Manninen Lab - The cell biology and genomics of prostate cancer

Our team focuses on characterization of transcriptional regulatory proteins, including transcription factors (TFs) and epigenome regulators and how their activities are orchestrated within the tumor microenvironment (TME). In this context we investigate the role of the integrin family of the extracellular matrix (ECM) receptors in the regulation of PCa genome organization. How the TME controls PCa genome to regulate PCa cell growth and invasive properties. Aberrant TF programmes and integrin signaling are often observed in PCa as well as in various other types of cancers. However, how these two events are linked remains incompletely understood. Understanding the misregulated transcriptional networks in cancer cells and clinical specimens or patient-derived organoids will facilitate the discovery of novel mechanisms and clinical biomarkers for cancer risk prediction and potential targets for therapy. Here we aim to uncover the cancerous role of multiple TFs in prostate cancer by integrated functional cell biology and genomics and clinical data analysis. Together with data from genome-wide association studies and validation using state-of-art cell biological models, we aim to explore how the cancer risk-associated single nucleotide polymorphisms alter the genetics of TF-DNA binding at sites of clinically important enhancers, thereby affecting gene expression programs and eventually PCa-TME interactions to regulate PCa susceptibility and progression. We will validate the key prioritized hits, including risk SNPs, enhancers, and causal genes relevant to integrin signaling pathways that are potential biomarkers and drug targets for precision cancer medicine.

Research group information

Unit and faculty

Disease Networks
Faculty of Biochemistry and Molecular Medicine

Contact information

Contact person

Researchers

Research group description

Selected publications:

Cruz SP, Q. Zhang Q, Devarajan R, Paia C, Luo B, Zhang K, Koivusalo S, Qin L, Xia J, Ahtikoski A, Vaarala M, Wenta T, Wei GH*, Manninen A*, (2024). Dampened Regulatory Circuitry of TEAD1/ITGA1/ITGA2 Promotes TGFβ1 Signaling to Orchestrate Prostate Cancer Progression. Adv. Sci. 2305547.

Yang X, Zhang Q, Li S, Devarajan R, Luo B, Tan Z, Wang Z, Giannareas N, Wenta T, Ma W, Li Y, Yang Y, Manninen A*, Wu S*, Wei GH* (2023). GATA2 co-opts TGFβ1/SMAD4 oncogenic signaling and inherited variants at 6q22 to modulate prostate cancer progression. J. Exp. Clin. Cancer. Res. 42: 198.

Giannareas N, Zhang Q, Yang X, Tian Y, Zhang P, Yang Y, Manninen A, Wang L, Wei GH (2022) Extensive germline-somatic interplay drives prostate cancer through HNF1B co-option of TMPRSS2-ERG. Nature Communications 13:7320.

Schmidt A, Kaakinen M, Wenta T, Manninen A (2022) Loss of α6β4 Integrin-Mediated Hemidesmosomes Promotes Prostate Epithelial Cell Migration by Stimulating Focal Adhesion Dynamics. Front Cell Dev Biol. 10:886569.

Wenta T, Schmidt A, Zhang Q, Devarajan R, Singh P, Yang X, Ahtikoski A, Vaarala M, Wei GH, Manninen A (2022) Disassembly of α6β4-mediated hemidesmosomal adhesions promotes tumorigenesis in PTEN-negative prostate cancer by targeting plectin to focal adhesions. Oncogene 41:3804-3820. doi: 10.1038/s41388-022-02389-5.

Myllymäki SM, Kämäräinen UR, Liu X, Cruz SP, Miettinen S, Vuorela M, Varjosalo, M, Manninen A. (2019) Assembly of the β4-integrin interactome based on proximal biotinylation in the presence and absence of heterodimerization. MCP, 18:277-293.

Gao P, Xia JH, Sipeky C, Dong XM, Zhang Q, Yang Y, Zhang P, Cruz SP, Zhang K, Zhu J, Lee HM, Suleman S, Giannareas N, Liu S; PRACTICAL Consortium, Tammela TLJ, Auvinen A, Wang X, Huang Q, Wang L, Manninen A, Vaarala MH, Wang L, Schleutker J, Wei GH. (2018) Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus. Cell. 174:576-589.

Zhang P, Xia J, Zhu J, Gao P, Tian YJ, Du M, Guo CY, Suleman S, Zhang Q, Kohli M, Tillmans L, Thibodeau SN, French AJ, Cerhan JR, Wang LD, Wei GH & Wang L. (2018) High-throughput screening of prostate cancer risk loci by single nucleotide polymorphisms sequencing. Nature Communications 9, 2022.

Zhang K, Myllymäki SM, Gao P, Devarajan R, Kytölä V, Nykter M, Wei GH, Manninen A. (2017) Oncogenic K-Ras upregulates ITGA6-expression via FOSL1 to induce anoikis resistance and synergizes with αV-class integrins to promote EMT. Oncogene 36: 5681-5694

Huang Q, Whitington T, Gao P, Lindberg JF, Yang Y, Sun J, Väisänen MR, Szulkin R, Annala M, Yan J, Egevad LA, Zhang K, Lin R, Jolma A, Nykter M, Manninen A, Wiklund F, Vaarala MH, Visakorpi T, Xu J, Taipale J, Wei GH. (2014) A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding. Nature Genetics 46:126-135.

Projects

Project
2024 – 2027

The ECM control of the prostate cancer genome

Going up

Prof. Aki Manninen, PI; email: aki.manninen@oulu.fi; tel.: +358-294 486081

ORCID-ID: 0000-0002-6263-8101

https://www.researchgate.net/profile/Aki-Manninen

https://www.linkedin.com/in/aki-manninen-45aa855/

Dr. Raman Devarajan; (Alumnus)

ORCiD: https://orcid.org/0000-0002-8728-0476

Linkedin: https://www.linkedin.com/in/raman-devarajan-869a6816/

I am a post-doctoral fellow in Manninen’s Lab and my foremost research interest embraces the regulatory mechanisms of Cell-ECM interplay in tumor microenvironment. In addition, understanding the regulation of ECM proteins in cancer, particularly in breast and prostate cancers. Currently working on multicellular patient-derived organoid modelling which could predict drug response in a personalized fashion and have important ramification for development of future cancer therapies.

Dr. Nikolaos Giannareas; (Alumnus)

Prostate cancer (PCa) is the second most commonly diagnosed cancer type in men and among the most heritable forms of cancer with an estimated familiar risk of 57%. Genome-wide association studies (GWASs) have identified more than 280 single nucleotide polymorphism (SNP) loci associated with PCa risk and aggressiveness. However, the molecular and biological mechanisms, as well as the clinical impact of many PCa susceptibility loci remain to be investigated. In our study we found that PCa risk loci are greatly enriched for TF genes including HNF1B at 17q12. While aiming to unravel the oncogenic regulatory circuits of the 17q12/HNF1B locus, we observed strong expression quantitative trait loci (eQTL) signals for the plausible causative gene HNF1B with the SNPs involved in HNF1B regulation in PCa. HNF1B has been found to biologically direct pathways of genes associated with cell cycle progression and PCa severity. An unbiased genome-wide co-expression analysis reveals the most frequent somatic alteration TMPRSS2-ERG fusion in PCa as a transcriptional mediator of the 17q12 locus. We try to demonstrate an extensive germline-somatic interaction between TMPRSS2-ERG and the HNF1B locus which implies a genetic predisposition and progression of PCa. This is currently an excellent example of discovering the mechanistic action of the 17q12 multicancer locus and the role of HNF1B in other types of cancers.

Dr. Zenglai Tan; email: zenglai.tan@oulu.fi

Dr. Xiayun Yang; email: xiayun.yang@oulu.fi

Dr. Sara Cruz: (Alumna)

My PhD project consisted in unveiling the role of the collagen binding a1- and a2-integrins in the prostate cancer progression. We found that the dual loss of these integrins leads to a worse prognosis by activating EMT through TGFb activation. Also, we discovered that Tead1, an transcription factor, is regulating the expression of these two integrins. In conclusion, the mutual loss of ITGA1/ITGA2/TEAD1 could be a biomarker for aggressive prostate cancer.

M.Sc. Qin Zhang; email: qin.zhang@oulu.fi

M.Sc. Anette Schmidt; email: anette.schmidt@oulu.fi

ORCID: 0000-0002-8242-0484

LinkedIn: www.linkedin.com/in/anette-schmidt-31a580204

I am doing my PhD on integrin mediated cell adhesions in normal and prostate epithelial cells. Thus far my project has mainly focused on loss of α6β4-integrin mediated hemidesmosomes and its effect on cell behavior.

M.Sc. Saara Koivusalo; e-mail: saara.koivusalo@oulu.fi

LinkedIn: www.linkedin.com/in/saarakoivusalo

ORCID ID: 0000-0001-7847-196X

I am applying Digital Holographic Microscopy for organoid imaging. In Digital holographic microscopy (DHM) Light from a coherent laser illuminates the sample which changes the phase of the light. When compared to referense beam, these two beams are combined to form a hologram which is captured by camera and interpreted by the computer. This allowes a real-time imaging and quantitative measurements of morphological parameters without any staining or labeling. By using DHM we are analyzing the morphology of prostate cancer organoids in relation to pathology. The quantitative phase information from DHM may accurately classify cancer cell subpopulations with clinical relevance. A future goal is to make the morphological analysis ability of DHM as a fast, automatic, and cost efficient tool for testing different cancer treatments.

M.Sc. Binjie Luo (Clinical medicine (Urology)); email: Binjie.Luo@oulu.fi

Research project brief introduction: Research Prostate cancer (PCa) is one of the most common cancers and the second most common cause of cancer-related death in men worldwide, with ~ 1100000 new cases diagnosed and ~ 360000 deaths every year. FOXA2, also known as hepatocyte nuclear factor 3-beta (HNF-3B), is a transcription factor that plays an important role during development and in mature tissues and diseases, and it was found specifically expressed in neuroendocrine prostate cancer (NEPC), which has a poor prognosis in clinical observation. Understanding the molecular mechanisms of FOXA2 in NEPC is critical for improving therapeutic interventions for poor prognosis NEPC patients. Our research interest is mainly to identify if the FOXA2 can harbor some the risky susceptibility alleles that modulating chromatin binding and lead to NEPC. Combing our ChIP-seq results, RNA-seq results and clinical cohorts results to find the FOXA2 possible clinical target genes driving NEPC. And to define how the FOXA2 cooperate with other signal pathways or TFs thus may regulate some oncogenic and tumor suppressive genes and pathways contributing to NEPC susceptibility, initiation and development.

M.Sc. Liang Mao; email: liang.mao@oulu.fi

M.Sc. Thanh Nga Nguyen; email: Nga.T.Nguyen@oulu.fi

M.Sc. Kari Kunnas; email: kari.kunnas@oulu.fi

Yuehong Yang, lab manager; email: yuehong.yang@oulu.fi

Riitta Jokela, technician; email: riitta.k.jokela@oulu.fi