Multi-site clonality analyses uncovers pervasive subclonal heterogeneity and branching evolution across melanoma metastases

Rabbie, Roy; Ansari-Pour, Naser; Cast, Oliver; Lau, Doreen; Scott, Francis; Welsh, Sarah J.; Parkinson, Christine; Khoja, Leila; Moore, Luiza; Tullett, Mark; Wong, Kim; Ferreira, Ingrid; Gómez, Julia M. Martínez; Levesque, Mitchell P.; Gallagher, Ferdia A.; Jiménez-Sánchez, Alejandro; Riva, Laura; Miller, Martin L.; Allinson, Kieren; Campbell, Peter J.; Corrie, Pippa; Wedge, David C.; Adams, David J.

doi:10.1101/848390

Cited by 4 publications

(2 citation statements)

References 61 publications

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“…8a). The accelerated anatomic dissemination we describe at relapse is similar to the metastatic seeding recently reported in different solid cancers 31,32 . This process is likely the result of a combination of two factors: (1) the selection of a more aggressive/proliferative clones, and (2) treatment-related immunosuppression.…”

Section: Discussionsupporting

confidence: 86%

Accelerated single cell seeding in relapsed multiple myeloma

et al. 2020

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Multiple myeloma (MM) progression is characterized by the seeding of cancer cells in different anatomic sites. To characterize this evolutionary process, we interrogated, by whole genome sequencing, 25 samples collected at autopsy from 4 patients with relapsed MM and an additional set of 125 whole exomes collected from 51 patients. Mutational signatures analysis showed how cytotoxic agents introduce hundreds of unique mutations in each surviving cancer cell, detectable by bulk sequencing only in cases of clonal expansion of a single cancer cell bearing the mutational signature. Thus, a unique, single-cell genomic barcode can link chemotherapy exposure to a discrete time window in a patient′s life. We leveraged this concept to show that MM systemic seeding is accelerated at relapse and appears to be driven by the survival and subsequent expansion of a single myeloma cell following treatment with high-dose melphalan therapy and autologous stem cell transplant.

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Section: Discussionsupporting

confidence: 86%

Accelerated single cell seeding in relapsed multiple myeloma

et al. 2020

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“…82 Metastases, particularly in tissues different from the primary tumor, exhibit cancer cells that are different genetically and phenotypically. 83 Like plant biomes, this would be expected as different tissues offer different hazards, opportunities, and cellular structure. 84 For instance melanomas metastasizing to the brain are going from a stiff, relatively resource poor and immune cell rich environment to one that is quite the opposite.…”

Section: In Naturementioning

confidence: 99%

Cancer Community Ecology

Kotler

Brown

2020

Cancer Control

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Here we advocate Cancer Community Ecology as a valuable focus of study in Cancer Biology. We hypothesize that the heterogeneity and characteristics of cancer cells within tumors should vary systematically in space and time and that cancer cells form local ecological communities within tumors. These communities possess limited numbers of species determined by local conditions, with each species in a community possessing predictable traits that enable them to cope with their particular environment and coexist with each other. We start with a discussion of concepts and assumptions that ecologists use to study closely related species. We then discuss the competitive exclusion principle as a means for knowing when two species should not coexist, and as an opening towards understanding how they can. We present the five major categories of mechanisms of coexistence that operate in nature and suggest that the same mechanisms apply towards understanding the diversification and coexistence of cancer cell species. They are: Food-Safety Tradeoffs, Diet Choice, Habitat Selection, Variance Partitioning, and Competition-Colonization Tradeoffs. For each mechanism, we discuss how it works in nature, how it might work in cancers, and its implications for therapy.

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Accelerated single cell seeding in relapsed multiple myeloma

Landau

Yellapantula

Diamond

et al. 2020

Preprint

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The malignant progression of multiple myeloma is characterized by the seeding of cancer cells in different anatomic sites followed by their clonal expansion. It has been demonstrated that this spatial evolution at varying anatomic sites is characterized by genomic heterogeneity. However, it is unclear whether each anatomic site at relapse reflects the expansion of pre-existing but previously undetected disease or secondary seeding from other sites. Furthermore, genomic evolution over time at spatially distinct sites of disease has not been investigated in a systematic manner.To address this, we interrogated 25 samples, by whole genome sequencing, collected at autopsy from 4 patients with relapsed multiple myeloma and demonstrated that each site had a unique evolutionary trajectory characterized by distinct single and complex structural variants and copy number changes. By analyzing the landscape of mutational signatures at these sites and for an additional set of 125 published whole exomes collected from 51 patients, we demonstrate the profound mutagenic effect of melphalan and platinum in relapsed multiple myeloma. Chemotherapy-related mutagenic processes are known to introduce hundreds of unique mutations in each surviving cancer cell. These mutations can be detectable by bulk sequencing only in cases of clonal expansion of a single cancer cell bearing the mutational signature linked to chemotherapy exposure thus representing a unique single-cell genomic barcode linked to a discrete time window in each patient's life. We leveraged this concept to show that multiple myeloma systemic seeding is accelerated at clinical relapse and appears to be driven by the survival and subsequent expansion of a single myeloma cell 4 following treatment with high dose melphalan therapy and autologous stem cell transplant.5

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Multi-site clonality analyses uncovers pervasive subclonal heterogeneity and branching evolution across melanoma metastases

Cited by 4 publications

References 61 publications

Accelerated single cell seeding in relapsed multiple myeloma

Accelerated single cell seeding in relapsed multiple myeloma

Cancer Community Ecology

Accelerated single cell seeding in relapsed multiple myeloma

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