It is widely known that tumor lesions harbor diverse subpopulations of cell types each genetically and phenotypically unique. However, it is not always clear which cell types are actually promoting or sustaining the tumor. Typically, tumors consist of two class of cells—a subpopulation of cells that are fully differentiated and possess little to none tumor promoting abilities, and a subpopulation of undifferentiated cells with high tumor promoting ability i.e. cancer stem cells (CSCs). The ability to differentiate the tumor sustaining cells from a diverse cell population would open a new era for targeted therapy and future care.
Paolo Scaffidi and colleagues have previously demonstrated that hierarchically organized human primary tumors containing functionally distinct subsets of cancer cells can be generated in a controlled manner using de novo transformed cells. Additionally, they discovered that expressing human telomerase (hTERT) and oncogenic HRAS alongside concomitant inhibition of P53 and pRB by SV40 T antigens confers tumorigenic potential to various cell types. Moreover, they showed that experimental transformation of primary dermal fibroblasts, a subpopulation of cells marked by the CSC marker SSEA1, acquired uncontrolled long-term proliferative potential and multipotency.
Having mastered the technology to generate hierarchically organized human tumors in a controlled fashion, Paola and the team decided to find out the epigenetic mechanism responsible for establishing intratumor heterogeneity. Using a controlled system to model functional intratumor heterogeneity, the team discovered that:
- H1F0, which encodes the linker histone H1.0 variant, was strongly downregulated in the SSEA1+ cells found in multiple tumors
- Analysis of protein levels confirmed low levels of histone H1.0 protein in self-renewing SSEA1+
- Contrastingly, SSEA1– cells expressed high levels of histone H1.0
- Other H1 variants were either expressed at very low levels in all tumor cells or expressed similarly between SSEA1+ and the fully differentiated SSEA1–
- Combined analysis of pan-cancer patient data sets and experimental alteration of the H1F0locus in tumor cells showed that heterogeneous expression of H1.0 is partly due to differential methylation of an enhancer region that dynamically modulates H1.0 expression in tumors
The team conclude that their findings “uncover the determinants of tumor-maintaining cells”. To learn more about this important work, link yourself to Science, September 2016.