PO.BCS01.04 · 生物信息与计算
酸性肿瘤微环境通过LPL乳酸化介导的巨噬细胞胆固醇代谢重编程促进结直肠癌肝转移
The acidic tumor microenvironment facilitates colorectal cancer liver metastasis through LPL lactylation-mediated reprogramming of macrophage cholesterol metabolism
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摘要 Abstract
中文摘要
结直肠癌肝转移(CRLM)仍是临床治疗中的一大挑战，其复发和不良预后与肿瘤微环境(TME)重编程和免疫细胞功能障碍密切相关。作为CRLM微环境中核心的免疫调节细胞，肿瘤相关巨噬细胞(TAM)在疾病进展过程中经历显著的代谢重编程；然而，代谢重编程调控TAM表型并促进肿瘤转移的机制尚未完全阐明。一项多组学策略整合了单细胞RNA测序(scRNA-seq)和ICGC-ARGO/GEO转录组数据，以分析CRLM病灶中的代谢动态。TAM根据胆固醇代谢活性被分层为高(HCTAM)、中和低(LCTAM)亚组。空间转录组学(ST)验证了空间基因表达和代谢活性，体外功能实验验证了基因功能和调控关系。胆固醇代谢通路在CRLM病灶中异常上调，TAM在免疫细胞和基质细胞中表现出最高的胆固醇代谢活性。HCTAM的M2极化评分显著升高，定位于巨噬细胞分化的晚期阶段，并共表达多个M2标志物。五种机器学习算法鉴定出脂蛋白脂酶(LPL)在HCTAM中显著过表达，高LPL表达与晚期CRC分期和不良总生存独立相关。机制上，乳酸脱氢酶A(LDHA)在HCTAM中显著上调，且TAM胆固醇代谢活性与TME酸中毒评分呈正相关。ST证实LPL在酸中毒区域富集，多重免疫荧光显示LPL与泛乳酸化共定位。乳酸诱导的乳酸化修饰调控了LPL的表达。转录组分析揭示高LPL组的CRC细胞中EMT通路显著富集。体外实验证实LPL与M2 TAM标志物CD163共定位；敲低TAM中的LPL可降低胆固醇水平并下调M2极化标志物。共培养实验显示LPL敲低的TAM抑制CRC细胞的侵袭和迁移，并下调EMT相关标志物的表达。总之，本研究证实CRLM病灶中的酸性微环境通过乳酸依赖性乳酸化修饰驱动TAM中LPL的过表达。这一效应维持了TAM中高胆固醇代谢活性并促进其M2极化，进一步增强CRC细胞的EMT进展和侵袭性，最终加剧CRLM的发展。
查看英文原文 English abstract
Colorectal cancer liver metastasis (CRLM) remains a major challenge in clinical treatment, with its recurrence and poor prognosis closely linked to tumor microenvironment (TME) reprogramming and immune cell dysfunction. As core immunoregulatory cells in the CRLM microenvironment, tumor-associated macrophages (TAMs) undergo significant metabolic reprogramming during disease progression; however, the mechanism by which metabolic reprogramming regulates TAM phenotype and promotes tumor metastasis has not been fully elucidated.A multi-omics strategy integrated single-cell RNA sequencing (scRNA-seq) and ICGC-ARGO/GEO transcriptomic data to analyze metabolic dynamics in CRLM lesions. TAMs were stratified into high (HCTAM), medium, and low (LCTAM) subgroups by cholesterol metabolic activity. Spatial transcriptomics (ST) verified spatial gene expression and metabolic activity, and in vitro functional experiments validated gene functions and regulatory relationships.Cholesterol metabolic pathways were abnormally upregulated in CRLM lesions, with TAMs exhibiting the highest cholesterol metabolic activity among immune and stromal cells. HCTAMs had significantly elevated M2 polarization scores, localized to late-stage macrophage differentiation, and co-expressed multiple M2 markers. Five machine learning algorithms identified lipoprotein lipase (LPL) as significantly overexpressed in HCTAMs, with high LPL expression independently associated with advanced CRC stages and poor overall survival. Mechanistically, lactate dehydrogenase A (LDHA) was significantly upregulated in HCTAMs, and TAM cholesterol metabolic was activity positively correlated with TME acidosis scores. ST confirmed LPL enrichment in acidotic regions, and multiplex immunofluorescence showed LPL colocalization with pan-lactylation. Lactate-induced lactylation modification regulated the expression of LPL . Transcriptomic analysis revealed significant EMT pathway enrichment in CRC cells of high-LPL group. In vitro experiments confirmed LPL colocalization with M2 TAM marker CD163; TAM LPL knockdown reduced cholesterol levels and downregulated M2 polarization markers. Co-culture experiments showed LPL-knockdown TAMs inhibited the invasion and migration of CRC cells and downregulated EMT-related marker expression.In conclusion, this study confirms that the acidic microenvironment in CRLM lesions drives LPL overexpression in TAMs through lactate-dependent lactylation modification. This effect maintains high cholesterol metabolic activity in TAMs and promotes their M2 polarization, further enhancing CRC cell EMT progression and invasiveness, ultimately exacerbating CRLM development.
利益披露 Disclosure
Y. Zheng, None..
Z. Wei, None..
Z. Zhou, None..
P. Hu, None.