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Traditionally, mature cells in specific tissues and organs have been regarded as the cell-of-origin of the corresponding tumors. However, the observation that tumor cells need to accumulate genetic and phenotypic alterations over extended time periods has turned the view to stem cells or progenitors with a prolonged lifespan, which are broadly distributed in local reservoirs. These cells, in charge of maintaining tissue homeostasis, are contemplated as the target of neoplastic transformation.
Our laboratory is studying whether certain sarcomas originate from mesenchymal progenitors and whether melanomas result from transformation of melanocytic stem cells. Moreover, we hypothesize that alterations in the normal differentiation process of these progenitors act at early stages of tumor initiation, and that the retention or reactivation of stem cell properties may contribute to tumor progression and aggressive behavior (resistance to therapy, metastasis). A limitation for these studies is our partial understanding of the normal differentiation process of these two lineages.
To overcome this limitation, our laboratory has established and characterized the in vitro differentiation of human Mesenchymal Stem Cells (hMSCs) into smooth-muscle (SMC), the lineage of origin of Leiomyosarcomas (LMS), tumors that appear in the uterus, the retroperitoneum and the extremities. We have found that some miRNAs down-regulated during hMSC differentiation are overexpressed in uterine LMS compared to normal myometrium. We are currently determining whether these candidate miRNAs play an active role in SM differentiation in vitro and in vivo and whether their alteration leads to a blockade in SM maturation, increased proliferation and/or MSC transformation.
In addition, we have developed a leiomyosarcoma mouse model based on the inactivation of Pten in an early smooth-muscle progenitor (using the transgelin promoter, Tgln). MSCs isolated from Tgln-cre/Ptenlox/lox mice are being analyzed for the effect of Pten inactivation in stem cell maintenance, proliferation and differentiation. Mice heterozygous for Pten and p53 in the SM lineage develop very aggressive LMS that are able to spontaneously metastasize to distal organs.
Melanomas also show phenotypic heterogeneity both in vivo and in vitro, suggesting an origin from a cell with multilineage differentiation abilities. Moreover, malignant melanoma seems to evoke the migratory nature of neural crest and melanoblasts from which melanocytes arise, suggesting that transformation may occur in a melanocytic stem cell.
Our lab has found that a miRNA cluster (miR-182-96-183) located in a genomic region frequently amplified in melanoma (7q31-34) is overexpressed in melanoma tissues and cell lines. A member of this cluster, miR-182, controls MITF, a transcription factor with a critical role in melanocytic differentiation. We have demonstrated that upregulation of a member of this cluster, miR-182, promotes migration in vitro and metastasis in vivo. Interestingly, miR-182 targets MITF, a master regulator of melanocytic differentiation. Ongoing work using stem cells, melanoma cell lines, and mouse models should unravel the mechanism(s) by which this miRNA contributes to melanoma progression.
BET and BRAF inhibitors act synergistically against BRAF-mutant melanoma
Paoluzzi, Luca; Hanniford, Douglas; Sokolova, Elena; Osman, Iman; Darvishian, Farbod; Wang, Jinhua; Bradner, James E; Hernando, Eva. BET and BRAF inhibitors act synergistically against BRAF-mutant melanoma. Cancer medicine. 2016 May 11;5(6):1183-1193 (2107752)
SPROUTY-2 represses the epithelial phenotype of colon carcinoma cells via upregulation of ZEB1 mediated by ETS1 and miR-200/miR-150
Barbachano, A; Fernandez-Barral, A; Pereira, F; Segura, M F; Ordonez-Moran, P; Carrillo-de Santa Pau, E; Gonzalez-Sancho, J M; Hanniford, D; Martinez, N; Costales-Carrera, A; Real, F X; Palmer, H G; Rojas, J M; Hernando, E; Munoz, A. SPROUTY-2 represses the epithelial phenotype of colon carcinoma cells via upregulation of ZEB1 mediated by ETS1 and miR-200/miR-150. Oncogene. 2015 Oct 12;35(23):2991-3003 (1803562)
Identification of Metastasis-Suppressive microRNAs in Primary Melanoma
Hanniford, Doug; Segura, Miguel F; Zhong, Judy; Philips, Elliot; Jirau-Serrano, Xavier; Darvishian, Farbod; Berman, Russell S; Shapiro, Richard L; Pavlick, Anna C; Brown, Brian; Osman, Iman; Hernando, Eva. Identification of Metastasis-Suppressive microRNAs in Primary Melanoma. Journal of the National Cancer Institute. 2015 Feb 12;107(3):?-? appiajp201414070908 (1461902)
A miRNA-based signature detected in primary melanoma tissue predicts development of brain metastasis
Hanniford, Douglas; Zhong, Judy; Koetz, Lisa; Gaziel-Sovran, Avital; Lackaye, Daniel J; Shang, Shulian; Pavlick, Anna; Shapiro, Richard L; Berman, Russell S; Darvishian, Farbod; Shao, Yongzhao; Osman, Iman; Hernando, Eva. A miRNA-based signature detected in primary melanoma tissue predicts development of brain metastasis. Clinical cancer research. 2015 Jun 18;21(21):4903-4912 (1631082)
FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification
Kourtis, Nikos; Moubarak, Rana S; Aranda-Orgilles, Beatriz; Lui, Kevin; Aydin, Iraz T; Trimarchi, Thomas; Darvishian, Farbod; Salvaggio, Christine; Zhong, Judy; Bhatt, Kamala; Chen, Emily I; Celebi, Julide T; Lazaris, Charalampos; Tsirigos, Aristotelis; Osman, Iman; Hernando, Eva; Aifantis, Iannis. FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification. Nature cell biology. 2015 Mar ;17(3):322-332 (1474022)