senescence; Notch/CSL transcription; skin cancer; epithelial-mesenchymal interactions; cancer associated fibroblasts; autophagy; p53
Kim D. E., Procopio M. G., Ghosh S., Jo S. H., Goruppi S., Magliozzi F., Bordignon P., Neel V., Angelino P., Dotto G. P. (2017), Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation, in J Exp Med
, 214, 2349-2368.
Dziunycz P. J., Neu J., Lefort K., Djerbi N., Freiberger S. N., Iotzova-Weiss G., French L. E., Dotto G. P., Hofbauer G. F. (2017), CYFIP1 is directly controlled by NOTCH1 and down-regulated in cutaneous squamous cell carcinoma, in PLoS One
, 12, 0173000-0173000.
Ozdemir B. C., Dotto G. P. (2017), Racial Differences in Cancer Susceptibility and Survival: More Than the Color of the Skin?, in Trends Cancer
, 3, 181-197.
Goruppi S., Procopio M. G., Jo S., Clocchiatti A., Neel V., Dotto G. P. (2017), The ULK3 Kinase Is Critical for Convergent Control of Cancer-Associated Fibroblast Activation by CSL and GLI, in Cell Rep
, 20, 2468-2479.
Procopio M. G., Laszlo C., Dotto G. P. (2016), CSL-p53: From senescence to CAF activation, in Cell Cycle
, 15, 485-6.
Lefort K., Ostano P., Mello-Grand M., Calpini V., Scatolini M., Farsetti A., Dotto G. P., Chiorino G. (2016), Dual tumor suppressing and promoting function of Notch1 signaling in human prostate cancer, in Oncotarget
, 7, 48011-48026.
Menietti E., Xu X., Ostano P., Joseph J. M., Lefort K., Dotto G. P. (2016), Negative control of CSL gene transcription by stress/DNA damage response and p53, in Cell Cycle
, 15, 1767-78.
Jo S. H., Kim D. E., Clocchiatti A., Dotto G. P. (2016), PDCD4 is a CSL associated protein with a transcription repressive function in cancer associated fibroblast activation, in Oncotarget
, 7, 58717-58727.
Clocchiatti A., Cora E., Zhang Y., Dotto G. P. (2016), Sexual dimorphism in cancer, in Nat Rev Cancer
, 16, 330-9.
Dotto G. P., Rustgi A. K. (2016), Squamous Cell Cancers: A Unified Perspective on Biology and Genetics, in Cancer Cell
, 29, 622-637.
Procopio M. G., Laszlo C., Al Labban D., Kim D. E., Bordignon P., Jo S. H., Goruppi S., Menietti E., Ostano P., Ala U., Provero P., Hoetzenecker W., Neel V., Kilarski W. W., Swartz M. A., Brisken C., Lefort K., Dotto G. P. (2015), Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation, in Nat Cell Biol
, 17, 1193-204.
Procopio M. G., Laszlo C., Al Labban D., Kim D. E., Bordignon P., Jo S. H., Goruppi S., Menietti E., Ostano P., Ala U., Provero P., Hoetzenecker W., Neel V., Kilarski W. W., Swartz M. A., Brisken C., Lefort K., Dotto G. P. (2015), Corrigendum: Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation, in Nat Cell Biol
, 17, 1370-1370.
Kurinna S., Schafer M., Ostano P., Karouzakis E., Chiorino G., Bloch W., Bachmann A., Gay S., Garrod D., Lefort K., Dotto G. P., Beer H. D., Werner S. (2014), A novel Nrf2-miR-29-desmocollin-2 axis regulates desmosome function in keratinocytes, in Nat Commun
, 5, 5099-5099.
Dotto G. P., Karine L. (2014), miR-34a/SIRT6 in squamous differentiation and cancer, in Cell Cycle
, 13, 1055-6.
Brooks Y. S., Ostano P., Jo S. H., Dai J., Getsios S., Dziunycz P., Hofbauer G. F., Cerveny K., Chiorino G., Lefort K., Dotto G. P. (2014), Multifactorial ERbeta and NOTCH1 control of squamous differentiation and cancer, in J Clin Invest
, 124, 2260-76.
Dotto G. P. (2014), Multifocal epithelial tumors and field cancerization: stroma as a primary determinant, in J Clin Invest
, 124, 1446-53.
Field cancerization is a condition of major clinical significance involving multifocal and recurrent epithelial tumors associated with widespread changes in surrounding tissues ("cancer fields"). We have recently shown that stromal alterations can play primary role in this process. In particular, we have found that mice with deletion of the CSL/RBP-J? gene in the mesenchymal compartment of the skin develop multifocal keratinocyte tumors preceded by stromal atrophy, matrix alterations and inflammation. By additional and ongoing studies with dermal fibroblasts of both mouse and human origin we have found that CSL functions as a negative regulator of genes involved in activation of Cancer Associated Fibroblasts (CAFs) as well as dermal fibroblast senescence and autophagy. CSL is a transcriptional repressor and key effector of Notch activation, which can also function independently of Notch activation through binding to other transcription factors and/or modulators of gene expression. We will be pursuing the following two aims. 1) We will be testing the hypothesis that CSL acts in concert with p53 in integrated control of dermal fibroblast senescence and CAF activation. A link between stromal cell senescence and CAF activation is well established. However, very little is known on how these processes are commonly controlled. In preliminary work we have found that HDF senescence resulting from CSL silencing is rescued by concomitant p53 knockdown, while CAF phenotype activation is enhanced. We have further found that, in HDFs, endogenous as well as exogenously expressed CSL physically associates with p53. We will confirm and expand these findings assessing how the CSL-p53 cross-talk affects intrinsic control of senescence and CAF - related gene transcription in HDFs and what is its in vivo impact on neighboring keratinocytes and SCC cells. 2) A close but complex interconnection exists between autophagy, senescence and control of tumour development. We will be testing the hypothesis that CSL functions in dermal fibroblasts as a negative regulator of autophagy and that CSL-dependent autophagy is involved in control of dermal fibroblast senescence and CAF activation. In preliminary studies, we have found that, in parallel with senescence and CAF activation, silencing of CSL in HDFs results in increased expression of key autophagy-effectors genes, while induction of autophagy suppresses CSL expression. Autophagy has been reported to be also a p53-regulated process. We will therefore assess to what extent expression of autophagy effector genes in HDFs are controlled by CSL in a possible cross-talk with p53 and whether autophagy impinges positively or negatively on HDF senescence and CAF activation and has an impact on paracrine control of keratinocyte tumour development.