Chemotherapy-driven de novo Wnt pathway activation dictates a dynamic shift to a drug-tolerant state in breast cancer cells

El Laithy, Youssef; Abreu De Oliveira, Willy Anton; Pabba, Aniruhd; Qualizza, Alessandra; Richard, François; ATHANASOULI, Paraskevi; RIOS LUCI, CARLA; De Wispelaere, Wout; Mourao, Larissa; Siân, Siân; Moens, Stijn; De Jaime-Soguero, Anchel; Baietti, Maria Francesca; Huten, Stefan J; Jonkers, Jos; Sammut, Stephen-John; Soenen, Stefaan; Scheele, Colinde LGJ; Bruna, Alejandra; Desmedt, Christine; Annibali, Daniela; Lluis, Frederic

doi:10.1101/2024.03.08.584051

Author:

El Laithy, Youssef

Abreu De Oliveira, Willy Anton ; Pabba, Aniruhd ; Qualizza, Alessandra ; Richard, François ; ATHANASOULI, Paraskevi ; RIOS LUCI, CARLA ; De Wispelaere, Wout ; Mourao, Larissa ; Siân, Siân ; Moens, Stijn ; De Jaime-Soguero, Anchel ; Baietti, Maria Francesca ; Huten, Stefan J ; Jonkers, Jos ; Sammut, Stephen-John ; Soenen, Stefaan ; Scheele, Colinde LGJ ; Bruna, Alejandra ; Desmedt, Christine ; Annibali, Daniela ; Lluis, Frederic

Abstract:

ABSTRACT

The efficacy of chemotherapy is often hindered by the enrichment of drug-tolerant persister (DTP) cells, which are known to drive therapy resistance. Unraveling and targeting the early events leading to therapy-induced DTP cell-enrichment presents a potential avenue for innovative therapeutic strategies. In this study, we identified the activation of the Wnt/β-catenin signaling pathway as a common mechanism underlying early DTP cell-enrichment in response to different chemotherapeutic agents in Triple-negative breast cancer (TNBC). Live-imaging reveals de novo transcriptional Wnt-activation prevailing over intrinsic selection post chemotherapy. Importantly, Wnt-active (Wnt High ) cells exhibit transcriptional and functional similarities to DTP cells, such as a diapause transcriptional signature, reduced proliferation, and marked chemoresistance. The transition to a post-treatment Wnt High state is driven by increased expression of key components involved in canonical Wnt ligand-secretion and -activation. Genetic interference or concomitant, rather than sequential, pharmacologic inhibition of Wnt ligand-secretion alongside chemotherapy prevents treatment-induced Wnt High enrichment, sensitizing TNBC tumors to chemotherapy. This study enhances our understanding of the introductory mechanisms driving DTP cell-enrichment upon chemotherapy.