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Clinical Proteomics of Metastatic Melanoma Reveals Profiles of Organ-Specificity and Treatment Resistance

ABSTRACT: Immunotherapy and targeted therapy dramatically changed the treatment of metastatic melanoma. Yet, many patients do not respond to these treatments and improve the understanding of response and resistance is an urgent need. Thus, we utilized mass spectrometry-based proteomic analysis of 185 metastatic melanoma samples. Metastases from different sites demonstrate differences in cellular processes such as immune, metabolism, translation and proliferation. Complementary epidemiology analysis uncovers prognosis variance between different metastases locations after treated with anti-PD1. Examination of lung melanoma metastases reveals clinical and molecular heterogeneity that mainly reflected in immune-related processes. Analysis of BRAF mutation status and prior treatments with MAPK inhibitors also indicate differences in immune and metabolic processes and suggest a molecular basis for the combination of immunotherapy and targeted therapy. These results shed new light into biology and therapeutic resistant mechanisms and the pathogenesis of metastatic melanoma.

INSTRUMENT(S): Q Exactive Plus, Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Melanocyte, Whole Body

DISEASE(S): Skin Melanoma

SUBMITTER: Tamar Geiger

LAB HEAD: Tamar Geiger

PROVIDER: PXD020618 | Pride | 2020-12-23

REPOSITORIES: Pride

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Project description:Metastatic disease remains one of the most urgent clinical challenges accounting for over 90% of cancer-related deaths. Yet, the identification of novel therapeutic targets to fight or prevent metastatic disease has been hampered by the limited availability of clinically relevant mouse models of metastasis formation. To address this caveat, we developed a novel preclinical mouse model of spontaneous metastatic breast cancer that recapitulates the key biological events of the metastatic cascade and mimics the clinical course of metastatic disease in humans. Exploiting the conditional K14cre;CdhF/F;Trp53F/F mouse model of de novo mammary tumor formation, we orthotopically transplanted K14cre;CdhF/F;Trp53F/F derived mouse invasive lobular carcinoma (mILC) fragments into mammary glands of wild-type syngeneic hosts. Once recipient mammary tumors were established, we mimicked the clinical setting and performed a mastectomy. Following surgery, recipient mice eventually succumbed to wide-spread clinically overt metastatic disease in lymph nodes, lungs and gastrointestinal tract. Using aCGH analyses, we explored the relationship between the genomic profiles of mammary donor tumors and paired recipient outgrowths and observed a strong correlation, indicating that the genomic profile of the parental K14cre;CdhF/F;Trp53F/F mILC is highly conserved in recipient mammary tumors. To investigate the genomic relationship between recipient mammary tumors and their metastases, we examined the correlation structure of genomic profiles derived from paired sets of primary tumors and metastases. Genomic profiles of clonally-related recipient mammary tumors were highly conserved in local and distant metastases, indicating that few genomic alterations occur during transition from a primary tumor to a distant site. To more thoroughly examine potential site-specific genomic alterations, we constructed so-called ‘delta-profiles’ by calculating the difference between the genomic profile of a recipient mammary tumor and its paired lymph node- and lung metastasis. Site-specific recurrent alterations were not observed in lymph node nor lung metastases. Taken together, these data show that genomic profiles of metastases are highly similar to those of parental recipient tumors and that, if changes occurred, they did not recur in different independent samples. We performed aCGH analyses on DNA isolated from K14cre;Cdh-/-;Trp53-/- derived donor mILCs (n=3) and their recipient mammary tumor outgrowths (n=10). Furthermore, we also analyzed genomic profiles derived from lung (n=10), tumor-draining (n=7) and distant lymph node metastases (n=5) isolated from the same recipient mice. DNA from each of these samples was hybridized against related donor splenic DNA.

Project description:Circulating tumor cells (CTCs) are critical in the development of distant organ tumor metastasis, and are associated with advanced cancer stage and poor patient outcome. Here, we present the first genome-wide nucleotide-level characterization of CTCs. Our single-nucleotide polymorphism (SNP) analysis in patients with melanoma involved: 1) global comparative genomic analysis of CTCs and matched regional metastases, 2) identification of key genomic aberrations in CTCs, 3) verification of these target genes in aggressive distant tumor metastases, and 4) evidence of selective expression and functional consequence of CTC-associated genes in melanomas. We report 131 aberrant loci in CTCs that are potentially pro-metastatic, and show that such expression of a 5-marker gene panel (CSMD2, CNTNAP5, FLJ14051, ADAM6, TRPM2) in melanomas confers prognostic utility. Successful treatment of melanoma requires understanding of the metastatic process and identification of patients with tumors most likely to develop aggressive metastatic disease. Melanomas are heterogeneous, and CTCs have long been recognized as vehicles for cancer spread, representing particularly aggressive tumor clones that can evolve into successful clinical metastases. Elucidation of genomic aberrations in CTCs will aid in the development of prognostic biomarkers and therapeutic strategies to target CTCs to prevent or control distant cancer spread. This study provides the first detailed genomic confirmation of the close relation between CTCs and tumor metastases, and illustrates how CTCs can be utilized as a novel approach and rational source for identification of pro-metastatic genes in cancer research. Three individual patient cohorts were utilized in the study. CNV and LOH loci were evaluated initially in metastatic melanoma patients (n=13) in a discovery cohort. SNP loci that harbored CNV/LOH in CTCs were then separately verified for: (a) presence in distant organ metastasis (AJCC Stage IV melanoma) (n=27), and (b) relevance to prognosis in regional melanoma metastasis (AJCC Stage III melanoma) (n=35). The first discovery patient cohort group was utilized for capture of CTCs, and consisted of peripheral blood mononuclear cell (PBMC) and tumor specimens from metastatic melanoma patients (n=13). CTC-related loci were verified in a second cohort of patients with Stage IV distant organ metastases (n=27), including 15 brain, 4 lung, and 8 gastrointestinal (bowel, liver) metastases. The third patient cohort consisted of early passage (<12) established melanoma cell lines derived from 35 regional melanoma metastases (Stage III) for evaluation of the prognostic utility of the CTC-associated aberrant loci.

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Clinical Proteomics of Metastatic Melanoma Reveals Profiles of Organ-Specificity and Treatment Resistance

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