Dr Sakari Vanharanta
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 metastatic cancer progression may be intimately linked with the 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 molecular mechanisms that modulate the phenotypic output of tumour-initiating mutations in support of metastasis, and test the hypothesis that this optimisation of oncogenic signalling results in molecular vulnerabilities in the most aggressive cancer clones.
Understanding the origins of metastatic cancer phenotypes 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.
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 carcinoma. Al-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