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RET activation controlled by MAB21L4-CacyBP interaction drives squamous cell carcinoma

Ankit Srivastava, Cristina Tommasi, Dane Sessions, Angela Mah, View ORCID ProfileTomas Bencomo, Jasmine M. Garcia, Tiffany Jiang, Michael Lee, Joseph Y. Shen, Lek Wei Seow, Audrey Nguyen, Kimal Rajapakshe, Cristian Coarfa, Kenneth Y. Tsai, Vanessa Lopez-Pajares, Carolyn S. Lee
doi: https://doi.org/10.1101/2022.01.19.476979
Ankit Srivastava
1Stanford Program in Epithelial Biology, Stanford University, Stanford, CA 94305 USA
2Department of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institute, Stockholm 17177, Sweden
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Cristina Tommasi
1Stanford Program in Epithelial Biology, Stanford University, Stanford, CA 94305 USA
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Dane Sessions
1Stanford Program in Epithelial Biology, Stanford University, Stanford, CA 94305 USA
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Angela Mah
1Stanford Program in Epithelial Biology, Stanford University, Stanford, CA 94305 USA
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Tomas Bencomo
1Stanford Program in Epithelial Biology, Stanford University, Stanford, CA 94305 USA
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  • ORCID record for Tomas Bencomo
Jasmine M. Garcia
1Stanford Program in Epithelial Biology, Stanford University, Stanford, CA 94305 USA
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Tiffany Jiang
1Stanford Program in Epithelial Biology, Stanford University, Stanford, CA 94305 USA
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Michael Lee
1Stanford Program in Epithelial Biology, Stanford University, Stanford, CA 94305 USA
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Joseph Y. Shen
1Stanford Program in Epithelial Biology, Stanford University, Stanford, CA 94305 USA
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Lek Wei Seow
1Stanford Program in Epithelial Biology, Stanford University, Stanford, CA 94305 USA
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Audrey Nguyen
1Stanford Program in Epithelial Biology, Stanford University, Stanford, CA 94305 USA
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Kimal Rajapakshe
3Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
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Cristian Coarfa
3Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
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Kenneth Y. Tsai
4Departments of Anatomic Pathology & Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute; Tampa, FL 33612, USA
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Vanessa Lopez-Pajares
1Stanford Program in Epithelial Biology, Stanford University, Stanford, CA 94305 USA
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Carolyn S. Lee
1Stanford Program in Epithelial Biology, Stanford University, Stanford, CA 94305 USA
5Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA 94304 USA
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  • For correspondence: carilee@stanford.edu
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Abstract

Epithelial squamous cell carcinomas (SCC) most commonly originate in the skin, where they display disruptions in the normally tightly regulated homeostatic balance between keratinocyte proliferation and terminal differentiation. We performed a transcriptome-wide screen for genes of unknown function that possess inverse expression patterns in differentiating keratinocytes compared to cutaneous SCC (cSCC) and identified MAB21L4 (C2ORF54) as an enforcer of terminal differentiation that suppresses carcinogenesis. Loss of MAB21L4 in human cSCC organoids enabled malignant transformation through increased expression of the receptor tyrosine kinase rearranged during transfection (RET). In addition to transcriptional upregulation of RET, MAB21L4 deletion preempted recruitment of the CacyBP-Siah1 E3 ligase complex to RET and reduced its ubiquitylation. Both genetic disruption of RET or selective RET inhibition with BLU-667 (pralsetinib) suppressed tumorigenesis in SCC organoids and in vivo tumors while inducing concomitant differentiation. Our results suggest that targeting RET activation is a potential therapeutic strategy for treating SCC.

Statement of Significance Few targeted therapies are available to individuals with cSCC who seek or require non-surgical management. Our study demonstrates that downregulation of RET is required for epithelial differentiation and opposes carcinogenesis in cSCC as well as SCC arising from other epithelial tissues.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Financial support: CSL is the recipient of a Clinical Scientist Development Award from the Doris Duke Charitable Foundation (#2018094), a Kimmel Scholar Award from the Sidney Kimmel Foundation, and a Milstein Research Scholar Award from the American Skin Association. Additionally, she is mentored and financially supported by Stanford’s SPARK Translational Research Program and the LEO Foundation. AS is supported by an International Postdoctoral Grant from the Swedish Research Council (Vetenskapsrådet-VR). CT received a Stanford Dean’s Postdoctoral Fellowship. VLP is the recipient of K01 AR070895 from NIH/NIAMS.

  • The authors declare no potential conflicts of interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 22, 2022.
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RET activation controlled by MAB21L4-CacyBP interaction drives squamous cell carcinoma
Ankit Srivastava, Cristina Tommasi, Dane Sessions, Angela Mah, Tomas Bencomo, Jasmine M. Garcia, Tiffany Jiang, Michael Lee, Joseph Y. Shen, Lek Wei Seow, Audrey Nguyen, Kimal Rajapakshe, Cristian Coarfa, Kenneth Y. Tsai, Vanessa Lopez-Pajares, Carolyn S. Lee
bioRxiv 2022.01.19.476979; doi: https://doi.org/10.1101/2022.01.19.476979
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RET activation controlled by MAB21L4-CacyBP interaction drives squamous cell carcinoma
Ankit Srivastava, Cristina Tommasi, Dane Sessions, Angela Mah, Tomas Bencomo, Jasmine M. Garcia, Tiffany Jiang, Michael Lee, Joseph Y. Shen, Lek Wei Seow, Audrey Nguyen, Kimal Rajapakshe, Cristian Coarfa, Kenneth Y. Tsai, Vanessa Lopez-Pajares, Carolyn S. Lee
bioRxiv 2022.01.19.476979; doi: https://doi.org/10.1101/2022.01.19.476979

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