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Significance of heterogeneous WNT and MAPK signaling in colorectal cancer
Significance of heterogeneous WNT and MAPK signaling in colorectal cancer
Constitutively active WNT signaling in colorectal cancers is hallmark and driver of malignant progression in these tumors. However, therapeutic targeting of WNT signaling is difficult due to anticipated side effects on WNT dependent normal tissue homeostasis. Using transcriptome, proteome and cell biology approaches, weidentified the transcription factor ADNP as a repressor of WNT signaling in colon cancer that can be induced pharmacologically by treatment with sub-narcotic doses of ketamine. Treatment results in significantly slowed tumor growth in pre-clinical xenograft models of colon cancer. Moreover, high ADNP expression in human colorectal cancers predicts improved disease outcome. Our findings indicate ADNP as a tumor suppressor and promising prognostic marker, and ketamine treatment with ADNP induction as a potential therapeutic approach that may add to current treatment protocols with benefits for colorectal cancer patients. Beside mutational WNT activation, about 40 % of colorectal cancers have mutations in KRAS with downstream activation of MAPK signaling that promotes tumor invasion and progression. We demonstrate that MAPK signaling shows strong intratumoral heterogeneity, and surprisingly remains regulated in colorectal cancer, irrespective of the tumors’ KRAS mutation status. Using primary colorectal cancer tissues,xenografts and MAPK reporter constructs, we show that tumor cells with high MAPK activity specifically reside at the leading tumor edge, cease to proliferate, undergo epithelial-mesenchymal transition (EMT), and express markers related to colon cancer stem cells. In KRAS mutant colon cancer cells, regulation of MAPK signaling is preserved through remaining wild-type RAS isoforms. Moreover, using a lineage tracing strategy, we provide evidence that high MAPK activity marks a progenitor cell compartment of growth fueling colon cancer cells in vivo. Our results imply that differential MAPK signaling balances EMT, cancer stem cell potential, and tumor growth in colorectal cancer. The positive crosstalk between WNT and MAPK signaling in colorectal cancer has strong implications for the development of combination therapies and a better understanding of the underlying mechanisms may lead to improved therapeutic strategies.
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Blaj, Cristina
2017
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Blaj, Cristina (2017): Significance of heterogeneous WNT and MAPK signaling in colorectal cancer. Dissertation, LMU München: Faculty of Medicine
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Abstract

Constitutively active WNT signaling in colorectal cancers is hallmark and driver of malignant progression in these tumors. However, therapeutic targeting of WNT signaling is difficult due to anticipated side effects on WNT dependent normal tissue homeostasis. Using transcriptome, proteome and cell biology approaches, weidentified the transcription factor ADNP as a repressor of WNT signaling in colon cancer that can be induced pharmacologically by treatment with sub-narcotic doses of ketamine. Treatment results in significantly slowed tumor growth in pre-clinical xenograft models of colon cancer. Moreover, high ADNP expression in human colorectal cancers predicts improved disease outcome. Our findings indicate ADNP as a tumor suppressor and promising prognostic marker, and ketamine treatment with ADNP induction as a potential therapeutic approach that may add to current treatment protocols with benefits for colorectal cancer patients. Beside mutational WNT activation, about 40 % of colorectal cancers have mutations in KRAS with downstream activation of MAPK signaling that promotes tumor invasion and progression. We demonstrate that MAPK signaling shows strong intratumoral heterogeneity, and surprisingly remains regulated in colorectal cancer, irrespective of the tumors’ KRAS mutation status. Using primary colorectal cancer tissues,xenografts and MAPK reporter constructs, we show that tumor cells with high MAPK activity specifically reside at the leading tumor edge, cease to proliferate, undergo epithelial-mesenchymal transition (EMT), and express markers related to colon cancer stem cells. In KRAS mutant colon cancer cells, regulation of MAPK signaling is preserved through remaining wild-type RAS isoforms. Moreover, using a lineage tracing strategy, we provide evidence that high MAPK activity marks a progenitor cell compartment of growth fueling colon cancer cells in vivo. Our results imply that differential MAPK signaling balances EMT, cancer stem cell potential, and tumor growth in colorectal cancer. The positive crosstalk between WNT and MAPK signaling in colorectal cancer has strong implications for the development of combination therapies and a better understanding of the underlying mechanisms may lead to improved therapeutic strategies.