Jensen, R. L. | Search bioRxiv

bioRxiv2021

A breast cancer patient-derived xenograft and organoid platform for drug discovery and precision oncology

Model systems that recapitulate the complexity of human tumors and the reality of variable treatment responses are urgently needed to better understand cancer biology and to develop more effective cancer therapies. Here we report development and characterization of a large bank of patient-derived xenografts (PDX) and matched organoid cultures from tumors that represent some of the greatest unmet needs in breast cancer research and treatment. These include endocrine-resistant, treatment-refractory, and metastatic breast cancers and, in some cases, multiple tumor collections from the same patients. The models can be grown long-term with high fidelity to the original tumors. We show that development of matched PDX and PDX-derived organoid (PDxO) models facilitates high-throughput drug screening that is feasible and cost-effective, while also allowing in vivo validation of results. Our data reveal consistency between drug screening results in organoids and drug responses in breast cancer PDX. Moreover, we demonstrate the feasibility of using these patient-derived models for precision oncology in real time with patient care, using a case of a triple negative breast cancer with early metastatic recurrence as an example. Our results uncovered an FDA-approved drug with high efficacy against the models. Treatment with the PDxO-directed therapy resulted in a complete response for the patient and a progression-free survival period more than three times longer than her previous therapies. This work provides valuable new methods and resources for functional precision medicine and drug development for human breast cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=189 HEIGHT=200 SRC="FIGDIR/small/433268v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@134d5cdorg.highwire.dtl.DTLVardef@1c0a419org.highwire.dtl.DTLVardef@556a4forg.highwire.dtl.DTLVardef@1b68c9c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

A Unique Renal Architecture in Tribolium castaneum Informs the Evolutionary Origins of Systemic Osmoregulation in Beetles

Maintaining internal salt and water balance in response to fluctuating external conditions is essential for animal survival. This is particularly true for insects as their high surface-to-volume ratio makes them highly susceptible to osmotic stress. However, the cellular and hormonal mechanisms that mediate the systemic control of osmotic homeostasis in beetles (Coleoptera), the largest group of insects, remain largely unidentified. Here, we demonstrate that eight neurons in the brain of the red flour beetle Tribolium castaneum respond to internal changes in osmolality by releasing diuretic hormone (DH) 37 and DH47 - homologues of vertebrate corticotropinreleasing factor (CRF) hormones - to control systemic water balance. Knockdown of the gene encoding the two hormones (Urinate, Urn8) reduces renal secretion and restricts organismal fluid loss, whereas injection of DH37 or DH47 reverses these phenotypes. We further identify a novel CRF-like receptor, Urinate Receptor (Urn8R), which is exclusively expressed in a unique secondary cell (SC) in the beetle renal organs, as underlying this response. Activation of Urn8R increases K+ secretion specifically through SCs, creating a lumen-positive transepithelial potential that drives fluid secretion. Together, these data show that beetle renal organs operate by fundamentally different mechanism than those of other insects. Finally, we adopt a fluorescent labelling strategy to identify the evolutionary origin of this unusual renal architecture within the large Order of Coleoptera. Our work thus uncovers an important homeostatic program that is key to maintaining osmotic control in beetles, which evolved in parallel to the radiation of the higher beetle families. Significance StatementBeetles are the most diverse animal group on the planet. Their evolutionary success suggests unique physiological adaptations in overcoming water stress, yet the mechanisms underlying this ability are unknown. Here we use molecular genetic, electrophysiology and behavioral studies to show that a group of brain neurons responds to osmotic disturbances by releasing diuretic hormones that regulate salt and water balance. These hormones bind to their receptor exclusively localized to a unique secondary cell in the renal organs to modulate fluid secretion and organismal water loss. This renal architecture, common to all higher beetle families, is novel within the insects, and provides an important clue to the evolutionary success of the beetles in colonizing an astounding range of habitats on Earth.

physiology↗