Targeted intracellular delivery of molecular cargo to hypoxic human breast cancer stem cells

IF 24.9 1区 医学 Q1 ONCOLOGY
Ashley V. Makela, Anthony Tundo, Huiping Liu, Doug Schneider, Terry Hermiston, Pavlo Khodakivskyi, Elena Goun, Christopher H. Contag
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PS, a negatively charged lipid, is typically confined to the inner leaflet of cell membranes [<span>3</span>]. However, its externalization occurs on dying and diseased cells, and as we demonstrated, on stem cells [<span>4</span>]. PS-targeting agents like Annexin V (AnnV) [<span>5</span>] and the monoclonal antibody bavituxumab (Bavi) [<span>6</span>] are under investigation for cancer therapy, but these are limited in their use as they remain surface bound and do not deliver payloads into cells. In contrast, we have found that a truncated protein S comprised of the PS-binding γ-carboxyglutamate (Gla) domain and four epidermal growth factor (EGF) domains (collectively referred to as GlaS), binds PS on the outer leaflet and is internalized after binding [<span>4</span>] enabling delivery of payloads to the cytoplasm of cells with externalized PS, which would include CSC in the hypoxic regions of tumors.</p><p>We used patient derived models of human breast cancer which are enriched in CD44<sup>+</sup>CD24<sup>−</sup> CSCs (Supplementary Materials and Methods). Following isolation, the CSC were propogated in mice and engineered so they express bioluminescent and fluorescent reporters. Cells collected from the CSC enriched tumors [<span>7</span>] were exposed to an oxygen level in culture that mimics the tumor microenvironment (TME) [<span>8, 9</span>], 4% O<sub>2</sub> (hypoxia), and compared to cells exposed to 7% O<sub>2</sub> (physoxia) and 21% O<sub>2</sub> (hyperoxia, typical cell culture). The percentage of CD44<sup>+</sup> cells did not show significant differences at different oxygen levels (F<sub>2,36</sub> = 1.32, <i>P</i> = 0.28, Figure 1A-B, Supplemental Figure S1A). However, the percentage of CD44<sup>+</sup>GlaS<sup>+</sup> cells (indicating GlaS binding) varied significantly (F<sub>2,36</sub> = 27.69, <i>P</i> &lt; 0.001, Figure 1C-D, Supplemental Figure S1B). Hypoxic conditions showed increased GlaS binding, with 61% of cells being CD44<sup>+</sup>GlaS<sup>+</sup> under hypoxic conditions, compared to 47% in physoxia (<i>P</i> = 0.01) and 28% in hyperoxia (<i>P</i> &lt; 0.001). There were no significant differences in GlaS binding in CD44<sup>−</sup> cells (<i>P</i> = 0.054), suggesting that oxygen dependent binding is specific to CD44<sup>+</sup> cells (Figure 1E-F). These findings were also validated using known PS-binding AnnV, and antibodies, 11.31 and Bavi (Supplemental Figure S2A-F). We confirmed that GlaS binds PS in a similar manner to these proteins, though there were differences in the overlapping populations of cells binding GlaS, AnnV, and PS antibodies (Supplemental Figure S2G-I). However, unlike AnnV and Bavi, GlaS was internalized into the cell, demonstrating its potential for delivering therapeutic payloads to the cytoplasm. This was revealed by confocal microscopy where GlaS can be seen on the cell membrane and in the cytoplasm, in contrast to the membrane-only localization of PS-binding controls (Figure 1G, Supplemental Figure S3); fluorescence localization of GlaS vs AnnV has been quantified previously [<span>4</span>]. This internalization indicated that GlaS can be used to target intracellular pathways, whereas cell surface binding of the other PS binders may be better suited for immune modulation.</p><p>Further analysis revealed two subpopulations within the CD44<sup>+</sup> cells based on size, CD44 expression and GlaS staining intensity (Figure 1H-K, Supplemental Figure S4). The smaller cells (low forward-scatter; FSC) with lower CD44 expression, likely representing quiescent CSCs [<span>10</span>], had greater GlaS fluorescence intensity (GlaS<sup>high</sup>small) than the larger cells (GlaS<sup>low</sup>large). Interestingly, GlaS<sup>high</sup>small cells exhibited significant differences in CD44 median fluorescence intensity (MFI) when exposed to different oxygen conditions (F<sub>2,36</sub> = 19.74, <i>P</i> &lt; 0.001), with higher expression under hypoxia versus physoxia and hyperoxia. GlaS<sup>low</sup>large cells had lower GlaS binding and were 1.5× larger versus the GlaS<sup>high</sup>small cells (<i>P</i> &lt; 0.001 in all oxygen conditions for FSC [t(24) = 13.49; hypoxic, t(24) = 9.58; physoxic and t(16.54) = 9.72; hyperoxic] and GlaS MFI [t(12.05) = 10.45; hypoxic and t(12.11) = 10.47; hyperoxic]. GlaS MFI was 21×, 18×, and 10× higher in the smaller vs larger CD44<sup>+</sup> population at hypoxic, physoxic and hyperoxic conditions, respectively. Differences in GlaS MFI relative to oxygen conditions were apparent in the GlaS<sup>high</sup>small population (<i>P</i> &lt; 0.001), but not in the GlaS<sup>low</sup>large population (F<sub>2,36</sub> = 1.63, <i>P</i> = 0.21). These findings underscore the potential of GlaS for selectively targeting the small, tumorigenic CSCs within the hypoxic TME, which are often the most resistant to treatment.</p><p>After a systemic (intravenous; IV) administration of GlaS conjugated to a fluorophore (HiLyte750), fluorescent imaging identified accumulation within hypoxic regions of tumors In vivo (Figure 1L). While bioluminescent imaging (BLI) identified viable CSCs throughout the tumor, HypoxySense was used to visualize hypoxic areas, with the tumor cores exhibiting higher levels of hypoxia compared to the surrounding tumor tissue. GlaS accumulated not only within the tumor but also in the gut, knees, ankles, and teeth. In a bisected excised tumor, the localization and spatial resolution of the fluorophores were improved. GlaS localized primarily in the tumor core, where hypoxia was also more pronounced, supporting its potential as a hypoxia-targeted therapeutic agent.</p><p>To demonstrate GlaS functional delivery capabilities, we used GlaS conjugated via a disulfide linkage to luciferin (GlaS-SS-luc), with an imaging approach to validate cellular internalization and cargo release (due to intracellular glutathione). Because the CSC in the patient derived xenograft (PDX) models express luciferase, this allowed for real-time tracking of GlaS-mediated delivery using BLI (Figure 1M, Supplemental Figure S5). GlaS-SS-luc showed delayed and sustained bioluminescent signals compared to free D-luciferin (Figure 1N-O), with similar patterns observed after IV and intraperitoneal (IP) administration. After IP administration of D-luciferin, signals peaked at 33 mins, which was similar to the onset of the IP GlaS-SS-luc peak. However, GlaS-SS-luc signals were sustained for 31 mins, while D-luciferin signals declined immediately after peaking despite luciferin concentrations being equimolar. Following IV administration of D-luciferin, the peak signal was detected instantly (&lt; 1 min post-injection), whereas GlaS-SS-luc showed a delayed peak at 15 mins. Overall, peak bioluminescent signals were higher after the administration of equimolar D-luciferin compared to GlaS-SS-luc, with 7.5-fold increase for IV and a 30-fold increase for IP administration. Area under the curve (AUC) was calculated for each treatment (Figure 1P), to quantify luciferin delivered over that time period, with significant differences in AUC between the different materials and injection routes (F<sub>3,8</sub> = 99.11, <i>P</i> &lt; 0.001). IV D-luciferin as well as IV and IP GlaS-SS-luc conjugates delivered significantly less luciferin than IP D-luciferin (<i>P</i> &lt; 0.001 for all). There were no differences when GlaS-SS-luc was administered IP or IV (<i>P</i> = 0.908), nor when GlaS-SS-luc or D-luciferin were administered IV (<i>P</i> = 0.133). Together these results indicated that GlaS must first bind to PS, be internalized, and release its cargo inside the cell, compared to free diffusion of D-luciferin. This suggests that GlaS could be used to target and treat CSCs with therapies that affect intracellular signaling pathways, as well as indicating potential for prolonged therapeutic action.</p><p>This study highlights GlaS as a promising tool for the targeted delivery of therapies to CSCs in their native, hypoxic niches (further discussed in Supplementary Information). By exploiting PS externalization, particularly in hypoxic CSCs, GlaS could provide a strategy to overcome the challenge of CSC-mediated tumor relapse, metastasis and resistance to conventional treatments. Overall, the study highlights that hypoxia increases GlaS binding to CSCs, particularly on the smaller, more stem-like populations, and GlaS can deliver intracellular therapeutic molecules to these cells effectively both in vitro and In vivo.</p><p>Ashley V Makela, Anthony Tundo, Terry Hermiston, and Christopher H Contag conceptualized the study. Ashley V Makela and Anthony Tundo performed experiments, data analysis and statistics. Ashley V Makela, Anthony Tundo, Terry Hermiston, and Christopher H Contg contributed to the analysis and/or interpretation of the data. Doug Schneider and Terry Hermiston helped design the GlaS and GlaS-Fc. Huiping Liu provided the PDX cell lines and technical advice surrounding growth and maintenance. Pavlo Khodakivskyi and Elena Goun developed the GlaS-SS-luc, GlaS-Fc-SS-luc and AnnV-SS-luc materials, and provided guidance on their use. Ashley V Makela drafted the manuscript. All authors revised and edited the manuscript.</p><p>Huiping Liu is a co-founder of ExoMira Medicine although the current studies are not relevant. Terry Hermiston is founder and CEO of GLAdiator Biosciences. Pavlo Khodakivskyi is affiliated with VitaLume Biotechnologies LLC.</p><p>This work was supported in part by GLAdiator Biosciences and The James and Kathleen Cornelius Endowment (to Christopher Contag). This work is partially supported by NIH/NCI R01CA245699 and American Cancer Society ACS0137006 (to Huiping Liu).</p><p>This research was conducted in accordance with the protocols approved by MSU IACUC (PROTO202400041). The patient derived xenograft models were established previously at Stanford University and Northwestern University, with informed consent obtained from the patients.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 6","pages":"714-718"},"PeriodicalIF":24.9000,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70018","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Communications","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cac2.70018","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Despite advances in breast cancer therapy, effective targeting of cancer stem cells (CSCs) remains a challenge. CSCs, which have self-renewal, tumorigenic and metastatic properties, are often quiescent and located in hypoxic regions of tumors [1], making them resistant to conventional chemo- and radiotherapies [2]. These characteristics allow CSCs to survive, leading to relapse and metastasis. Studying CSCs under conditions similar to their hypoxic niche is essential for evaluating therapies that target these cells.

We show that CSCs can be targeted via binding to externalized phosphatidylserine (PS). PS, a negatively charged lipid, is typically confined to the inner leaflet of cell membranes [3]. However, its externalization occurs on dying and diseased cells, and as we demonstrated, on stem cells [4]. PS-targeting agents like Annexin V (AnnV) [5] and the monoclonal antibody bavituxumab (Bavi) [6] are under investigation for cancer therapy, but these are limited in their use as they remain surface bound and do not deliver payloads into cells. In contrast, we have found that a truncated protein S comprised of the PS-binding γ-carboxyglutamate (Gla) domain and four epidermal growth factor (EGF) domains (collectively referred to as GlaS), binds PS on the outer leaflet and is internalized after binding [4] enabling delivery of payloads to the cytoplasm of cells with externalized PS, which would include CSC in the hypoxic regions of tumors.

We used patient derived models of human breast cancer which are enriched in CD44+CD24 CSCs (Supplementary Materials and Methods). Following isolation, the CSC were propogated in mice and engineered so they express bioluminescent and fluorescent reporters. Cells collected from the CSC enriched tumors [7] were exposed to an oxygen level in culture that mimics the tumor microenvironment (TME) [8, 9], 4% O2 (hypoxia), and compared to cells exposed to 7% O2 (physoxia) and 21% O2 (hyperoxia, typical cell culture). The percentage of CD44+ cells did not show significant differences at different oxygen levels (F2,36 = 1.32, P = 0.28, Figure 1A-B, Supplemental Figure S1A). However, the percentage of CD44+GlaS+ cells (indicating GlaS binding) varied significantly (F2,36 = 27.69, P < 0.001, Figure 1C-D, Supplemental Figure S1B). Hypoxic conditions showed increased GlaS binding, with 61% of cells being CD44+GlaS+ under hypoxic conditions, compared to 47% in physoxia (P = 0.01) and 28% in hyperoxia (P < 0.001). There were no significant differences in GlaS binding in CD44 cells (P = 0.054), suggesting that oxygen dependent binding is specific to CD44+ cells (Figure 1E-F). These findings were also validated using known PS-binding AnnV, and antibodies, 11.31 and Bavi (Supplemental Figure S2A-F). We confirmed that GlaS binds PS in a similar manner to these proteins, though there were differences in the overlapping populations of cells binding GlaS, AnnV, and PS antibodies (Supplemental Figure S2G-I). However, unlike AnnV and Bavi, GlaS was internalized into the cell, demonstrating its potential for delivering therapeutic payloads to the cytoplasm. This was revealed by confocal microscopy where GlaS can be seen on the cell membrane and in the cytoplasm, in contrast to the membrane-only localization of PS-binding controls (Figure 1G, Supplemental Figure S3); fluorescence localization of GlaS vs AnnV has been quantified previously [4]. This internalization indicated that GlaS can be used to target intracellular pathways, whereas cell surface binding of the other PS binders may be better suited for immune modulation.

Further analysis revealed two subpopulations within the CD44+ cells based on size, CD44 expression and GlaS staining intensity (Figure 1H-K, Supplemental Figure S4). The smaller cells (low forward-scatter; FSC) with lower CD44 expression, likely representing quiescent CSCs [10], had greater GlaS fluorescence intensity (GlaShighsmall) than the larger cells (GlaSlowlarge). Interestingly, GlaShighsmall cells exhibited significant differences in CD44 median fluorescence intensity (MFI) when exposed to different oxygen conditions (F2,36 = 19.74, P < 0.001), with higher expression under hypoxia versus physoxia and hyperoxia. GlaSlowlarge cells had lower GlaS binding and were 1.5× larger versus the GlaShighsmall cells (P < 0.001 in all oxygen conditions for FSC [t(24) = 13.49; hypoxic, t(24) = 9.58; physoxic and t(16.54) = 9.72; hyperoxic] and GlaS MFI [t(12.05) = 10.45; hypoxic and t(12.11) = 10.47; hyperoxic]. GlaS MFI was 21×, 18×, and 10× higher in the smaller vs larger CD44+ population at hypoxic, physoxic and hyperoxic conditions, respectively. Differences in GlaS MFI relative to oxygen conditions were apparent in the GlaShighsmall population (P < 0.001), but not in the GlaSlowlarge population (F2,36 = 1.63, P = 0.21). These findings underscore the potential of GlaS for selectively targeting the small, tumorigenic CSCs within the hypoxic TME, which are often the most resistant to treatment.

After a systemic (intravenous; IV) administration of GlaS conjugated to a fluorophore (HiLyte750), fluorescent imaging identified accumulation within hypoxic regions of tumors In vivo (Figure 1L). While bioluminescent imaging (BLI) identified viable CSCs throughout the tumor, HypoxySense was used to visualize hypoxic areas, with the tumor cores exhibiting higher levels of hypoxia compared to the surrounding tumor tissue. GlaS accumulated not only within the tumor but also in the gut, knees, ankles, and teeth. In a bisected excised tumor, the localization and spatial resolution of the fluorophores were improved. GlaS localized primarily in the tumor core, where hypoxia was also more pronounced, supporting its potential as a hypoxia-targeted therapeutic agent.

To demonstrate GlaS functional delivery capabilities, we used GlaS conjugated via a disulfide linkage to luciferin (GlaS-SS-luc), with an imaging approach to validate cellular internalization and cargo release (due to intracellular glutathione). Because the CSC in the patient derived xenograft (PDX) models express luciferase, this allowed for real-time tracking of GlaS-mediated delivery using BLI (Figure 1M, Supplemental Figure S5). GlaS-SS-luc showed delayed and sustained bioluminescent signals compared to free D-luciferin (Figure 1N-O), with similar patterns observed after IV and intraperitoneal (IP) administration. After IP administration of D-luciferin, signals peaked at 33 mins, which was similar to the onset of the IP GlaS-SS-luc peak. However, GlaS-SS-luc signals were sustained for 31 mins, while D-luciferin signals declined immediately after peaking despite luciferin concentrations being equimolar. Following IV administration of D-luciferin, the peak signal was detected instantly (< 1 min post-injection), whereas GlaS-SS-luc showed a delayed peak at 15 mins. Overall, peak bioluminescent signals were higher after the administration of equimolar D-luciferin compared to GlaS-SS-luc, with 7.5-fold increase for IV and a 30-fold increase for IP administration. Area under the curve (AUC) was calculated for each treatment (Figure 1P), to quantify luciferin delivered over that time period, with significant differences in AUC between the different materials and injection routes (F3,8 = 99.11, P < 0.001). IV D-luciferin as well as IV and IP GlaS-SS-luc conjugates delivered significantly less luciferin than IP D-luciferin (P < 0.001 for all). There were no differences when GlaS-SS-luc was administered IP or IV (P = 0.908), nor when GlaS-SS-luc or D-luciferin were administered IV (P = 0.133). Together these results indicated that GlaS must first bind to PS, be internalized, and release its cargo inside the cell, compared to free diffusion of D-luciferin. This suggests that GlaS could be used to target and treat CSCs with therapies that affect intracellular signaling pathways, as well as indicating potential for prolonged therapeutic action.

This study highlights GlaS as a promising tool for the targeted delivery of therapies to CSCs in their native, hypoxic niches (further discussed in Supplementary Information). By exploiting PS externalization, particularly in hypoxic CSCs, GlaS could provide a strategy to overcome the challenge of CSC-mediated tumor relapse, metastasis and resistance to conventional treatments. Overall, the study highlights that hypoxia increases GlaS binding to CSCs, particularly on the smaller, more stem-like populations, and GlaS can deliver intracellular therapeutic molecules to these cells effectively both in vitro and In vivo.

Ashley V Makela, Anthony Tundo, Terry Hermiston, and Christopher H Contag conceptualized the study. Ashley V Makela and Anthony Tundo performed experiments, data analysis and statistics. Ashley V Makela, Anthony Tundo, Terry Hermiston, and Christopher H Contg contributed to the analysis and/or interpretation of the data. Doug Schneider and Terry Hermiston helped design the GlaS and GlaS-Fc. Huiping Liu provided the PDX cell lines and technical advice surrounding growth and maintenance. Pavlo Khodakivskyi and Elena Goun developed the GlaS-SS-luc, GlaS-Fc-SS-luc and AnnV-SS-luc materials, and provided guidance on their use. Ashley V Makela drafted the manuscript. All authors revised and edited the manuscript.

Huiping Liu is a co-founder of ExoMira Medicine although the current studies are not relevant. Terry Hermiston is founder and CEO of GLAdiator Biosciences. Pavlo Khodakivskyi is affiliated with VitaLume Biotechnologies LLC.

This work was supported in part by GLAdiator Biosciences and The James and Kathleen Cornelius Endowment (to Christopher Contag). This work is partially supported by NIH/NCI R01CA245699 and American Cancer Society ACS0137006 (to Huiping Liu).

This research was conducted in accordance with the protocols approved by MSU IACUC (PROTO202400041). The patient derived xenograft models were established previously at Stanford University and Northwestern University, with informed consent obtained from the patients.

Abstract Image

低氧人乳腺癌干细胞的靶向细胞内分子转运。
尽管乳腺癌治疗取得了进展,但有效靶向癌症干细胞(CSCs)仍然是一个挑战。CSCs具有自我更新、致瘤性和转移性,通常处于静止状态,位于肿瘤缺氧区[1],使其对常规化疗和放疗[1]具有抗性。这些特征使得csc能够存活,从而导致复发和转移。在类似于其缺氧生态位的条件下研究CSCs对于评估针对这些细胞的治疗方法至关重要。我们发现CSCs可以通过与外化磷脂酰丝氨酸(PS)结合而靶向。PS是一种带负电荷的脂质,通常局限于细胞膜的内小叶b[3]。然而,它的外化发生在死亡和患病细胞上,正如我们所证明的,在干细胞[4]上。ps靶向药物如膜联蛋白V (AnnV)[5]和单克隆抗体巴伐单抗(bai)[6]正在研究用于癌症治疗,但这些药物的使用受到限制,因为它们保持表面结合,不能将有效载荷传递到细胞中。相反,我们发现一个截断的蛋白S由结合PS的γ-羧谷氨酸(Gla)结构域和四个表皮生长因子(EGF)结构域(统称为GlaS)组成,在外层小叶上结合PS,并在结合[4]后被内化,从而将有效载荷传递到外化PS的细胞的细胞质中,其中包括肿瘤缺氧区域的CSC。我们使用了富含CD44+CD24−CSCs的患者衍生的人乳腺癌模型(补充材料和方法)。分离后,CSC在小鼠中繁殖并进行工程改造,使其表达生物发光和荧光报告基因。从CSC富集的肿瘤[7]中收集的细胞暴露于模拟肿瘤微环境(TME)[8,9]的培养中,4% O2(缺氧),并与暴露于7% O2(生理缺氧)和21% O2(高氧,典型细胞培养)的细胞进行比较。不同氧浓度下CD44+细胞百分比无显著差异(F2,36 = 1.32, P = 0.28,图1A-B,补充图S1A)。然而,CD44+GlaS+细胞的百分比(表明GlaS结合)差异显著(F2,36 = 27.69, P &lt;0.001,图1C-D,补充图S1B)。低氧条件下GlaS结合增加,低氧条件下61%的细胞为CD44+GlaS+,而缺氧条件下为47% (P = 0.01),高氧条件下为28% (P &lt;0.001)。在CD44−细胞中,GlaS结合无显著差异(P = 0.054),提示氧依赖性结合是CD44+细胞特异性的(图1E-F)。这些发现也被已知的ps结合AnnV和抗体11.31和bai验证(补充图S2A-F)。我们证实,GlaS以与这些蛋白相似的方式结合PS,尽管结合GlaS、AnnV和PS抗体的细胞重叠群体存在差异(补充图S2G-I)。然而,与AnnV和bai不同的是,GlaS被内化到细胞中,显示出其向细胞质输送治疗有效载荷的潜力。这是通过共聚焦显微镜显示的,在细胞膜和细胞质中可以看到GlaS,与ps结合对照组的膜定位相反(图1G,补充图S3);GlaS与AnnV的荧光定位先前已被量化。这种内化表明,GlaS可用于靶向细胞内途径,而其他PS结合物的细胞表面结合可能更适合免疫调节。进一步分析显示,基于大小、CD44表达和GlaS染色强度,CD44+细胞中存在两个亚群(图1H-K,补充图S4)。较小的单元格(低前向散射;CD44表达较低的FSC可能代表静止CSCs[10],其玻璃荧光强度(GlaShighsmall)高于较大的细胞(GlaSlowlarge)。有趣的是,暴露于不同氧条件下的GlaShighsmall细胞在CD44中位荧光强度(MFI)上表现出显著差异(F2,36 = 19.74, P &lt;0.001),低氧条件下比生理缺氧和高氧条件下表达更高。glashighlarge细胞的GlaS结合较低,比GlaShighsmall细胞大1.5倍(P &lt;FSC在所有氧气条件下均为0.001 [t(24) = 13.49;缺氧,t(24) = 9.58;生理和t(16.54) = 9.72;GlaS MFI [t(12.05) = 10.45;缺氧,t(12.11) = 10.47;氧)。在低氧、生理和高氧条件下,小CD44+群体的GlaS MFI分别比大CD44+群体高21倍、18倍和10倍。GlaS MFI相对于氧气条件的差异在GlaShighsmall人群中是明显的(P &lt;0.001),但在GlaSlowlarge人群中没有(F2,36 = 1.63, P = 0.21)。 本研究按照MSU IACUC批准的协议(PROTO202400041)进行。患者来源的异种移植物模型先前在斯坦福大学和西北大学建立,并获得患者的知情同意。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cancer Communications
Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
25.50
自引率
4.30%
发文量
153
审稿时长
4 weeks
期刊介绍: Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.
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