Periodic Reporting for period 5 - PLEIO-RANK (Pleiotropic treatment of cancer: RANK inhibitors targeting cancer stem cells and immunity)
Reporting period: 2022-08-01 to 2023-03-31
Our main goal was to understand the pleiotropic actions of RANK signaling and their contribution to homeostasis and disease. We have focused our research objectives in understanding the role of RANK pathway in mammary gland development as well as in breast cancer.
In the mammary gland, using complex genetic models, we have demonstrated that RANK signaling governs mammary cell lineage identity. Besides, increased RANK signaling in the mammary luminal epithelial cells induces senescence, which is required for RANK-driven stemness in the mammary epithelium but also in luminal breast cancer. In oncogenic contexts, Rank-driven senescence delays tumor onset but increases tumor aggressiveness. This opens new venues that can be therapeutically exploited combining Rank modulators with senolytics and senomorphics.
Regarding breast cancer treatment, our results show that RANK contributes to resistance to targeted therapies in breast cancer. Using preclinical models and clinical samples, we have also demonstrated that RANK is a biomarker of poor prognosis and a therapeutic target in estrogen receptor negative and postmenopausal breast cancer. Moreover, preclinical and clinical results show that inhibition of RANK signaling in breast tumor cells induces an anti-tumor immune response.
Our results represent a major advance in the knowledge of RANK biology with relevance for society, in particular, in terms of their clinical impact. Our findings will help stratify BC patients who may benefit from denosumab and provide a rationale for combination therapies with denosumab and immunotherapies for cancer and metastasis.
In the mammary gland, using complex genetic models, we have demonstrated that RANK signaling governs mammary cell lineage identity. Besides, increased RANK signaling in the mammary luminal epithelial cells induces senescence, which is required for RANK-driven stemness in the mammary epithelium but also in luminal breast cancer. In oncogenic contexts, Rank-driven senescence delays tumor onset but increases tumor aggressiveness. This opens new venues that can be therapeutically exploited combining Rank modulators with senolytics and senomorphics.
Regarding breast cancer treatment, our results show that RANK contributes to resistance to targeted therapies in breast cancer. Using preclinical models and clinical samples, we have also demonstrated that RANK is a biomarker of poor prognosis and a therapeutic target in estrogen receptor negative and postmenopausal breast cancer. Moreover, preclinical and clinical results show that inhibition of RANK signaling in breast tumor cells induces an anti-tumor immune response.
Our results represent a major advance in the knowledge of RANK biology with relevance for society, in particular, in terms of their clinical impact. Our findings will help stratify BC patients who may benefit from denosumab and provide a rationale for combination therapies with denosumab and immunotherapies for cancer and metastasis.
RANK IN EPITHELIAL HOMEOSTASIS
1. Increased RANK signaling in the mammary luminal epithelial cells induces senescence through p16/p19. RANK-induced senescence is required for RANK-driven stemness in the mammary epithelium but also in luminal breast cancer. Rank-driven senescence delays tumor onset but increases tumor aggressiveness (Benitez, Cordero et al., Dev Cell in 2021).
2. RANK signaling governs mammary cell identity and awakening of basal stemness. Aiming to understand the contribution of RANK signaling to the crosstalk between mammary gland cell compartments, we are using basal/luminal-specific inducible Cre mouse models to delete or overexpress RANK at different times during the development. We have found that luminal RANK loss impairs lactation and promotes basal bipotency in parous glands to restore epithelial homeostasis. This work is under review (Semiao, Collado et al., Nat Commun).
RANK IN CANCER AND TUMOR IMMUNOLOGY
3. Preclinical and clinical results (D-BEYOND clinical trial) show that inhibition of RANK signaling in tumor cells induces an anti-tumor immune response (Gomez-Aleza et al., Nat Commun, 2020).
4. We have found that RANK contributes to resistance to HER2-targeted therapies (Sanz-Moreno et al., BCR, 2021).
5. Using PDX tumor models and clinical samples, we have demonstrated that RANK is a biomarker of poor prognosis and a therapeutic target in ER negative and postmenopausal breast cancer (Ciscar, Trinidad et al., EMBO Mol Med 2023).
1. Increased RANK signaling in the mammary luminal epithelial cells induces senescence through p16/p19. RANK-induced senescence is required for RANK-driven stemness in the mammary epithelium but also in luminal breast cancer. Rank-driven senescence delays tumor onset but increases tumor aggressiveness (Benitez, Cordero et al., Dev Cell in 2021).
2. RANK signaling governs mammary cell identity and awakening of basal stemness. Aiming to understand the contribution of RANK signaling to the crosstalk between mammary gland cell compartments, we are using basal/luminal-specific inducible Cre mouse models to delete or overexpress RANK at different times during the development. We have found that luminal RANK loss impairs lactation and promotes basal bipotency in parous glands to restore epithelial homeostasis. This work is under review (Semiao, Collado et al., Nat Commun).
RANK IN CANCER AND TUMOR IMMUNOLOGY
3. Preclinical and clinical results (D-BEYOND clinical trial) show that inhibition of RANK signaling in tumor cells induces an anti-tumor immune response (Gomez-Aleza et al., Nat Commun, 2020).
4. We have found that RANK contributes to resistance to HER2-targeted therapies (Sanz-Moreno et al., BCR, 2021).
5. Using PDX tumor models and clinical samples, we have demonstrated that RANK is a biomarker of poor prognosis and a therapeutic target in ER negative and postmenopausal breast cancer (Ciscar, Trinidad et al., EMBO Mol Med 2023).
Based on our results that support that RANK can be a superior therapeutic target than RANKL, we have been awarded an ERC-PoC to generate novel RANK inhibitors. The project is ongoing in collaboration with Experimental Therapeutics Unit at CNIO.