Mechanisms regulating tumor heterogeneity

 

The importance of tumor heterogeneity and its potential impact for personalized medicine is widely recognized. Different mechanisms including genetic and non-genetic factors such as the existence of different populations of tumor cells including cancer stem cells to regulate tumor heterogeneity.

We have assessed the importance of genetic determinants of tumor heterogeneity using next generation sequencing of tumor cells. We demonstrated the importance of the mutation landscape in regulating skin squamous cell carcinoma (SCC) heterogeneity (Nature Medicine 2015). It remains a matter of intense debate to whether aneuploidy is the cause or the consequence of tumorigenesis. We demonstrated that aneuploidy is associated with malignant transition (Nature Medicine 2015) and can promote tumor development only in p53 deficient context, resolving a long-standing debate in the field (Nature Cell Biology 2016). Cancer stem cell potential is usually assessed by the ability of cancer cells to propagate the tumor upon transplantation into immunodeficient mice. Our lab has been pioneered to develop new genetic approaches to assess the fate of tumor cells within their natural environment.

We have performed for the first time clonal analysis to unravel the mode of tumour growth and provide the first experimental evidence for the existence of cancer stem cells during primary tumour growth in vivo (Nature 2012). We also used lineage ablation to demonstrate the critical role of a small population of cancer stem cells expressing Sox2 that are responsible for tumor maintenance in squamous cell carcinoma (Nature 2014). These two new methods become the gold standard to assess cancer stem cells in vivo.

 

We uncovered a dual role for VEGF in regulating cancer stem cells. The secretion of VEGF by tumor cells stimulates neoangiogenesis, which create a vascular niche for cancer stem cells. VEGF also acts directly on tumor cells in an autocrine loop through a Nrp1 dependent mechanism to promote cancer stem cell renewal and tumour growth (Nature 2011). We have demonstrated the critical role of the transcription factors Sox2 and Twist1 in regulating the renewal and differentiation of cancer stem cells (Nature 2014 and Cell Stem Cell 2015).

 

By screening a large panel of cell surface markers and performing single cell RNA sequencing, we have identified different tumor states associated with different degree of epithelial to mesenchymal transition (EMT) including intermediate hybrid states in different mouse and human cancers and identified populations of EMT states associated with increased metastatic potential (Nature 2018).

Tumor heterogeneity was also proposed to regulate response to therapy. We identified a population of tumour cells that persists despite the administration of smoothened inhibitor and is responsible for basal cell carcinoma relapse after therapy. We discovered that inhibition of Wnt signalling combined with smoothened inhibitor leads to the eradication of the persisting tumor cells, showing that dual Wnt and hedgehog inhibition is a clinically relevant strategy for overcoming tumour relapse in patients with basal cell carcinoma (Nature 2018).

We are studying in more details the epigenetic and genetic mechanisms regulating tumor heterogeneity, the mechanisms that regulate metastasis, and resistance to therapy. Finally, we are developing new approaches to better model human cancers, to identify circulating tumor cells in patients with cancer and identifying clinically relevant strategy to eradicate cancers in humans.

People

Eugenia Pastushenko, postdoctoral fellow
Adriana Sanchez Danes, postdoctoral fellow
Gaelle Lapouge, postdoctoral fellow
Federico Mauri, postdoctoral fellow
Maylis Raphael, postdoctoral fellow
Manuel Zocco, postdoctoral fellow
Magdalena Sznurkowska, postdoctoral fellow
Pauline Vieugue, postdoctoral fellow
Maud Debaugnies, PhD student
Tatiana Revenco, PhD student
Yura Song, PhD student
Milan Malfait, PhD student
Mélanie Liagre, technician
Erwin Nkusi, technician
Marie-Astrid Parent, technician
Virginie Moers, technician
Sébastien Delcambre, technician
Benoit Durdu, technician
Samuel Scozzaro, technician

Selected publications

The vascular niche and a VEGF/Nrp1 loop regulates the initiation and stemness of skin tumours. Beck B , Driessens G, Goossens G, Kass Youssef K, Loges S, Caauwe A, Kuchnio A, Sotiropoulou PA, Candi A, Mascre M, Haigh JJ,  Carmeliet P, and Blanpain C. Nature 2011 Oct 9;479(7372):189-93. Highlighted by a preview and news and views in Nature and Nature Reviews Molecular and Cellular Biology.

Defining the mode of tumour growth by clonal analysis. Driessens G, Beck B, Caauwe A, Simons BD, Blanpain C. Nature. 2012 Aug 23;488(7412):527-30. Highlighted by a preview and news and views in Nature, Science, Nature Biotech, Nature Methods, Nature Reviews Cancer, and Science and Business exchange and the popular press around the world.

Skin squamous cell carcinoma propagating cells increase with tumour progression and invasiveness. Lapouge G, Beck B, Nassar D, Dubois C, Dekoninck S, Blanpain C. EMBO J. 2012 Nov 27;31(24):4563-75.

Unravelling cancer stem cell potential. Beck B, Blanpain C. Nat Rev Cancer 2013-13, 727–738.

Sox2 controls tumour initiation and cancer stem cell functions in squamous cell carcinoma. Boumahdi S, Driessens G, Lapouge G, Rorive S, Nassar D, Lemercier M, Delatte B, Caauwe A, Lenglez S, Nkusi E, Brohée S, Salmon I, Dubois C, del Marmol V, Fuks F, Beck B & Blanpain C. Nature 2014 Jul 10;511(7508):246-50. Highlighted in Cancer Cell and EMBOJ.

Different Twist1 levels regulates tumor intiation, stemness and progression
Beck B, Lapouge G, Drogat B, Desaedelaere K, Delafaille S, Willekens K, Marine J.C. and Blanpain C. Cell Stem Cell 2015 Jan 8;16(1):67-79.
Cover article

Genomic landscape of carcinogen and genetically-induced mouse skin squamous cell carcinoma. Nassar D, Latil M, Boeckx B, Lambrechts D, Blanpain C. Nat Med. 2015 Aug;21(8):946-54.

Toward understanding and exploiting tumor heterogeneity. Alizadeh AA, Aranda V, Bardelli A, Blanpain C, Bock C, Borowski C, Caldas C, Califano A, Doherty M, Elsner M, Esteller M, Fitzgerald R, Korbel JO, Lichter P, Mason CE, Navin N, Pe’er D, Polyak K, Roberts CW, Siu L, Snyder A, Stower H, Swanton C, Verhaak RG, Zenklusen JC, Zuber J, Zucman-Rossi J. Nat Med. 2015 Aug;21(8):846-53. doi: 10.1038/nm.3915.

Transient PLK4 overexpression accelerates tumorigenesis in p53-deficient epidermis. Sercin O, Larsimont JC, Karambelas AE,Marthiens V, Moers V, Boeckx B, Le Mercier M, Lambrechts D, Basto R, Blanpain C. Nature Cell Biology, 2016 Jan;18(1):100-10.

Cancer Stem Cells: Basic Concepts and Therapeutic Implications. Nassar D, Blanpain C. Annu Rev Pathol. 2016 May 23;11:47-76.

Identification of the tumour transition states occurring during EMT Pastushenko I, Brisebarre A, Sifrim A, Fioramonti M, Renvenco T, Boumahdi S, Van Keymeulen A, Brown D, Moers V, Lemaire S, De Clercq S, Minguijon E, Cédric Balsat C, Sokolow Y, Dubois C, de Cock F, Scozzaro S, Sopena F, Lanas A, D’Haene N, Salmon I, Marine JC, Voet T, Sotiropoulou P and Blanpain C. Nature. 2018 Apr;556(7702):463-468. Highlighted by a news and views in Nature

A slow-cycling LGR5 tumour population mediates basal cell carcinoma relapse after therapy. Sánchez-Danés A, Larsimont JC, Liagre M, Muñoz-Couselo E, Lapouge G, Brisebarre A, Dubois C, Suppa M, Sukumaran V, Del Marmol V, Tabernero J, Blanpain C. Nature. 2018 Oct;562(7727):434-438.