A human vascularized microtumor model of patient-derived colorectal cancer recapitulates clinical disease

Hachey, Stephanie J.; Sobrino, Agua; Lee, John G.; Jafari, Mehraneh D.; Klempner, Samuel J.; Puttock, Eric J.; Edwards, Robert A.; Lowengrub, John; Waterman, Marian L.; Zell, Jason A.; Hughes, Christopher C.W.

doi:10.1016/j.trsl.2022.11.011

Cited by 10 publications

(18 citation statements)

References 36 publications

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“…This achieved a near-complete knockdown of Alk1 mRNA that persisted for at least 7 days in primary human umbilical vein EC (HUVEC), but this knockdown fully recovered to control levels by day 12 ( Supplemental Figure 1A ). We seeded EC transfected with si- ACVRL1 (or scrambled si-Ctrl) into our previously described VMO platform 28,29,31,35 at equal starting cell densities ( Supplemental Figure 1B-C ) and observed that microvasculature that formed from si- ACVRL1 EC were hyperdense relative to si-Ctrl ( Supplemental Figure 1D-I ). We observed a similar phenotype with siRNA knockdown of ENG ( Supplemental Figure 2 ), suggesting that this hyperdense phenotype arises from loss of signaling through the Alk1/Eng HHT-associated signaling pathway.…”

Section: Resultsmentioning

confidence: 99%

“…Network formation took 6-8 days following initial cell seeding ( Figure 2C ), consistent with how the microvasculature develops in our published VMO models. 28,29,31,35 Once vessel formation was complete, addition of 70kDa fluorescent dextran to the media reservoirs marked lumenized microvessels and revealed that vessels are perfused and that flow is only through vessels ( Figure 2D ). To model the normal developmental process, we next developed a two-step flow protocol to support the development of a perfused microvasculature under physiologic flow, wherein EC are initially exposed to bidirectional low flow for the first 6 days, mirroring the hemodynamic conditions of developing microvessels.…”

Section: Resultsmentioning

confidence: 99%

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A Microphysiological HHT-on-a-Chip Platform Recapitulates Patient Vascular Lesions

Fang,

Hatch,

Andrejecsk

et al. 2024

Preprint

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Hereditary Hemorrhagic Telangiectasia (HHT) is a rare congenital disease in which fragile vascular malformations focally develop in multiple organs. These can be small (telangiectasias) or large (arteriovenous malformations, AVMs) and may rupture leading to frequent, uncontrolled bleeding. There are few treatment options and no cure for HHT. Most HHT patients are heterozygous for loss-of-function mutations for Endoglin (ENG) or Alk1 (ACVRL1), however, why loss of these genes manifests as vascular malformations remains poorly understood. To complement ongoing work in animal models, we have developed a microphysiological system model of HHT. Based on our existing vessel-on-a-chip (VMO) platform, our fully human cell-based HHT-VMO recapitulates HHT patient vascular lesions. Using inducible ACVRL1 (Alk1)-knockdown, we control timing and extent of endogenous Alk1 expression in primary human endothelial cells (EC) in the HHT-VMO. HHT-VMO vascular lesions develop over several days, and are dependent upon timing of Alk1 knockdown. Interestingly, in chimera experiments AVM-like lesions can be comprised of both Alk1-intact and Alk1-deficient EC, suggesting possible cell non-autonomous effects. Single cell RNA sequencing data are consistent with microvessel pruning/regression as contributing to AVM formation, while loss of PDGFB expression implicates mural cell recruitment. Finally, lesion formation is blocked by the VEGFR inhibitor pazopanib, mirroring the positive effects of this drug in patients. In summary, we have developed a novel HHT-on-a-chip model that faithfully reproduces HHT patient lesions and that is sensitive to a treatment effective in patients. The VMO-HHT can be used to better understand HHT disease biology and identify potential new HHT drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A Microphysiological HHT-on-a-Chip Platform Recapitulates Patient Vascular Lesions

Fang,

Hatch,

Andrejecsk

et al. 2024

Preprint

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“…Device fabrication and loading has been described previously [13,14,16,17,57]. Briefly, a customized polyurethane master mold is fabricated using 2-part polyurethane liquid plastic (Smooth Cast 310, Smooth-On Inc.).…”

Section: Microfluidic Device Fabricationmentioning

confidence: 99%

“…Herein we establish human vascularized micro-tumor (VMT) models to recreate the TNBC TME in vitro, using primary stromal cells isolated freshly from healthy human breast tissue, endothelial cells (ECs) and two representative TNBC cell lines, HCC1599 and MDA-MB-231. The VMT is a microphysiologic in vitro cancer model that we have validated for disease modeling, drug screening and personalized medicine applications for solid tumors [13][14][15][16][17]. By co-culturing multiple cell types within a complex ECM under dynamic flow conditions, the stromal cells and endothelium spontaneously selforganize into a perfused vascular network that plays a vital role in supporting tumor growth and serves as a physiological conduit for the delivery of therapeutic agents to the tumor.…”

Section: Introductionmentioning

confidence: 99%

Targeting tumor-stromal interactions in triple-negative breast cancer using a human vascularized micro-tumor model

Hachey,

Hatch,

Gaebler

et al. 2023

Preprint

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Triple-negative breast cancer (TNBC) is highly aggressive with limited available treatments. Stromal cells in the tumor microenvironment (TME) are crucial in TNBC progression; however, understanding the molecular basis of stromal cell activation and tumor-stromal crosstalk in TNBC is limited. To investigate therapeutic targets in the TNBC stromal niche, we used an advanced human in vitro microphysiological system called the vascularized micro-tumor (VMT). Using single-cell RNA sequencing (scRNA-seq), we revealed that normal breast-tissue stromal cells activate neoplastic signaling pathways in the TNBC TME. By comparing interactions in VMTs with clinical data, we identified therapeutic targets at the tumor-stromal interface with potential clinical significance. Combining treatments targeting Tie2 signaling with paclitaxel resulted in vessel normalization and increased efficacy of paclitaxel in the TNBC VMT. Dual inhibition of Her3 and Akt also demonstrated efficacy against TNBC. These data demonstrate the potential of inducing a favorable TME as a targeted therapeutic approach in TNBC.

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“…Herein we establish human vascularized micro-tumor (VMT) models to recreate the TNBC TME in vitro, using primary stromal cells isolated freshly from healthy human breast tissue, endothelial cells (ECs) and two representative TNBC cell lines, HCC1599 and MDA-MB-231. The VMT is a microphysiologic in vitro cancer model that we have validated for disease modeling, drug screening and personalized medicine applications for solid tumors [13][14][15][16][17]. By co-culturing multiple cell types within a complex ECM under dynamic flow conditions, the stromal cells and endothelium spontaneously self-organize into a perfused vascular network that plays a vital role in supporting tumor growth and serves as a physiological conduit for the delivery of therapeutic agents to the tumor.…”

Section: Introductionmentioning

confidence: 99%

Targeting tumor–stromal interactions in triple-negative breast cancer using a human vascularized micro-tumor model

Hachey,

Hatch,

Gaebler

et al. 2024

Breast Cancer Res

Self Cite

View full text Add to dashboard Cite

Triple-negative breast cancer (TNBC) is highly aggressive with limited available treatments. Stromal cells in the tumor microenvironment (TME) are crucial in TNBC progression; however, understanding the molecular basis of stromal cell activation and tumor–stromal crosstalk in TNBC is limited. To investigate therapeutic targets in the TNBC stromal niche, we used an advanced human in vitro microphysiological system called the vascularized micro-tumor (VMT). Using single-cell RNA sequencing, we revealed that normal breast tissue stromal cells activate neoplastic signaling pathways in the TNBC TME. By comparing interactions in VMTs with clinical data, we identified therapeutic targets at the tumor–stromal interface with potential clinical significance. Combining treatments targeting Tie2 signaling with paclitaxel resulted in vessel normalization and increased efficacy of paclitaxel in the TNBC VMT. Dual inhibition of HER3 and Akt also showed efficacy against TNBC. These data demonstrate the potential of inducing a favorable TME as a targeted therapeutic approach in TNBC.

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A human vascularized microtumor model of patient-derived colorectal cancer recapitulates clinical disease

Cited by 10 publications

References 36 publications

A Microphysiological HHT-on-a-Chip Platform Recapitulates Patient Vascular Lesions

A Microphysiological HHT-on-a-Chip Platform Recapitulates Patient Vascular Lesions

Targeting tumor-stromal interactions in triple-negative breast cancer using a human vascularized micro-tumor model

Targeting tumor–stromal interactions in triple-negative breast cancer using a human vascularized micro-tumor model

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