Astrocytic laminin-211 drives disseminated breast tumor cell dormancy in brain.

Although dormancy is thought to play a key role in the metastasis of breast tumor cells to the brain, our knowledge of the molecular mechanisms regulating disseminated tumor cell (DTC) dormancy in this organ is limited. Here using serial intravital imaging of dormant and metastatic triple-negative breast cancer lines, we identify escape from the single-cell or micrometastatic state as the rate-limiting step towards brain metastasis. We show that every DTC occupies a vascular niche, with quiescent DTCs residing on astrocyte endfeet.

The PI3K/mTOR inhibitor Gedatolisib eliminates dormant breast cancer cells in organotypic culture, but fails to prevent metastasis in preclinical settings.

Dormant, disseminated tumor cells (DTCs) are thought to be the source of breast cancer metastases several years or even decades after initial treatment. To date, a selective therapy that leads to their elimination has not been discovered. While dormant DTCs resist chemotherapy, evidence suggests that this resistance is driven not by their lack of proliferation, but by their engagement of the surrounding microenvironment, via integrin-β1-mediated interactions.

Anti-angiogenic Therapy-Mediated Endothelial Damage: A Driver of Breast Cancer Recurrence?

Anti-angiogenic therapy was conceived originally as a silver bullet able to maintain tumor dormancy indefinitely. By targeting new blood vessel formation, anti-angiogenic agents were expected to suppress the growth of any type of primary or metastatic tumor, independent of their subtype or genetic landscape. However, more that 20 years after the first anti-angiogenic preclinical trial, the astonishing inhibition of metastatic outgrowth originally observed in mouse models never translated into clinics.

Laminin α1 orchestrates VEGFA functions in the ecosystem of colorectal carcinoma.

Background Information: Tumor stroma remodeling is a key feature of malignant tumors and can promote cancer progression. Laminins are major constituents of basement membranes that physically separate the epithelium from the underlying stroma.

Results: By employing mouse models expressing high and low levels of the laminin α1 chain (LMα1), we highlighted its implication in a tumor-stroma crosstalk, thus leading to increased colon tumor incidence, angiogenesis and tumor growth.

Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy.

Despite the approval of several anti-angiogenic therapies, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. Here, we demonstrate potent anti-angiogenic efficacy of the multi-kinase inhibitors nintedanib and sunitinib in a mouse model of breast cancer. However, after an initial regression, tumors resume growth in the absence of active tumor angiogenesis.

An immature B cell population from peripheral blood serves as surrogate marker for monitoring tumor angiogenesis and anti-angiogenic therapy in mouse models.

Tumor growth depends on the formation of new blood vessels (tumor angiogenesis) either from preexisting vessels or by the recruitment of bone marrow-derived cells. Despite encouraging results obtained with preclinical cancer models, the therapeutic targeting of tumor angiogenesis has thus far failed to deliver an enduring clinical response in cancer patients. One major obstacle for improving anti-angiogenic therapy is the lack of validated biomarkers, which allow patient stratification for suitable treatment and a rapid assessment of therapy response.

VEGF-mediated angiogenesis links EMT-induced cancer stemness to tumor initiation.

An epithelial-mesenchymal transition (EMT) underlies malignant tumor progression and metastatic spread by enabling cancer cells to depart from the primary tumor, invade surrounding tissue, and disseminate to distant organs. EMT also enriches for cancer stem cells (CSC) and increases the capacity of cancer cells to initiate and propagate tumors upon transplantation into immune-deficient mice, a major hallmark of CSCs. However, the molecular mechanisms promoting the tumorigenicity of cancer cells undergoing an EMT and of CSCs have remained widely elusive.

Repression of malignant tumor progression upon pharmacologic IGF1R blockade in a mouse model of insulinoma.

NVP-AEW541, a specific ATP-competitive inhibitor of the insulin-like growth factor-1 receptor (IGF1R) tyrosine kinase, has been reported to interfere with tumor growth in various tumor transplantation models. We have assessed the efficacy of NVP-AEW541 in repressing tumor growth and tumor progression in the Rip1Tag2 transgenic mouse model of pancreatic β-cell carcinogenesis. In addition, we have tested NVP-AEW541 in Rip1Tag2;RipIGF1R double-transgenic mice which show accelerated tumor growth and increased tumor malignancy compared with Rip1Tag2 single-transgenic mice.