by an agent that acts opposite to chemotherapeutic agents. Based on this strategy, induced tumor-suppressing cells (iTSCs) have been generated from tumor cells and mesenchymal stem cells. Here, we examined the possibility of generating iTSCs from lymphocytes by activating PKA signaling for suppressing the progression of osteosarcoma (OS). While lymphocyte-derived CM did not present anti-tumor capabilities, the activation of PKA converted them into iTSCs. Inhibiting PKA conversely generated tumor-promotive secretomes. In a mouse model, PKA-activated CM suppressed tumor-induced bone destruction. Proteomics analysis revealed that moesin (MSN) and calreticulin (Calr), which are highly expressed intracellular proteins in many cancers, were enriched in PKA-activated CM, and they acted as extracellular tumor suppressors through CD44, CD47, and CD91. The study presented a unique option for cancer treatment by generating iTSCs that secret tumor-suppressive proteins such as MSN and Calr. We envision that identifying these tumor suppressors and predicting their binding partners such as CD44, which is an FDA-approved oncogenic target to be inhibited, may contribute to developing targeted protein therapy.
Insights
Researchers converted lymphocytes into induced tumor-suppressing cells (iTSCs) by activating protein kinase A (PKA) signaling. PKA-activated iTSCs secrete proteins like moesin and calreticulin, suppressing osteosarcoma progression and bone destruction.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Cancer cells develop chemoresistance and aggressiveness.
- A novel strategy involves using agents that counteract cancer aggressiveness.
- Induced tumor-suppressing cells (iTSCs) have been generated from various cell types.
Purpose of the Study:
- To investigate generating iTSCs from lymphocytes via protein kinase A (PKA) signaling activation.
- To assess the potential of these iTSCs in suppressing osteosarcoma (OS) progression.
- To identify the molecular mechanisms underlying iTSC-mediated tumor suppression.
Main Methods:
- Lymphocytes were cultured and treated to activate or inhibit PKA signaling.
- Conditioned media (CM) from treated lymphocytes were analyzed for anti-tumor capabilities.
- Osteosarcoma progression and bone destruction were evaluated in a mouse model.
- Proteomics analysis identified key proteins in PKA-activated CM.
Main Results:
- PKA activation converted lymphocytes into iTSCs, producing tumor-suppressive CM.
- PKA inhibition generated tumor-promotive secretomes.
- PKA-activated CM significantly suppressed osteosarcoma progression and tumor-induced bone destruction in vivo.
- Moesin (MSN) and calreticulin (Calr) were enriched in PKA-activated CM and acted as extracellular tumor suppressors via CD44, CD47, and CD91.
Conclusions:
- Lymphocytes can be reprogrammed into iTSCs by activating PKA signaling.
- PKA-activated iTSCs offer a novel therapeutic approach for osteosarcoma by secreting tumor-suppressive proteins.
- Identifying these secreted tumor suppressors and their binding partners could lead to targeted protein therapies for cancer.
