Pericytes Elicit Resistance to Vemurafenib and Sorafenib Therapy in Thyroid Carcinoma via the TSP-1/TGFβ1 Axis.
Pericytes Elicit Resistance to Vemurafenib and Sorafenib Therapy in Thyroid Carcinoma via the TSP-1/TGFβ1 Axis.
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DOI：
10.1158/1078-0432.ccr-18-0693
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发表时间：
2018-12-01
期刊：
影响因子：
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通讯作者：
Nucera C
中科院分区：
文献类型：
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作者：
Prete A;Lo AS;Sadow PM;Bhasin SS;Antonello ZA;Vodopivec DM;Ullas S;Sims JN;Clohessy J;Dvorak AM;Sciuto T;Bhasin M;Murphy-Ullrich JE;Lawler J;Karumanchi SA;Nucera C
BRAFV 600 E癌基因调节甲状腺乳头状癌（PTC）微环境，其中周细胞是酪氨酸激酶（TK）依赖性信号通路的关键调节因子。虽然BRAFV 600 E和TK抑制剂是可用的，但它们作为BRAFV 600 E-PTC中的双峰治疗剂的功效仍然未知。我们使用细胞自主、周细胞共培养和原位小鼠模型，评估了维罗非尼（BRAFV 600 E抑制剂）和索拉非尼（TKI）作为单一药物或组合在BRAFWT/V600 E-PTC和BRAFWT/WT细胞中的作用。我们还使用BRAFWT/V600 E-PTC和BRAFWT/WT-PTC临床样品来鉴定对肿瘤微环境至关重要的差异表达基因。联合治疗通过体外甲状腺肿瘤细胞中的BRAFV 600 E抑制阻断肿瘤细胞增殖，增加细胞死亡，并降低运动性。维罗非尼在原位肿瘤中产生细胞生长抑制作用，而联合治疗（可能反映索拉非尼活性）产生生物学波动，肿瘤抑制与肿瘤生长交替。我们证明，周细胞分泌TSP-1和TGFβ1，并诱导pERK 1/2、pAKT和pSMAD 3水平反弹，以克服靶向治疗对PTC细胞的抑制作用。这导致BRAFV 600 E-PTC细胞存活和细胞死亡难治性增加。我们发现BRAFWT/V600 E-PTC临床样本富含周细胞，TSP 1和TGFβ1表达在BRAFWT/V600 E-PTC细胞存活所必需的微环境中引起基因调控网络和途径。重要的是，TSP-1/TGFβ1轴的拮抗作用减少了肿瘤细胞生长并克服了耐药性。周细胞通过TSP-1和TGFβ1保护BRAFV 600 E-PTC细胞免受靶向治疗，表明该轴作为克服对BRAFV 600 E和TK抑制剂耐药性的新治疗靶点。
The BRAFV600E oncogene modulates the papillary thyroid carcinoma (PTC) microenvironment, in which pericytes are critical regulators of tyrosine-kinase (TK)-dependent signaling pathways. Although BRAFV600E and TK inhibitors are available, their efficacy as bimodal therapeutic agents in BRAFV600E-PTC is still unknown. We assessed the effects of vemurafenib (BRAFV600E inhibitor) and sorafenib (TKI) as single agents or in combination in BRAFWT/V600E-PTC and BRAFWT/WT cells using cell-autonomous, pericyte co-culture, and an orthotopic mouse model. We also used BRAFWT/V600E-PTC and BRAFWT/WT-PTC clinical samples to identify differentially expressed genes fundamental to tumor microenvironment. Combined therapy blocks tumor cell proliferation, increases cell death, and decreases motility via BRAFV600E inhibition in thyroid tumor cells in vitro. Vemurafenib produces cytostatic effects in orthotopic tumors, whereas combined therapy (likely reflecting sorafenib activity) generates biological fluctuations with tumor inhibition alternating with tumor growth. We demonstrate that pericytes secrete TSP-1 and TGFβ1, and induce the rebound of pERK1/2, pAKT and pSMAD3 levels to overcome the inhibitory effects of the targeted therapy in PTC cells. This leads to increased BRAFV600E-PTC cell survival and cell death refractoriness. We find that BRAFWT/V600E-PTC clinical samples are enriched in pericytes, and TSP1 and TGFβ1 expression evoke gene-regulatory networks and pathways in the microenvironment essential for BRAFWT/V600E-PTC cell survival. Critically, antagonism of the TSP-1/TGFβ1 axis reduces tumor cell growth and overcomes drug resistance. Pericytes shield BRAFV600E-PTC cells from targeted therapy via TSP-1 and TGFβ1, suggesting this axis as a new therapeutic target for overcoming resistance to BRAFV600E and TK inhibitors.