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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Spontaneous tumour regression in keratoacanthomas is driven by Wnt/retinoic acid signalling cross-talk
Giovanni Zito1, Ichiko Saotome1, Zongzhi Liu2
1Department of Genetics, Yale Stem Cell Center, Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut 06510, USA.
Abstract:
A fundamental goal in cancer biology is to identify the cells and signalling pathways that are keys to induce tumour regression. Here we use a spontaneously self-regressing tumour, cutaneous keratoacanthoma (KAs), to identify physiological mechanisms that drive tumour regression. By using a mouse model system that recapitulates the behaviour of human KAs, we show that self-regressing tumours shift their balance to a differentiation programme during regression. Furthermore, we demonstrate that developmental programs utilized for skin hair follicle regeneration, such as Wnt, are hijacked to sustain tumour growth and that the retinoic acid (RA) signalling pathway promotes tumour regression by inhibiting Wnt signalling. Finally, we find that RA signalling can induce regression of malignant tumours that do not normally spontaneously regress, such as squamous cell carcinomas. These findings provide new insights into the physiological mechanisms of tumour regression and suggest therapeutic strategies to induce tumour regression.
Insights
Tumor regression is driven by cellular differentiation and the retinoic acid (RA) pathway inhibiting Wnt signaling. This discovery offers new therapeutic strategies for inducing regression in cancers like squamous cell carcinomas.
Area of Science:
- Cancer Biology
- Developmental Biology
- Signaling Pathways
Background:
- Identifying mechanisms of tumor regression is crucial in cancer biology.
- Cutaneous keratoacanthomas (KAs) are a model for studying spontaneous tumor regression.
Purpose of the Study:
- To elucidate the physiological mechanisms underlying spontaneous tumor regression.
- To investigate the role of signaling pathways in tumor regression and growth.
Main Methods:
- Utilized a mouse model system mimicking human KAs.
- Analyzed the shift towards differentiation programs during tumor regression.
- Investigated the Wnt and retinoic acid (RA) signaling pathways.
Main Results:
- Self-regressing tumors exhibit a shift towards differentiation.
- Wnt signaling pathways are co-opted for tumor growth.
- Retinoic acid (RA) signaling inhibits Wnt, promoting tumor regression.
- RA signaling induced regression in normally non-regressing squamous cell carcinomas.
Conclusions:
- Tumor regression involves a balance between differentiation and signaling pathways.
- The RA pathway presents a potential therapeutic strategy for inducing regression in various cancers.
- Understanding these mechanisms can lead to novel cancer treatments.
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