Adenoid Cystic Carcinoma Stem Cells Depend on NOTCH1 and SOX10 Signaling

Although the existence of cancer stem cells (CSC) in ACC had been proposed, lack of assays for their propagation and uncertainty about molecular markers prevented their characterization.

Investigators at Yale University (New Haven, CT, USA) used differential cell culture techniques followed by immunomagnetic cell sorting to isolate CSCs from mixtures of ACC cells. In vitro and in vivo assays for CSC viability and tumorigenicity confirmed their identity.

In a paper published in the April 15, 2016, online edition of the journal Clinical Cancer Research the investigators reported the identification in ACC of CD133-positive CSCs that expressed the signaling factors NOTCH1 and SOX10, formed spheroids, and initiated tumors in nude mice. The rare CD133+ CSC population is one that undergoes self-renewal and differentiation, and can propagate tumors when injected into immune-compromised mice. However, previous studies had indicated the difficulty in isolating pure CSC populations.

The investigators reported that CD133+ ACC cells produced activated NOTCH1 and generated CD133− cells that expressed JAG1 (Jagged1 - one of five cell surface proteins that interact with four receptors in the mammalian Notch signaling pathway) as well as several neural differentiation factors.

The Notch family of transmembrane proteins share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple, different domain types. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling network is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells.

“Within ACC cells, we found the especially aggressive cancer stem cells. As important, we found the Achilles heel of these cells, which is their addiction to NOTCH1, a signaling molecule that helps these cells to survive therapy and multiply,” said senior author Dr. Sergey Ivanov, research scientist in surgery at Yale University. “Fortunately, cancer stem cells can be killed by blocking NOTCH1 production.”

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