Description

The standard treatment for locally advanced rectal cancers consists of preoperative 5-FU-based chemoradiotherapy (CRT) followed by radical surgery. However, clinical response to CRT varies greatly, and a considerable percentage of rectal cancers are resistant, even if intensified regimens are being pursued. This represents a substantial clinical and socioeconomic problem, as it exposes patients to the potential side effects of cytotoxic therapies and radiation without a clear benefit. Thus, it remains of utmost clinical importance to determine the molecular characteristics underlying this resistance, and to identify effective strategies to overcome it. We have therefore systematically explored genes and pathways that were suggested, based on high-throughput profiling analyses of primary rectal cancers and colorectal cancer (CRC) cell lines, to mediate treatment resistance. Briefly, there is now convincing evidence that targeting Wnt/β-catenin and JAK/STAT signaling represents a promising strategy to increase therapeutic responsiveness to chemoradiotherapy.

Aberrant Wnt/β-catenin signaling plays a central role in embryonic development and in the maintenance of tissue homeostasis, but is also found important in the development and progression of various human malignancies. Mutations in and deregulation of components of this pathway are defining features of colorectal tumorigenesis. In Wnt/β-catenin-active CRC cell lines, we found that knock down of the main Wnt transcription factor TCF7L2 by RNAi caused a significant sensitization to clinically relevant doses of X-rays. In further analyses, we focused on the Wnt signaling regulator protein β-catenin to identify if this effect was mediated by a TCF7L2 inherent mechanism or if CRT-sensitization is dependent on Wnt/β-catenin signaling in general. Recently, we showed that siRNA-mediated silencing of β-catenin resulted in sensitization of CRC cell lines to CRT. Stimulation of the Wnt signaling pathway by either addition of the ligand Wnt-3a or by overexpression of a mutated active β-catenin in non-tumorigenic RPE-1 cells led to increased therapy resistance. Therefore, Wnt/β-catenin signaling seems to play a central role in mediating resistance of colorectal cancer cells to CRT.

In a second project, we established an in vitro model for chemoradiosensitivity testing in CRC cell lines, and generated signatures of CRT-sensitivity, leading to the identification of the transcription factor STAT3. JAK/STAT signaling constitutes an essential and ubiquitous pathway that regulates development and differentiation, control of cell growth, and homeostasis in many cell types. As a prominent member of JAK/STAT signaling, STAT3 is known for its function as an oncogene, and is therefore capable of promoting tumor cell survival and migration. Recently, STAT3 has also been implicated in resistance to radiation in several tumor entities. In our own studies, we discovered that resistant CRC cell lines could be sensitized to CRT after knock down of STAT3 by RNAi or after treatment by the STAT3 specific inhibitor STATTIC. Using STATTIC and CRT in vivo, we could reduce tumor growth in mice, and importantly, survival of STATTIC treated mice was prolonged in comparison to control animals. Taken together, STAT3 reveals a promising target in treatment of resistant tumors.

Publications

• NOTCH Activation via gp130/STAT3 Signaling Confers Resistance to Chemoradiotherapy.
  Koerdel K, Spitzner M, Meyer T, Engels N, Krause F, Gaedcke J, Conradi LC, Haubrock M, Beißbarth T, Leha A, Johnsen SA, Ghadimi BM, Rose-John S, Grade M, Wienands J. Cancers (Basel). 2021 Jan 26;13(3):455.
• Epigenome Mapping Identifies Tumor-Specific Gene Expression in Primary Rectal Cancer.
  Flebbe H, Hamdan FH, Kari V, Kitz J, Gaedcke J, Ghadimi BM, Johnsen SA, Grade M. Cancers (Basel). 2019 Aug 9;11(8).
• Combined targeting of HER-2 and HER-3 represents a promising therapeutic strategy in colorectal cancer.
  Conradi LC, Spitzner M, Metzger AL, Kisly M, Middel P, Bohnenberger H, Gaedcke J, Ghadimi MB, Liersch T, Rüschoff J, Beißbarth T, König A, Grade M. BMC Cancer. 2019 Sep 5;19(1):880.
• Colorectal cancer susceptibility loci as predictive markers of rectal cancer prognosis after surgery.
  Hu Y, Gaedcke J, Emons G, Beissbarth T, Grade M, Jo P, Yeager M, Chanock SJ, Wolff H, Camps J, Ghadimi BM, Ried T. Genes Chromosomes Cancer. 2018 Mar;57(3):140-149. doi: 10.1002/gcc.22512. Epub 2017 Nov 28.
• Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/β-catenin Signaling.
  Emons G, Spitzner M, Reineke S, Möller J, Auslander N, Kramer F, Hu Y, Beissbarth T, Wolff HA, Rave-Fränk M, Heßmann E, Gaedcke J, Ghadimi BM, Johnsen SA, Ried T, Grade M. Mol Cancer Res. 2017 Nov;15 (11):1481-1490.
• STAT3 inhibition sensitizes colorectal cancer to chemoradiotherapy in vitro and in vivo.
  Spitzner M, Roesler B, Bielfeld C, Emons G, Gaedcke J, Wolff HA, Rave-Fränk M, Kramer F, Beissbarth T, Kitz J, Wienands J, Ghadimi BM, Ebner R, Ried T, Grade M. Int J Cancer. 2014 Feb 15;134(4):997-1007.
• Silencing of the Wnt transcription factor TCF4 sensitizes colorectal cancer cells to (chemo-)radiotherapy.
  Kendziorra E, Ahlborn K, Spitzner M, Rave-Fränk M, Emons G, Gaedcke J, Kramer F, Wolff AH, Becker H, Beissbarth T, Ebner R, Ghadimi BM, Pukrop T, Ried T, Grade M. Carcinogenesis. 2011 Dec;32(12):1824-31.