Biology subjects

Kerr, B. A.

Publications and source records attributed to Kerr, B. A..

4 recordsLinked to original sources

bioRxiv2021

A Novel Model of Estrogen Receptor-Positive Breast Cancer Bone Metastasis with Antiestrogen Responsiveness

Most women diagnosed with breast cancer (BC) have estrogen receptor alpha positive (ER+) disease. ER+ BC preferentially metastasizes to bone; at which time it is considered incurable. Treatments for bone metastasis have not advanced in decades, in part due to a lack of appropriate ER+ BC bone metastasis models. We developed an immunocompetent ER+ BC murine model with spontaneous bone metastasis and antiestrogen responsiveness. To do this, we transduced triple-negative (TN) bone-tropic murine BC cell lines 4T1.2 and E0771/Bone to express ER. These cells were then injected into the mammary fat pads of Balb/c (n=21) or C57Bl/6 (n=27), respectively. Once tumors established, mice were treated with either the selective estrogen receptor modulator (SERM) tamoxifen (TAM), the selective estrogen receptor degrader (SERD) ICI 182,780 (ICI, Faslodex, fulvestrant), or vehicle control for 21 days. Tumor volumes and weights significantly decreased in the ER+ groups treated with TAM and ICI compared with ER+ vehicle-treated groups. Staining for immune profiles and total RNA sequencing demonstrated modified immune cell infiltration between TN and ER-derived tumors. Approximately 25% of the mice with ER+ 4T1.2 tumors developed metastases to long bones while none of the mice with TN tumors developed metastases. This immunocompetent ER+ 4T1.2 BC model may allow for further exploration of ER+ BC bone metastasis mechanisms and for the development of new therapeutics for women diagnosed with bone metastasis from ER+ BC. Simple SummaryEstrogen receptor alpha positive (ER+) breast cancer is the most common subtype of breast cancer. When it metastasizes to bone, it becomes incurable. Little advancement has occurred in the treatment of bone metastasis from ER+ breast cancer, partly due to the lack of animal models. To establish an animal model of ER+ BC, we genetically modified two triple-negative breast cancer cell lines to express ER and injected the cell lines into murine mammary glands. Mice were treated with standard antiestrogen therapies, the selective estrogen receptor modulator tamoxifen or the selective estrogen receptor degrader ICI 182,780. We found that compared to mice with triple-negative breast cancer, mice with ER+ breast cancer developed bone metastases and were responsive to antiestrogen therapy. This model allows for further exploration of bone metastasis mechanisms and for the development of new therapeutics, translating into improved clinical outcomes for women with bone metastasis from ER+ breast cancer.

cancer biology↗

bioRxiv2020

Platelet TSP-1 Controls Prostate Cancer-Induced Osteoclast Differentiation and Bone Marrow-Derived Cell Mobilization through TGFβ-1

The development of distant metastasis is the main cause of prostate cancer (CaP)-related death with the skeleton being the primary site of metastasis. While the progression of primary tumors and the growth of bone metastatic tumors are well described, the mechanisms controlling pre-metastatic niche formation and homing of CaP to bone remain unclear. Through prior studies, we demonstrated that platelet secretion was required for ongoing tumor growth and pre-metastatic tumor-induce bone formation and bone marrow-derived cell mobilization to cancers supporting angiogenesis. We hypothesized that proteins released by the platelet granules were responsible for inducing changes in the pre-metastatic bone niche. We found that the classically anti-angiogenic protein thrombospondin (TSP)-1 was significantly increased in the platelets of mice bearing tumors. To determine the role of increased TSP-1, we implanted tumors in TSP-1 null animals and assessed changes in tumor growth and pre-metastatic niche formation. TSP-1 loss resulted in increased tumor size and enhanced angiogenesis but reduced bone marrow-derived cell mobilization and tumor-induced bone formation with enhanced osteoclast formation. We hypothesized that these changes in the pre-metastatic niche were due to the retention of TGF-{beta}1 in the platelets of mice with TSP-1 deleted. To assess the importance of platelet-derived TGF-{beta}1, we implanted CaP tumors in mice with platelet-specific deletion of TGF-{beta}1. Similar to TSP-1 deletion, loss of platelet TGF-{beta}1 resulted in increased angiogenesis with a milder effect on tumor size and BMDC release. Within the bone microenvironment, platelet TGF-{beta}1 deletion prevented tumor-induced bone formation due to increased osteoclastogenesis. Thus, we demonstrate that the TSP-1/TGF-{beta}1 axis regulates pre-metastatic niche formation and tumor-induced bone turnover. Targeting the platelet release of TSP-1 or TGF-{beta}1 represents a potential method to interfere with the process of CaP metastasis to bone.

cancer biology↗

bioRxiv2018

Proving Osteoinductive Potential of a Decellularized Xenograft Bone Substitute

BackgroundLarge bone defects remain a major clinical challenge for orthopaedic surgeons. Tissue engineered bone grafts have garnered increased attention as a solution to this problem. One ideal property of any bone graft is osteoinductivity or the ability to stimulate progenitor cell differentiation into a bone forming lineage.\n\nQuestionsO_LIIs the osteoinductive potential of a porcine bone xenograft maintained in vitro after undergoing a novel decellularization and oxidation process?\nC_LIO_LIAre porcine bone scaffolds osteoinductive in an in vivo animal model?\nC_LI\n\nMethodsO_LIIn Vitro - C2C12 pre-osteoblasts were seeded on the scaffold or a commercial grade demineralized bone matrix (DBM) to study osteogenic differentiation and compare osteoinductive potential. MC3T3-E1 pre-osteoblasts were seeded on the scaffold and compared to a control monolayer to identify early markers of osteogenic differentiation.\nC_LIO_LIIn Vivo - MC3T3-E1-seeded scaffolds were implanted subcutaneously in mice and assessed for markers of early osteogenic differentiation, new bone formation (micro-computed tomography and histological assessment), and vascular infiltration (histology).\nC_LI\n\nResultsOsteoinductive potential was demonstrated in in vitro experiments by similar osteogenic marker expression compared to DBM and significantly greater expression than a control monolayer.\n\nOsteoinductivity was confirmed with in vivo experiments showing both new bone formation and vascular infiltration.\n\nConclusionPorcine bone maintains osteoinductive properties after decellularization and oxidation.\n\nClinical RelevanceThis construct could potentially serve as a bone graft substitute maintaining the osteoinductive potential of native bone. The unrestricted supply and controlled donor biology may satisfy a large clinical need for orthopaedic cases requiring bone grafting.

bioengineering↗

bioRxiv2018

CD117/c-kit in Cancer Stem Cell-Mediated Progression and Therapeutic Resistance

Metastasis is the primary cause of cancer patient morbidity and mortality but due to persisting gaps in our knowledge, it remains untreatable. Metastases often occur as patients' tumors progress or recur after initial therapy. Tumor recurrence at the primary site may be driven by a cancer stem-like cell or tumor progenitor cell, while recurrence at a secondary site is driven by metastatic cancer stem cells or metastasis-initiating cells. Ongoing efforts are aimed at identifying and characterizing these stem-like cells driving recurrence and metastasis. One potential marker for the cancer stem-like cell subpopulation is CD117/c-kit, a tyrosine kinase receptor associated with cancer progression and normal stem cell maintenance. In our analyses, CD117 was expressed in several tissues and was highly expressed in bone marrow progenitor cells. Also, we uncovered that CD117 gene amplifications and mutations occurred in multiple cancers. Further, activation of CD117 by its ligand stem cell factor (SCF; kit ligand) in the progenitor cell niche stimulates several signaling pathways driving proliferation, survival, and migration. These signaling pathways were commonly altered in patients with CD117 amplifications and mutations. Here, we examine evidence that the SCF/CD117 signaling axis controls cancer progression through the regulation of stemness and resistance to tyrosine kinase inhibitors.\n\nAbbreviations

cancer biology↗