Abstract
Simple SummaryThe coexistence of genetically distinct cancer cell clones, their phenotypic plasticity, and the presence of different constituents of the tumor microenvironment create intra-tumor heterogeneity, which affects cancer development and its response to therapy. We observed that a higher degree of phenotypic heterogeneity revealed by mass spectrometry imaging was associated with a favorable outcome in HER2-positive breast cancer. This phenomenon putatively reflects the presence of heterotypic components of the microenvironment, which could facilitate the response to anticancer treatment.Intra-tumor heterogeneity (ITH) results from the coexistence of genetically distinct cancer cell (sub)populations, their phenotypic plasticity, and the presence of heterotypic components of the tumor microenvironment (TME). Here we addressed the potential association between phenotypic ITH revealed by mass spectrometry imaging (MSI) and the prognosis of breast cancer. Tissue specimens resected from 59 patients treated radically due to the locally advanced HER2-positive invasive ductal carcinoma were included in the study. After the on-tissue trypsin digestion of cellular proteins, peptide maps of all cancer regions (about 380,000 spectra in total) were segmented by an unsupervised approach to reveal their intrinsic heterogeneity. A high degree of similarity between spectra was observed, which indicated the relative homogeneity of cancer regions. However, when the number and diversity of the detected clusters of spectra were analyzed, differences between patient groups were observed. It is noteworthy that a higher degree of heterogeneity was found in tumors from patients who remained disease-free during a 5-year follow-up (n = 38) compared to tumors from patients with progressive disease (distant metastases detected during the follow-up, n = 21). Interestingly, such differences were not observed between patients with a different status of regional lymph nodes, cancer grade, or expression of estrogen receptor at the time of the primary treatment. Subsequently, spectral components with different abundance in cancer regions were detected in patients with different outcomes, and their hypothetical identity was established by assignment to measured masses of tryptic peptides identified in corresponding tissue lysates. Such differentiating components were associated with proteins involved in immune regulation and hemostasis. Further, a positive correlation between the level of tumor-infiltrating lymphocytes and heterogeneity revealed by MSI was observed. We postulate that a higher heterogeneity of tumors with a better prognosis could reflect the presence of heterotypic components including infiltrating immune cells, that facilitated the response to treatment.
Highlights
Genetic alterations gained during cancer development are usuallyclonal events, and solid cancers evolve to mosaic entities composed of a mixture of cells with different genomes
Molecular maps of tryptic peptides were registered in sections of FFPE material by MALDI-mass spectrometry imaging (MSI) in a 600–3500 m/z range; 2527 spectral components were identified, which represented different peptide species with their isotope envelopes
Cancer regions of interest (ROIs) were delineated by a pathologist in each specimen, and all spectra from these ROIs were used in further experiments
Summary
Genetic alterations gained during cancer development are usually (sub)clonal events, and solid cancers evolve to mosaic entities composed of a mixture of cells with different genomes. It has been hypothesized that ITH would be associated with poorer clinical outcomes in cancer patients, supportive evidence has long been limited to specific contexts of resistance to the therapy of metastatic cancers [6,7,8,9]. A few studies used the pan-cancer TCGA dataset to show an association between the survival outcome in multiple cancer types and the degree of genetic ITH that was modeled based on the integration of the SNP array copy number and SNP mutation data from the whole-exome sequencing in large cohorts of patients. These reports showed that a high level of genetic ITH was generally associated with poorer survival across diverse types of cancers [10,11]
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