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.

中文翻译：

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混合侵袭性导管癌和小叶乳腺癌的空间分子分析揭示了内在分子亚型、致癌特征和突变的异质性


混合性浸润性导管和小叶癌 (MDLC) 是一种罕见的乳腺癌组织学亚型，在同一肿瘤内同时显示 E-钙粘蛋白阳性导管和 E-钙粘蛋白阴性小叶形态，这对预期的临床治疗提出了挑战。目前尚不清楚这些不同的形态是否也具有不同的生物学和复发风险。我们的空间解析转录组、基因组和单细胞分析揭示了导管和小叶肿瘤区域之间的临床显着差异，包括独特的内在亚型异质性 - 例如，三阴性乳腺癌 (TNBC) 或基底导管和雌激素受体阳性 (ER+) 的 MDLC管腔小叶区域，细胞周期停滞/衰老和致癌（ER 和MYC ) 特征、遗传和表观遗传CDH1小叶而非导管区域失活，以及具有独特致癌特征的单细胞导管和小叶亚群进一步凸显了区域内异质性。总而言之，我们证明 MDLC 内的瘤内形态学/组织学异质性是由内在亚型和致癌异质性支撑的，这可能导致预后不确定性和治疗困境。