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MRC Cancer Unit


sv smDr Sakari Vanharanta

Biography | Pubmed

Video Overview


Genetic control of tissue-specific carcinogenesis

A striking result from genetic analyses of human cancer is that mutations in most cancer driver genes are detected only in a small fraction of tumour types, and that this pattern is preserved even in advanced metastatic cancers. A prominent example of such tissue-selectivity is the von Hippel-Lindau tumour suppressor (VHL), which is ubiquitously inactivated in clear cell renal cancer but not in other cancer types. On the other hand, phenotypically normal tissues can contain clonal expansions that carry multiple driver mutations in cancer genes such as TP53. Thus, while cancers arise through the acquisition of specific driver mutations, the cellular context profoundly affects the phenotype of those mutations. How tissue-specific oncogenic programmes arise downstream of driver mutations remains a central unanswered question in cancer biology.

Normal development and tissue homeostasis depend on tightly controlled gene expression programmes. These physiological programmes are established and maintained by the combinatorial action of transcription factors (TFs) that have DNA binding specificities. TFs bind to specific gene regulatory elements, such as promoters and enhancers, which in turn regulate gene expression in a tissue and context-dependent manner. The strong effect of tissue of origin on carcinogenesis suggests that the transcriptional programmes that define normal cellular states are also critical modulators of oncogenic processes.

Despite the strong evidence linking tissue-specific programmes to cancer, several open questions remain. For example, it is unclear how some TFs that are highly expressed in normal cells acquire the capability to drive oncogenic signalling in the same lineage. It is also unclear what maintains the stability of the homeostatic transcriptional programmes even in advanced cancers and how they influence the functional output of cancer driver mutations. The role of homeostatic programmes is likely to be especially important during the early stages of cancer progression before the emergence of advanced cancer phenotypes. Understanding how cancer mutations and tissue-specific factors interact in support of carcinogenesis will therefore provide critical new insight into the origins of cancer and how it could be treated.

The general goal of our research is to characterize the molecular mechanisms that lead to the establishment of tissue-specific oncogenic programmes following tumour-initiating cancer mutations. With a focus on VHL mutant kidney cancer, a tumour type with unique genetic and phenotypic characteristics, we aim to understand (i) how physiological transcriptional programmes that maintain tissue homeostasis are co-opted for carcinogenesis, (ii) how these networks interact with genetically activated oncogenic pathways, (iii) what the critical pro-tumorigenic mechanisms activated by cancer mutations are, and (iv) whether cancer-specific mutations lead to molecular vulnerabilities that could be exploited for cancer therapy.

Our research approach combines experimental cancer models and human cancer data sets with state-of-the-art genomics (e.g. chromatin and transcriptional profiling), mechanistic analysis using various methods of genetic perturbation, and unbiased functional genetic screens. Our long-term goal is to identify novel approaches of early cancer intervention that could be used for patient benefit.



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