Laboratory of Skin Aging and Cancer Prevention

Head of laboratory : Gian-Paolo Dotto, M.D., Ph.D.

Research Program Overview

Cancer risk is exponentially increasing with aging and aging-related diseases. Cumulative exposure to environmental agents are connected with increased cancer risk.  There are significant sex-related differences in aging that may contribute to sexual dimorphism in cancer susceptibility.

Aging has been connected with senescence of cells, which can function both as a fail safe mechanism against cancer development but also facilitate this process. The dual tumor-suppressing and -promoting function of cellular senescence depends on cell types and cell-cell interactions. 

The risk of many cancer types increases exponentially with age and cumulative exposure to environmental agents such as UV light and smoke. There are significant differences in cancer susceptibility between individuals of different sexes and ancestries that cannot be attributed solely to socioeconomic factors and may be partly due to differences in the aging process. It is well known that melanin production in the skin provides protection against the damaging effects of sunlight. Less well known is that the few skin cancers that develop in people of Black African descent tend to be aggressive and metastatic through a variety of possible mechanisms, including increased cancer stem cell potential.

Cancer development in surface organs such as the skin is often associated with ‘‘field cancerization,’’ i.e., widespread alteration of surrounding tissues with multifocal and recurrent lesions and clones of cells carrying silent pro-oncogenic mutations that expand over time. A co-evolutionary process of cancer and stromal cells is likely, with genetic instability affecting both the cancerous cells of origin and the stromal cells (fibroblasts). Field cancerization of the skin is a major consequence of chronic exposure to sunlight and a leading cause of death in organ transplant recipients under immunosuppressive treatment.

Aging has been linked to cell senescence, which can act as a failsafe mechanism against cancer development but can also facilitate this process through the production of a battery of pro-inflammatory and pro-tumorigenic cytokines and matrix remodeling enzymes. The induction of these genes can be decoupled from the cell cycle and depends on converging transcriptional regulatory mechanisms linked to the DNA repair apparatus and androgen receptor signaling, which is altered in both aging and cancer. New targets have been identified for epigenetic reprogramming of cells to prevent and even reverse skin photoaging and cancer.

Recent Highlights

Laboratory Members

Representative papers

(for a complete list see bibliography)

Ghosh S, Isma J, Ostano P, Mazzeo L, Toniolo A, Das M, White JR, Simon C, Paolo Dotto G. Nuclear lamin A/C phosphorylation by loss of androgen receptor leads to cancer-associated fibroblast activation. Nat Commun. 2024 Sep 12;15(1):7984. doi: 10.1038/s41467-024-52344-z. PMID: 39266569; PMCID: PMC11392952.

Mazzeo L, Ghosh S, Di Cicco E, Isma J, Tavernari D, Samarkina A, Ostano P, Youssef MK, Simon C, Dotto GP. ANKRD1 is a mesenchymal-specific driver of cancer-associated fibroblast activation bridging androgen receptor loss to AP-1 activation. Nat Commun. 2024 Feb 3;15(1):1038. doi: 10.1038/s41467-024-45308-w. PMID: 38310103; PMCID: PMC10838290.

Samarkina A, Youssef MK, Ostano P, Ghosh S, Ma M, Tassone B, Proust T, Chiorino G, Levesque MP, Goruppi S, Dotto GP. Androgen receptor is a determinant of melanoma targeted drug resistance. Nat Commun. 2023 Oct 14;14(1):6498. doi: 10.1038/s41467-023-42239-w.

Goruppi S, Clocchiatti A, Bottoni G, Di Cicco E, Ma M, Tassone B, Neel V, Demehri S, Simon C, Dotto P.G. (2023). The ULK3 kinase is a determinant of keratinocyte self-renewal and tumorigenesis targeting the arginine methylome. Nat Commun. 2023 Feb 16;14(1):887. doi: 10.1038/s41467-023-36410-6.

Xu X, Tassone B, Ostano P, Katarkar A, Proust T, Joseph JM, Riganti C, Chiorino G, Kutalik Z, Lefort K and G.P. Dotto (2021) HSD17B7 gene in self-renewal and oncogenicity of keratinocytes from Black versus White populations. EMBO Mol Med 13: e14133

Ma, M., Ghosh,S., Tavernari, D., Katarkar, A., Clocchiatti, A., Mazzeo,L., Samarkina, A., Epiney, Yu, Y._R. Ho, P.-C., Levesque, M.P. Özdemir, B.C., Ciriello, G., Dummer, R. and G.P. Dotto (2021) Sustained Androgen Receptor signaling is a determinant of melanoma cell growth potential and tumorigenesis. J. Exp. Med. 218. PMID: 33112375

Katarkar, A., Bottoni, G., Clocchiatti, A., Goruppi, S., Bordignon, P., Lazzaroni^, F., Gregnanin, I., Ostano, P., Neel,V., and G.P. Dotto (2020) NOTCH1 gene amplification promotes expansion of Cancer Associated Fibroblast populations in human skin. Nature Comm. In press. doi:10.1038/s41467-020-18919-2 

Bottoni, G., Katarkar, A., Tassone, B., Ghosh, S., Clocchiatti, A., Goruppi, S., Bordignon, P., Jafari, P., Tordini, F., Lunardi, T., Hoetzenecker, W., Nell, V.,Lingner, J., and G.P. Dotto (2019). CSL controls telomere maintenance and genome stability in human dermal fibroblasts. Nature Comm. 29;10(1):3884. doi: 10.1038/s41467-019-11785-7.

Bordignon, P., Bottoni, G., Xu, X., Popescu, A., Truan, Z., Guenova, E., Kofler, L., Jafari, P., Ostano, P., Röcken, M., Neel, V., and G.P. Dotto (2019). Dualism of FGF and TGF-β Signaling in Heterogeneous Cancer-Associated Fibroblast Activation with ETV1 as a Critical Determinant. Cell Rep 28(9): 2358-2372.e6. doi: 10.1016/j.celrep.2019.07.092.

Al Labban, D., Jo, S.H., Ostano, P., Saglietti, C., Bongiovanni, M., Panizzon, R., and Dotto, G.P. (2018). Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B. J. Clin. Invest. 128, 2581-2599, doi.org/10.1172/JCI96915.

 Clocchiatti, A., S. Ghosh, M.G. Procopio, L. Mazzeo, P. Bordignon, P. Ostano, S. Goruppi, G. Bottoni, A. Katarkar, M. Levesque, P. Kölblinger, R. Dummer, V. Neel, B.C. Ozdemir, and G.P. Dotto. (2018). Androgen receptor functions as transcriptional repressor of Cancer Associated Fibroblast activation. J. Clin. Invest. 128(12): p. 5531-5548 doi: 10.1172/JCI99159.

Goruppi, S., Jo, S.H., Laszlo, C., Clocchiatti, A., Neel, V., and Dotto, G.P. (2018). Autophagy Controls CSL/RBPJkappa Stability through a p62/SQSTM1-Dependent Mechanism. Cell Rep 24, 3108-3114. PMID: 30231994

Goruppi, S., M.G. Procopio, S. Jo, A. Clocchiatti, V. Neel, and G.P. Dotto (2017). The ULK3 Kinase Is Critical for Convergent Control of Cancer-Associated Fibroblast Activation by CSL and GLI. Cell Rep 20:2468-2479,  doi: 10.1016/j.celrep.2017.08.048

Kim, D.E, Procopio,M.G., Ghosh, S., Jo, S.H, Goruppi, S., Magliozzi, F., Bordignon, P., Neel, V., Angelino,P.and Dotto G.P. (2017) Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation. J. Exp. Med. 214, 1-20, doi: 10.1084/jem.20170724

Procopio, M.G., Laszlo, C., Al Labban, D., Eun Kim, D., Bordignon, P., Jo, S., Goruppi, S., Menietti, E., Ostano, P., Ala, U., Provero, P., Hoetzenecker, W., Neel, V., Kilarski, W., Swartz, M.A., Brisken, C., Lefort, K. and Dotto, G.P. (2015) Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation. Nature Cell Bio. 17, 1193–1204  doi:10.1038/ncb3228 

Recent reviews

Dotto, G.P. (2019) Gender and sex—time to bridge the gap, EMBO Molecular Medicine. DOI: 10.15252/emmm.201910668

Özdemir, B.C. and Dotto, G.P. (2019) Sex hormones and anticancer immunity, Clinical Cancer Research. DOI:10.1158/1078-0432.CCR-19-0137

Goruppi, S., A. Clocchiatti, and Dotto, G.P. (2019). A role for stromal autophagy in cancer-associated fibroblast activation. Autophagy. 15:4,738739 DOI: 10.1080/15548627.2019.1569936

Özdemir, B.C. and Dotto, G.P., Racial Differences in Cancer Susceptibility and Survival: More Than the Color of the Skin? Trends in Cancer, 2017; 3, 181-197   DOI:10.1016/j.trecan.2017.02.002

Dotto, G.P, and Rustgi, A., Squamous cell cancers: a unified perspective on biology and genetics. Cancer Cell 2016; 29, 622-637

Clocchiatti, A., Cora, E.,^, Zhang, Y. and Dotto, G.P. Sexual dimorphism in cancer. Nature Reviews Cancer 2016; 16: p. 330-9