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Pre-clinical validation of a selective anti-cancer stem cell therapy for Numb-deficient human breast cancers
Daniela Tosoni1, Sarah Pambianco1, Blanche Ekalle Soppo2
1Istituto Europeo di Oncologia, Milan, Italy.
Abstract:
The cell fate determinant Numb is frequently downregulated in human breast cancers (BCs), resulting in p53 inactivation and an aggressive disease course. In the mouse mammary gland, Numb/p53 downregulation leads to aberrant tissue morphogenesis, expansion of the stem cell compartment, and emergence of cancer stem cells (CSCs). Strikingly, CSC phenotypes in a Numb-knockout mouse model can be reverted by Numb/p53 restoration. Thus, targeting Numb/p53 dysfunction in Numb-deficient human BCs could represent a novel anti-CSC therapy. Here, using patient-derived xenografts, we show that expansion of the CSC pool, due to altered self-renewing divisions, is also a feature of Numb-deficient human BCs. In these cancers, using the inhibitor Nutlin-3 to restore p53, we corrected the defective self-renewal properties of Numb-deficient CSCs and inhibited CSC expansion, with a marked effect on tumorigenicity and metastasis. Remarkably, a regimen combining Nutlin-3 and chemotherapy induced persistent tumor growth inhibition, or even regression, and prevented CSC-driven tumor relapse after removal of chemotherapy. Our data provide a pre-clinical proof-of-concept that targeting Numb/p53 results in a specific anti-CSC therapy in human BCs.
Insights
Restoring Numb and p53 function in breast cancer (BC) stem cells (CSCs) using Nutlin-3 inhibits tumor growth and metastasis. This approach offers a novel therapeutic strategy against aggressive, Numb-deficient human BCs.
Area of Science:
- Oncology
- Cell Biology
- Cancer Stem Cell Research
Background:
- Numb is frequently downregulated in human breast cancers (BCs), leading to p53 inactivation and aggressive disease.
- Numb/p53 loss drives aberrant tissue morphogenesis and expands the stem cell compartment, generating cancer stem cells (CSCs).
Purpose of the Study:
- To investigate the role of Numb/p53 dysfunction in human BC CSCs.
- To evaluate Numb/p53 restoration as a therapeutic strategy against Numb-deficient human BCs.
Main Methods:
- Utilized patient-derived xenografts (PDXs) from human BCs.
- Administered Nutlin-3, a p53-restoring inhibitor, to target Numb-deficient CSCs.
- Assessed effects on CSC self-renewal, tumorigenicity, metastasis, and tumor relapse.
Main Results:
- Numb-deficient human BCs exhibit CSC pool expansion due to altered self-renewal.
- Nutlin-3 treatment corrected defective CSC self-renewal, inhibited CSC expansion, and reduced tumorigenicity and metastasis.
- Combined Nutlin-3 and chemotherapy induced sustained tumor inhibition and prevented CSC-driven relapse.
Conclusions:
- Numb/p53 restoration is a viable therapeutic strategy targeting CSCs in Numb-deficient human BCs.
- This approach shows pre-clinical proof-of-concept for a novel anti-CSC therapy in human BC.
