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Soo Park, MD
Soo Park, MD
Posted: Monday, July 18, 2022
Some basal cell carcinomas persist after pharmacologic inhibition of upstream Hedgehog signaling, and preclinical research results appearing in Cell Reports offer a possible explanation. Sunny Y. Wong, PhD, of the University of Michigan–Ann Arbor, and colleagues noted that the functional significance of the many mutations frequently present in basal cell carcinomas remain unclear, but certain secondary mutations, they showed, may hyperactivate downstream Hedgehog signaling.
The cycle begins “when loss of Ptch1, the most common mutation that activates upstream Hedgehog signaling, initiates the formation of nascent basal cell carcinoma–like tumors that eventually enter into a dormant state,” wrote the team. But infrequently, a tumor can overcome dormancy and expand—uncontrolled—when it acquires certain somatic secondary mutations, including amplification of Gli1/2 and upregulation of MYCN, that hyperactivate downstream Hedgehog signaling. As such, essential downstream factors “may represent critical targets for therapy.” Their work demonstrates that the tumor progression features induced by MYCN overexpression include increased proliferation and reduced differentiation, they said.
“By utilizing basal cell carcinoma models that largely fail to progress, we [identified] genetic factors that enable rare tumors to succeed,” stated the investigators. In addition to loss of Ptch1, gain of Smo also contributes to upstream Hedgehog signaling that initiates nascent tumors that eventually regress and become dormant.
In either scenario, concomitant loss of Notch1 or of p53 can interfere with tumor regression and genomic instability, but neither the loss of Ptch1 nor the gain of Smo will foment tumor progression, the researchers said. “Ultimately, tumor-initiated cells must acquire additional changes that either directly or indirectly cause exuberant downstream Hedgehog pathway activation in order to progress,” explained Dr. Wong and colleagues. And MYCN overexpression, they concluded, “is likely situated at a critical nexus for driving basal cell carcinoma progression and possibly drug resistance.”
Disclosure: The study authors reported no conflicts of interest.
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