Epigenetic/Genetic Mismatch: Using Transdifferentiation as a Potential Cancer Therapy to Exploit the Cell Type...

Area of Science:

• Cell Biology
• Developmental Biology
• Cancer Research

Background:

• Malignant transformation can affect any proliferating cell type, but specific cancer mutations are not universally effective across all cell lineages.
• Epigenetic differences between cell types likely confer resistance to transformation by heterologous cancer mutations.
• Altering the developmental fate of cancer cells has been shown to reduce their malignancy.

Purpose of the Study:

• To investigate the role of epigenetic differences in cellular resistance to malignant transformation.
• To explore the therapeutic potential of reprogramming cancer cells to less malignant states.
• To identify novel therapeutic targets by understanding transcription and signaling network incompatibilities.

Main Methods:

• Reprogramming cancer cells to primitive states using induced pluripotent stem cells (iPS) or somatic nuclear transfer.
• Directed differentiation of reprogrammed cells into mature cell types distinct from the original tumor lineage.
• Direct transdifferentiation of cancer cells to alternative cell fates.
• Inducing redifferentiation of reprogrammed cells toward the original tumor cell type.

Main Results:

• Reprogramming to pluripotency or differentiation into distinct cell lineages suppressed the malignant phenotype and reduced tumorigenicity.
• Direct transdifferentiation also decreased tumor-forming potential.
• Redifferentiation toward the original tumor cell type after reprogramming resulted in renewed tumorigenicity.
• An epigenetic/genetic mismatch frequently led to malignancy suppression or cell death.

Conclusions:

• Cellular identity and epigenetic state are critical determinants of malignancy.
• Reprogramming and transdifferentiation strategies hold promise for cancer therapy by inducing incompatible cellular states.
• Understanding network incompatibilities can reveal new therapeutic targets and strategies to overcome therapeutic resistance in cancer.