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Abstract：
Mixed invasive ductal and lobular carcinoma (MDLC) is a rare histologic subtype of breast cancer displaying both E-cadherin positive ductal and E-cadherin negative lobular morphologies within the same tumor, posing challenges with regard to anticipated clinical management. It remains unclear whether these distinct morphologies also have distinct biology and risk of recurrence. Our spatially resolved transcriptomic, genomic, and single-cell profiling revealed clinically significant differences between ductal and lobular tumor regions including distinct intrinsic subtype heterogeneity - e.g., MDLC with triple-negative breast cancer (TNBC) or basal ductal and estrogen receptor positive (ER+) luminal lobular regions, distinct enrichment of cell cycle arrest/senescence and oncogenic (ER and MYC) signatures, genetic and epigenetic CDH1 inactivation in lobular but not ductal regions, and single-cell ductal and lobular subpopulations with unique oncogenic signatures further highlighting intraregional heterogeneity. Altogether, we demonstrated that the intratumoral morphological/histological heterogeneity within MDLC is underpinned by intrinsic subtype and oncogenic heterogeneity which may result in prognostic uncertainty and therapeutic dilemma.
摘要：
浸润性导管和小叶混合癌（MDLC）是一种罕见的乳腺癌组织学亚型，在同一肿瘤内表现出E-cadherin阳性导管和E-cadherin阴性小叶形态。对预期的临床管理构成挑战。尚不清楚这些不同的形态是否也具有不同的生物学特性和复发风险。我们的空间分辨转录组，基因组，和单细胞谱分析揭示了导管和小叶肿瘤区域之间的临床显着差异，包括不同的内在亚型异质性-例如，三阴性乳腺癌（TNBC）或基底导管和雌激素受体阳性（ER+）腔小叶区域的MDLC，细胞周期停滞/衰老和致癌（ER和MYC）特征的不同富集，小叶而非导管区域的遗传和表观遗传CDH1失活，以及具有独特致癌特征的单细胞导管和小叶亚群进一步突出了区域内异质性。总之,我们证明MDLC的瘤内形态/组织学异质性是由固有亚型和致癌异质性所支撑的,这可能导致预后不确定性和治疗困境.
