Systemic Influences of Mammary Cancer on Monocytes in Mice.
Systemic Influences of Mammary Cancer on Monocytes in Mice.
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DOI：
10.3390/cancers14030833
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发表时间：
2022-02-07
期刊：
影响因子：
5.2
通讯作者：
Pollard JW
中科院分区：
文献类型：
--
作者：
Robinson A;Burgess M;Webb S;Louwe PA;Ouyang Z;Skola D;Han CZ;Batada NN;González-Huici V;Cassetta L;Glass CK;Jenkins SJ;Pollard JW
通过乳腺上皮表达多瘤中间T癌蛋白驱动的乳腺癌小鼠模型，我们发现肿瘤从良性转移到恶性转移阶段，癌症导致循环单核细胞增加和脾肿大。单核细胞数量的增加是由于它们在骨髓中的增殖增加，而不是血液中的周转率。单细胞测序也表明，在癌症期间不会产生新的单核细胞群。癌症也驱动单核细胞转录组的系统性变化，干扰素信号的显著下调。这些系统性影响从骨髓开始，但在血液中加剧。比较携带相同致癌基因的易发和耐癌小鼠近交系，发现菌株的遗传背景导致不同的单核细胞转录变化。同样，小鼠转录组与人类乳腺癌单核细胞谱的比较表明，在干扰素信号在人类中增强的程度上，两者的相似性有限。同一物种内不同遗传背景的同一癌症模型的系统反应是不同的，甚至在不同物种之间发现了更大的变化。这些数据表明，在探索人类系统性变化背后的机制时，至少这个小鼠模型是有限的。越来越多的证据表明，癌症会引起全身的变化。这些影响在骨髓和血液中最为明显，特别是在髓腔室中。在这里，我们通过使用乳腺上皮表达多瘤中间T抗原引起的乳腺癌小鼠模型显示骨髓、循环和脾单核细胞数量增加。癌症不会影响循环中经典与非经典单核细胞的比例，也不会影响它们的半衰期。单细胞RNA测序也表明癌症不会诱导任何新的单核细胞群。癌症不改变骨髓中的单核细胞祖细胞数量，但单核细胞的增殖率较高，从而为循环数量的增加提供了解释。这些单核细胞群的深度RNA测序显示，癌症引起经典单核细胞区室的变化，骨髓单核细胞的变化明显，血液中的变化更明显，表明两个区室都受到影响，干扰素1型信号传导和抗原呈递的下调是其中最突出的。与此分析一致，下调基因的启动子中富含STAT1/STAT2结合位点，这是1型干扰素信号转导所需的转录因子。然而，小鼠的这些转录组变化并没有复制乳腺癌患者的转录组变化。因此，这种小鼠乳腺癌模型可能不足以研究人类癌症的全身影响。
Using a mouse model of breast cancer driven by the mammary epithelial expression of the polyoma middle T oncoprotein in which the tumors progress from benign to malignant metastatic stages, we show that cancer causes an increase in circulating monocytes and a splenomegaly. This increase in monocyte number is due to their increased proliferation in the bone marrow and not turnover rates in the blood. Single cell sequencing also shows that new populations of monocytes do not arise during cancer. Cancer also drives systemic changes in the monocyte transcriptome, with a notable down-regulation of interferon signaling. These systemic influences start in the bone marrow but intensify in the blood. Comparison of cancer prone and cancer resistant mouse inbred strains carrying the same oncogene reveals that the genetic background of the strain causes different monocyte transcriptional changes. Similarly, a comparison of the mouse transcriptome to human breast cancer monocyte profiles indicates limited similarities, to the extent that interferon signaling is enhanced in humans. Systemic responses are different in the same model of cancer on different genetic backgrounds within a species and even greater changes are found across species. These data suggest that at the very least this mouse model will be limited when it comes to exploring the mechanism behind systemic changes in humans. There is a growing body of evidence that cancer causes systemic changes. These influences are most evident in the bone marrow and the blood, particularly in the myeloid compartment. Here, we show that there is an increase in the number of bone marrow, circulating and splenic monocytes by using mouse models of breast cancer caused by the mammary epithelial expression of the polyoma middle T antigen. Cancer does not affect ratios of classical to non-classical populations of monocytes in the circulation nor does it affect their half-lives. Single cell RNA sequencing also indicates that cancer does not induce any new monocyte populations. Cancer does not change the monocytic progenitor number in the bone marrow, but the proliferation rate of monocytes is higher, thus providing an explanation for the expansion of the circulating numbers. Deep RNA sequencing of these monocytic populations reveals that cancer causes changes in the classical monocyte compartment, with changes evident in bone marrow monocytes and even more so in the blood, suggesting influences in both compartments, with the down-regulation of interferon type 1 signaling and antigen presentation being the most prominent of these. Consistent with this analysis, down-regulated genes are enriched with STAT1/STAT2 binding sites in their promoter, which are transcription factors required for type 1 interferon signaling. However, these transcriptome changes in mice did not replicate those found in patients with breast cancer. Consequently, this mouse model of breast cancer may be insufficient to study the systemic influences of human cancer.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1073/pnas.1113744109
发表时间：
2012-02-14
影响因子：
11.1
作者：
Cortez-Retamozo, Virna;Etzrodt, Martin;Pittet, Mikael J.
通讯作者：
Pittet, Mikael J.
肿瘤相关巨噬细胞的细胞和分子起源。
DOI：
10.1126/science.1252510
发表时间：
2014-05-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Franklin RA;Liao W;Sarkar A;Kim MV;Bivona MR;Liu K;Pamer EG;Li MO
通讯作者：
Li MO
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
8.8
作者：
Arwert EN;Harney AS;Entenberg D;Wang Y;Sahai E;Pollard JW;Condeelis JS
通讯作者：
Condeelis JS