Prof. Andreas Hecht

Molecular mechanisms of cancer cell invasion

Mortality among cancer patients rises sharply with the occurrence of distant organ metastases. The formation of these secondary neoplasms occurs in a stepwise process which is initiated when tumor cells begin to invade the surrounding tissue, detach from the primary tumor, disseminate via blood and lymphatic vessels, and eventually reach another organ.

Our research activities concentrate on the earliest steps of the metastasis cascade, the penetration of the basement membrane and the local invasion of the underlying stromal tissue. These events are greatly facilitated when cancer cells are induced to undergo an epithelial-to-mesenchymal transition (EMT). EMT is a conserved cell biological program which results in the disruption of cell-cell and cell-matrix adhesion, the gain of motility and invasiveness, alterations in stemness, and therapy resistance.

From a mechanistic perspective, EMT represents an extreme form of transcriptional reprogramming. Central to this process are the transcription factors SNAIL1, TWIST1 and ZEB1. However, the extent of EMT-associated gene expression changes reaches far beyond what can be explained solely by their activities. Moreover, it has become controversial whether cancer cells fully or only partially undergo EMT in order retain sufficient plasticity to revert to an epithelial phenotype at the metastatic site. For the molecular understanding of cancer cell invasion and metastasis it is therefore an important task to determine which signal transduction pathways and transcription factors control the generation, maintenance, and interconversion of gene expression programs that specify epithelial, mesenchymal, and intermediate epithelial/mesenchymal cancer cell states.

To investigate the gene regulatory networks that control the invasive behavior of cancer cells we apply cell biological techniques, molecular genetics, functional genomics, and bioinformatics, using human cell lines and genetically engineered murine intestinal organoids as model systems. Our long-term goal is to decisively advance our understanding of the molecular mechanisms operating in cancer cell invasion.

10 selected publications

• TGFβ1-Induced EMT in the MCF10A Mammary Epithelial Cell Line Model Is Executed Independently of SNAIL1 and ZEB1 but Relies on JUNB-Coordinated Transcriptional Regulation.
  Antón-García P, Haghighi EB, Rose K, Vladimirov G, Boerries M, Hecht A (2023).
  Cancers (Basel). 15(2):558
• Canonical TGFβ signaling induces collective invasion in colorectal carcinogenesis through a Snail1- and Zeb1-independent partial EMT.
  Flum M, Dicks S, Teng YH, Schrempp M, Nyström A, Boerries M, Hecht A (2022).
  Oncogene. 41(10):1492-1506.
• SMAD4 mutations do not preclude epithelial-mesenchymal transition in colorectal cancer.
  Frey P, Devisme A, Rose K, Schrempp M, Freihen V, Andrieux G, Boerries M, Hecht A (2022).
  Oncogene. 41(6):824-837.
• SNAIL1 employs β-Catenin-LEF1 complexes to control colorectal cancer cell invasion and proliferation.
  Freihen V, Rönsch K, Mastroianni J, Frey P, Rose K, Boerries M, Zeiser R, Busch H, Hecht A (2020).
  Int J Cancer 146, 2229-2242.
• Loss of the nuclear Wnt pathway effector TCF7L2 promotes migration and invasion of human colorectal cancer cells.
  Wenzel J, Rose K, Haghighi EB, Lamprecht C, Rauen G, Freihen V, Kesselring R, Boerries M, Hecht A (2020).
  Oncogene 39, 3893-3909.
• Genome-wide mapping of DNA-binding sites identifies stemness-related genes as directly repressed targets of SNAIL1 in colorectal cancer cells.
  Beyes S, Andrieux G, Schrempp M, Aicher D, Wenzel J, Antón-García P, Boerries M, Hecht A (2019).
  Oncogene 38, 6647-6661.
• SNAIL1-mediated downregulation of FOXA proteins facilitates the inactivation of transcriptional enhancer elements at key epithelial genes in colorectal cancer cells.
  Jägle S, Busch H, Freihen V, Beyes S, Schrempp M, Boerries M, Hecht A (2017).
  PLoS Genet 13, e1007109.
• SNAIL1 combines competitive displacement of ASCL2 and epigenetic mechanisms to rapidly silence the EPHB3 tumor suppressor in colorectal cancer.
  Rönsch K, Jägle S, Rose K, Seidl M, Baumgartner F, Freihen V, Yousaf A, Metzger E, Lassmann S, Schüle R, Zeiser R, Michoel T, Hecht A (2015).
  Mol Oncol 9, 335-354.
• Silencing of the EPHB3 tumor-suppressor gene in human colorectal cancer through decommissioning of a transcriptional enhancer.
  Jägle S, Rönsch K, Timme S, Andrlova H, Bertrand M, Jäger M, Proske A, Schrempp M, Yousaf A, Michoel T, Zeiser R, Werner M, Lassmann S, Hecht A (2014).
  Proc Natl Acad Sci U S A 111, 4886-4891.
• Alternative splicing of Tcf7l2 transcripts generates protein variants with differential promoter-binding and transcriptional activation properties at Wnt/beta-catenin targets.
  Weise A, Bruser K, Elfert S, Wallmen B, Wittel Y, Wöhrle S, Hecht A (2010).
  Nucleic Acids Res 38, 1964-1981.