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Cancer stromal cell genetic control

English title Cancer stromal cell genetic control
Applicant Dotto Gian-Paolo
Number 156191
Funding scheme Project funding (Div. I-III)
Research institution Département de Biochimie Faculté de Biologie et Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Cellular Biology, Cytology
Start/End 01.10.2014 - 30.09.2017
Approved amount 880'670.77
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Keywords (7)

senescence; Notch/CSL transcription; skin cancer; epithelial-mesenchymal interactions; cancer associated fibroblasts; autophagy; p53

Lay Summary (French)

Lead
SynthèseLe risque de développer un cancer augmente de façon exponentielle avec le vieillissement. Cette étude est focalisée sur le rôle du micro-environnement de la tumeur dans ce contexte, à l'interface entre vieillissement et développement du cancer.ObjectifsNous allons tester un modèle de co-évolution cancer/ stroma avec CSL et p53, comme facteurs de co-détermination et explorer la signification clinique des résultats. Le contexte socio-scientifiqueL’augmentation du cancer dépendant de l’âge et des tumeurs épithéliales récurrentes sont les principales causes de morbidité et de mortalité. Notre travail sur ce sujet est d'une capitale, car il peut conduire à de nouvelles approches préventives et thérapeutiques.
Lay summary

Les interactions épithélio-mésenchymateuses  jouent une fonction déterminante dans la morphogenèse de l’organe, l’homéostasie cellulaire et la carcinogenèse. La voie de signalisation Notch est une forme importante de communication inter-cellulaire qui joue un rôle capital dans le contrôle de la détermination du destin cellulaire.

Le rôle de cette voie dans le tissu épithélial d'organes comme la peau, est maintenant bien établi.

Dans nos précédents travaux, nous avons démontré que cette voie agit en tant que suppresseur de tumeur également dans le compartiment mésenchymateux. Pour la poursuite de notre recherche, nous allons disséquer les mécanismes moléculaires sous-jacents, en nous focalisant sur CSL, un répresseur transcriptionnel et effecteur clé de l’activation de la voie de signalisation Notch, qui peut aussi fonctionner indépendamment de l’activation de Notch, par la liaison à d’autres facteurs de transcription et/ou des modulateurs de l’expression du gène. L’activation des fibroblastes associés au cancer  (CAFs) est liée à la senescence des cellules stromales et l’autophagie. Cependant, peu de choses sont connues sur la manière dont ces processus sont contrôlés en général.  Nous allons donc tester l’hypothèse selon laquelle CSL agit comme régulateur négatif de ces processus par le biais d’interactions fonctionnelles et biochimiques avec d’autres protéines cellulaires clés, particulièrement p53.

 

Direct link to Lay Summary Last update: 07.10.2014

Lay Summary (English)

Lead
SynthesisThe risk of most cancer types increases exponentially with aging. This proposal is focused on the role of the tumor microenvironment in this context, at the interface between aging and cancer development. Subjects and ObjectivesOur main objective is to dissect the function of the CSL protein, the effector of canonical Notch signaling, in stromal cell senescence and Cancer Associated Fibroblast activation. We will be testing a cancer/stromal co-evolution model with CSL and p53 as co-determining factors and explore the clinical significance of the findings.Socio-scientific contextAge-dependent increase of cancer and recurrent epithelial tumors are major causes of morbidity and mortality. Development of epithelial cancer can result from an altered tissue microenvironment. Our work on this topic is of substantial socio-scientific relevance, as it may lead to novel preventive and therapeutic approaches to the cancer problem.
Lay summary

??Epithelial-mesenchymal interactions play a determining function in organ morphogenesis, tissue homeostasis and carcinogenesis. Notch signaling is an important form of cell-cell communication with a key role in control of cell fate commitment. The role of this pathway in the epithelial cell compartments of organs like the skin is by now well established. In our previous work we have demonstrated that it plays an equally important tumor suppressing function in the mesenchymal compartment. As a continuation of our work, we are now planning to dissect the underlying molecular mechanisms, focusing on CSL, 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. Activation of cancer associated fibroblasts (CAFs) has been linked with stromal cell senescence and autophagy. Yet, very little is known on how these processes are commonly controlled.  We will be testing the hypothesis that CSL acts as a negative regulator of these processes through functional and biochemical interactions with other key cellular regulatory proteins, specifically p53.

 

Direct link to Lay Summary Last update: 07.10.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation
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.
CYFIP1 is directly controlled by NOTCH1 and down-regulated in cutaneous squamous cell carcinoma
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.
Racial Differences in Cancer Susceptibility and Survival: More Than the Color of the Skin?
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.
The ULK3 Kinase Is Critical for Convergent Control of Cancer-Associated Fibroblast Activation by CSL and GLI
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.
CSL-p53: From senescence to CAF activation
Procopio M. G., Laszlo C., Dotto G. P. (2016), CSL-p53: From senescence to CAF activation, in Cell Cycle, 15, 485-6.
Dual tumor suppressing and promoting function of Notch1 signaling in human prostate cancer
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.
Negative control of CSL gene transcription by stress/DNA damage response and p53
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.
PDCD4 is a CSL associated protein with a transcription repressive function in cancer associated fibroblast activation
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.
Sexual dimorphism in cancer
Clocchiatti A., Cora E., Zhang Y., Dotto G. P. (2016), Sexual dimorphism in cancer, in Nat Rev Cancer, 16, 330-9.
Squamous Cell Cancers: A Unified Perspective on Biology and Genetics
Dotto G. P., Rustgi A. K. (2016), Squamous Cell Cancers: A Unified Perspective on Biology and Genetics, in Cancer Cell, 29, 622-637.
Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation
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.
Corrigendum: Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation
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.
A novel Nrf2-miR-29-desmocollin-2 axis regulates desmosome function in keratinocytes
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.
miR-34a/SIRT6 in squamous differentiation and cancer
Dotto G. P., Karine L. (2014), miR-34a/SIRT6 in squamous differentiation and cancer, in Cell Cycle, 13, 1055-6.
Multifactorial ERbeta and NOTCH1 control of squamous differentiation and cancer
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.
Multifocal epithelial tumors and field cancerization: stroma as a primary determinant
Dotto G. P. (2014), Multifocal epithelial tumors and field cancerization: stroma as a primary determinant, in J Clin Invest, 124, 1446-53.

Collaboration

Group / person Country
Types of collaboration
Group Goruppi/Massachusetts General Hospital/Harvard Medical School, Boston United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Group Delorenzi/Swiss Institute of Bioinformatics, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
176404 Genomic instability and evolution in cancer stromal cells 01.10.2017 Project funding (Div. I-III)
164119 In vivo cell dynamics in cancer, immunity and infection 01.07.2016 R'EQUIP

Abstract

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.
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