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Sakari Vanharanta

sv smDr Sakari Vanharanta

Biography | Pubmed



Transcriptional determinants of cancer progression

Metastatic dissemination remains one of the most devastating complications of cancer. Despite recent advances in both genetic and experimental dissection of the metastatic process, metastatic cancer remains incurable in most cases. Novel therapeutic approaches are thus needed.

In the clinic, metastases often present as the final step of disease progression. At the molecular level, however, the drivers of metastasis may be intimately linked to the cancer’s tissue of origin and early steps of carcinogenesis. Several lines of evidence suggest that instead of specific mutations, metastatic phenotypes can emerge from optimized output of the oncogenic pathways that drive tumour initiation and early progression. The molecular mechanisms as well as phenotypic consequences of such alterations in cancer cell signalling processes remain elusive. Understanding how metastatic cancer phenotypes arise and persist, to what extent this is dependent on the pathways that drive tumour initiation and early progression, and what genetic vulnerabilities advanced cancer clones have could profoundly affect our ability to fight metastatic cancer. 

Using an integrative approach combining experimental cancer models, high-throughput genomics, functional genetics, bioinformatics and clinical association analysis, this programme aims at identifying genetic dependencies in metastatic cancer. With a focus on VHL mutant renal cancer, we explore the molecular mechanisms that modulate the phenotypic output of tumour-initiating transcriptional pathways in support of cancer progression and metastasis, and test the hypothesis that this optimisation of oncogenic signalling results in molecular vulnerabilities in the most aggressive cancer clones.

Understanding the origins and nature of metastatic cancer will provide insights into the fundamental requirements of cancer cell states and help identify functionally relevant biomarkers as well as therapeutic targets.



Click here to contact Dr Sakari Vanharanta by email.


Recent Publications:

A KLF6-driven transcriptional network links lipid homeostasis and tumour growth in renal carcinoma. Syafruddin SE, Rodrigues P, Vojtasova E, Patel SA, Zaini MN, Burge J, Warren AY, Stewart GD, Eisen T, Bihary D, Samarajiwa SA, Vanharanta S. Nat Commun. 2019 Mar 11;10(1):1152. PMID: 30858363

Circulating Tumor Cells: Come Together, Right Now, Over Metastasis. Rodrigues P, Vanharanta S. Cancer Discov. 2019 Jan;9(1):22-24. PMID: 30626605

VHL-Mediated Regulation of CHCHD4 and Mitochondrial Function. Briston T, Stephen JM, Thomas LW, Esposito C, Chung YL, Syafruddin SE, Turmaine M, Maddalena LA, Greef B, Szabadkai G, Maxwell PH, Vanharanta S, Ashcroft M. Front Oncol. 2018 Oct 4;8:388. PMID: 30338240

Endogenous HIF2A reporter systems for high-throughput functional screening. Zaini MN, Patel SA, Syafruddin SE, Rodrigues P, Vanharanta S. Sci Rep. 2018 Aug 13;8(1):12063. PMID: 30104738 

NF-κB-Dependent Lymphoid Enhancer Co-option Promotes Renal Carcinoma Metastasis. Rodrigues P, Patel SA, Harewood L, Olan I, Vojtasova E, Syafruddin SE, Zaini MN, Richardson EK, Burge J, Warren AY, Stewart GD, Saeb-Parsy K, Samarajiwa SA, Vanharanta S. Cancer Discov. 2018 Jul;8(7):850-865. doi: 10.1158/2159-8290.CD-17-1211. PMID: 29875134

Epigenetic Determinants of Metastasis. Patel SA, Vanharanta S. Mol Oncol. 2016 Oct 8. pii: S1574-7891(16)30108-9. doi: 10.1016/j.molonc.2016.09.008. [Epub ahead of print]. PMID: 22756687

Tumor necrosis factor receptor 2-signaling in CD133-expressing cells in renal clear cell carcinomaAl-Lamki RS, Wang J, Yang J, Burrows N, Maxwell PH, Eisen T, Warren AY, Vanharanta S, Pacey S, Vandenabeele P, Pober JS, Bradley JR. Oncotarget. 2016 Apr 26;7(17):24111-24. doi: 10.18632/oncotarget.8125. PMID: 26992212

Metastatic Competence Can Emerge with Selection of Preexisting Oncogenic Alleles without a Need of New Mutations. Jacob LS, Vanharanta S, Obenauf AC, Pirun M, Viale A, Socci ND, Massagué J. Cancer Res. 2015 Sep 15;75(18):3713-9 doi: 10.1158/0008-5472.CAN-15-0562. Epub 2015 Jul 24. PMID: 26208905

A hypoxic ticket to the bone metastatic niche. Vanharanta, S. Breast Cancer Res. 2015 Sep 4;17:122. doi: 10.1186/s13058-015-0635-7. PMID: 26337273

Therapy-induced tumour secretomes promote resistance and tumour progression. Obenauf AC, Zou Y, Ji AL, Vanharanta S, Shu W, Shi H, Kong X, Bosenberg MC, Wiesner T, Rosen N, Lo RS, Massagué J. Nature. 2015 Apr 16;520(7547):368-72. doi: 10.1038/nature14336. Epub 2015 Mar 25. PMID: 25807485.

Loss of the multifunctional RNA-binding protein RBM47 as a source of selectable metastatic traits in breast cancer. Vanharanta S, Marney CB, Shu W, Valiente M, Zou Y, Mele A, Darnell RB, Massagué J. Elife. 2014 Jun 4:e02734. doi: 10.7554/eLife.02734. PMID: 24898756 

Origins of metastatic traits. Vanharanta S, Massagué J. Cancer Cell. 2013 Oct 14;24(4):410-21. doi: 10.1016/j.ccr.2013.09.007. PMID: 24135279 

Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer. Vanharanta S, Shu W, Brenet F, Hakimi AA, Heguy A, Viale A, Reuter VE, Hsieh JDD, Scandura JM, Massagué J. Nat Med. 2013 Jan;19(1):50-6. doi: 10.1038/nm.3029. Epub 2012 Dec 9. PMID: 23223005

A CXCL1 paracrine network links cancer chemoresistance and metastasis. Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim J, Morris PG, Manova-Todorova K, Leversha M, Hogg N, Seshan VE, Norton L, Brogi E, Massagué J. Cell. 2012 Jul 6;150(1):165-78. doi: 10.1016/j.cell.2012.04.042. PMID: 22770218

Field cancerization: something new under the sun. Vanharanta S, Massagué J. Cell. 2012, Jun 8;149:1179-81. doi: 10.1016/j.cell.2012.05.013. PMID: 22682238

Breast cancer cells producetenascin C as a metastatic niche component to colonize the lungs. Oskarsson T, Acharyya S, Zhang XHF, Vanharanta S, Tavazoie SF, Morris PG, Downey RJ, Manova-Todorova K, Brogi E, Massagué J. Nat Med. 2011 Jun 26;17(7):867-74. doi: 10.1038/nm.2379. PMID: 21706029