Cancer Stem Cells "Hedge” Their Bets with Noncanonical Signaling

A collaborative team of scientists working as part of the OncoTrack project – an international consortium of scientists funded as part of the European Innovative Medicines Initiative – have recently discovered that cancer stem cells (CSCs) utilize a noncanonical signaling pathway, employing the Hedgehog protein and a positive regulator of WNT. The research team focused in on this pathway as a potential treatment option aimed at treating cancers via the targeted elimination of CSCs.

Findings from the new study – published recently in Cell Reports in an article entitled “Non-Canonical Hedgehog Signaling Is a Positive Regulator of the WNT Pathway and Is Required for the Survival of Colon Cancer Stem Cells” – could significantly improve treatment outcomes, as this approach requires an in-depth understanding of both the relevant cellular communication pathways within the stem cells and of the genes regulating them.

“The targeted inhibition of the Hedgehog signaling pathway, used in combination with other standard treatments to shrink tumors, may provide a new strategy for the elimination of CSCs and the prevention of cancer recurrence,” explained lead study investigator Joseph Regan, Ph.D., research investigator at the Charité Comprehensive Cancer Center (CCCC). “Future research will set out to better define the downstream signaling components of the pathway and further investigate how Hedgehog signaling controls CSC survival.”

Colon cancer is the third most common cancer and fourth most common cause of death worldwide. Colon tumors consist of diverse types of cells, which play distinct roles in the growth of the tumor. The development and spread of cancer are thought to be caused by a subpopulation of cells that possess stem cell characteristics, including the capacity for self-renewal, differentiation, and therapy resistance. These CSCs are also thought to be the source cancer recurrence following initial treatment success.

As part of the current study, the researchers carried out genetic sequencing of the colon CSCs and performed functional studies using both mouse models and 3D cell cultures from patient-derived cancer cells. Their research revealed that CSC survival is controlled by a specific feature of the Hedgehog signaling pathway (SHH-PTCH1), which allows cells to respond to external signals in addition to inhibiting stem cell differentiation.

“To study CSCs in colon cancer, we used limiting-dilution spheroid and serial xenotransplantation assays to functionally define the frequency of CSCs in a panel of patient-derived cancer organoids,” the authors wrote. “These studies demonstrated cancer organoids to be enriched for CSCs, which varied in frequency between tumors. Whole-transcriptome analysis identified WNT and Hedgehog signaling components to be enhanced in CSC-enriched tumors and aldehyde dehydrogenase (ALDH)-positive CSCs.”

“The targeted inhibition of the Hedgehog signaling pathway, used in combination with other standard treatments to shrink tumors, may provide a new strategy for the elimination of CSCs and the prevention of cancer recurrence,” explains Dr. Regan. Similar targeting of the Hedgehog signaling pathway has also produced promising results in other preclinical studies on pancreatic and breast cancer cells. He adds: “Future research will set out to better define the downstream signaling components of the pathway and further investigate how Hedgehog signaling controls CSC survival.”

The authors concluded that “based on these data, we propose a model wherein noncanonical PTCH1-dependent Hedgehog signaling acts as a positive regulator of WNT to maintain CSCs in an undifferentiated state, whereas canonical SMO-dependent Hedgehog signaling, mediated by nuclear localization of GLI1 (a zinc-finger transcription factor), leads to a downregulation of WNT signaling and tumor cell differentiation.”