The ECM control of the prostate cancer genome
Project information
Project duration
-
Project funder
Project coordinator
University of Oulu
Unit and faculty
Contact information
Project leader
- Professor
Project description
Aberrant TF programs and integrin signaling are common features of PCa and various other cancers, yet their connection and interplay remain incompletely understood. Understanding the misregulated TF networks in cancer cells and clinical specimens or patient-derived organoids will facilitate the discovery of novel mechanisms, drug targets and clinical biomarkers for cancer risk prediction. We aim to uncover the cancerous role of multiple TFs in PCa by integrated functional cell biology, multiomics and clinical data analysis. Data from genome-wide association studies is validated using state-of-art cell biological models. Key question is how cancer risk-associated single nucleotide polymorphisms (SNP) alter TF-DNA binding at sites of clinically important enhancers, thereby affecting gene expression programs and eventually PCa-TME interactions to promote human prostate pathogenesis and tumorigenesis. 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 groups
Key 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.
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.
Göös H, Kinnunen M, Salokas K, Tan Z, Liu X, Yadav L, Zhang Q, Wei GH, Varjosalo M (2022). Human transcription factor protein interaction networks. Nature Communications 13:766.
Ahmed M, Soares F, Xia JH, Yang Y, Li J, Guo H, Su P, Tian Y, Lee HJ, Wang M, Akhtar N, Houlahan KE, Bosch A, Zhou S, Mazrooei P, Hua JT, Chen S, Petricca J, Zeng Y, Davies A, Fraser M, Quigley DA, Feng FY, Boutros PC, Lupien M, Zoubeidi A, Wang L, Walsh MJ, Wang T, Ren S, Wei GH, He HH. (2021). CRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer. Nature Communications 12:1781.
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. Molecular & Cellular Proteomics 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 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, Yuehong 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.