Integrin Signaling and Transcriptional Networks in Cancer - Aki Manninen
We focus on characterization of transcriptional regulatory proteins, including transcription factors (TFs) and epigenome regulators, and their interplay with integrin signaling pathways in gene regulation and accurate control of cell growth. Aberrant functioning of the TFs and integrins is often observed in various types of cancers, such as prostate malignancy. 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 genomics and clinical data analysis. Together with data from genome-wide association studies, 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 underpinning cancer 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.
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. Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus. Cell. 2018 Jul 26;174(3):576-589.
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. A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding. Nature Genetics. 46:126-135, 2014
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. High-throughput screening of prostate cancer risk loci by single nucleotide polymorphisms sequencing. Nature Communications. 9, 2022, 2018
Myllymäki SM, Kämäräinen UR, Liu X, Cruz SP, Miettinen S, Vuorela M, Varjosalo, M, Manninen A. Assembly of the β4-integrin interactome based on proximal biotinylation in the presence and absence of heterodimerization. MCP, 18:277-293, 2019
Zhang K, Myllymäki SM, Gao P, Devarajan R, Kytölä V, Nykter M, Wei GH, Manninen A. 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, 2017