Systemic Endocrine Instigation of Indolent Tumor Growth Requires Osteopontin

150

133

Melanoma is difficult to treat once it becomes metastatic. However, the precise ancestral relationship between primary tumors and their metastases is not well understood. We performed whole-exome sequencing of primary melanomas and multiple matched metastases from eight patients to elucidate their phylogenetic relationships. In six of eight patients, we found that genetically distinct cell populations in the primary tumor metastasized in parallel to different anatomic sites, rather than sequentially from one site to the next. In five of these six patients, the metastasizing cells had themselves arisen from a common parental subpopulation in the primary, indicating that the ability to establish metastases is a late-evolving trait. Interestingly, we discovered that individual metastases were sometimes founded by multiple cell populations of the primary that were genetically distinct. Such establishment of metastases by multiple tumor subpopulations could help explain why identical resistance variants are identified in different sites after initial response to systemic therapy. One primary tumor harbored two subclones with different oncogenic mutations in CTNNB1, which were both propagated to the same metastasis, raising the possibility that activation of wingless-type mouse mammary tumor virus integration site (WNT) signaling may be involved, as has been suggested by experimental models.A s in many other solid tumors, melanoma metastases often first present in lymph nodes in the draining area of the primary, whereas distant metastases tend to appear later (1). The conclusion that melanoma follows a linear progression from primary tumor to regional to distant metastases has supported preemptive surgical removal of regional lymph nodes with curative intent (2). However, several observations suggest that distant metastases are seeded early, contemporaneously with regional metastases. Patients who undergo resection of lymph node basins harboring metastasis do not experience a significantly extended life expectancy (3, 4). Furthermore, circulating melanoma cells were detected in the blood of 26% of patients who only have metastases detected regionally (5, 6).Melanoma, like other cancers, arises and evolves through the accumulation of genetic alterations within tumor cells (7-9). Comparing somatic mutations in primary tumor and regional and distant metastases from the same patient can provide insight into the phylogenetic relationships between these distinct tumor cell populations and the order of metastatic dissemination (8, 10). These analyses may also establish whether cells in the primary tumor that metastasize acquired this ability to disseminate and seed other anatomic sites by a newly acquired genetic alteration, or whether metastatic colonization is simply a stochastic process of which all cells in the primary are capable but few succeed.Using whole-exome sequencing (for discovery) and targeted sequencing (for validation), we analyzed mutation patterns of primary melanomas and two or more metastases in each of e...

Section: Discussionmentioning

confidence: 71%

Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination

Sanborn¹,

Chung

Purdom

et al. 2015

150

133

“…Recently, T cell-intrinsic OPN was reported to function as an autocrine prosurvival factor for CD4 ϩ T cells in vivo (31); thus, OPN also may contribute to the maintenance of PD-1 ϩ MP CD4 ϩ T cells in vivo. In addition, OPN may affect the growth and invasion of malignant cells, directly or indirectly, by recruiting host inflammatory cells (32,33). As such, these T cells may contribute to a proinflammatory trait in the elderly, as well as tumor progression.…”

Section: Discussionmentioning

confidence: 99%

PD-1⁺memory phenotype CD4⁺T cells expressing C/EBPα underlie T cell immunodepression in senescence and leukemia

Shimatani¹,

Nakashima

Hattori

et al. 2009

122

119

Although altered T cell function plays a part in immunosenescence, the mechanisms remain uncertain. Here we identify a bona fide age-dependent PD-1 ؉ memory phenotype (MP) CD4 ؉ T cell subpopulation that hardly proliferates in response to T cell receptor (TCR) stimulation and produces abundant osteopontin at the cost of typical T cell lymphokines. These T cells demonstrate impaired repopulation in Rag2 ؊/؊ mice, but a homeostatic proliferation in ␥-ray-irradiated mice. These T cells also reveal a unique molecular signature, including a strong expression of C/EBP␣ normally expressed in myeloid-lineage cells, with diminished c-Myc and cyclin D1. Transduction of Cebpa in regular CD4 ؉ T cells inhibited the TCR-mediated proliferation with c-Myc and cyclin D1 repression and caused a striking activation of Spp1 encoding osteopontin along with concomitant repression of T cell lymphokine genes. Although these T cells gradually increase in number with age and become predominant at the senescent stage in normal mice, the generation is robustly accelerated during leukemia. In both conditions, their predominance is associated with the diminution of specific CD4 ؉ T cell response. The results suggest that global T cell immunodepression in senescence and leukemia is attributable to the increase in PD-1 ؉ MP CD4 ؉ T cells expressing C/EBP␣.immunosenescence ͉ osteopontin

“…Little is known about the long-range systemic effects of tumorderived factors on distant microenvironments (58), although there is evidence that tumor-derived factors can activate BM cells to provide a supportive systemic environment to promote growth of distant tumors (59)(60)(61)(62). We demonstrated that tumor production of G-CSF induces chronic activation of myeloid differentiation in the BM, which ultimately results in inefficient erythropoiesis, anemia, and enlarged spleens to meet the demands of neutrophil and RBC cell production during tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils

Casbon¹,

Reynaud

Park³

et al. 2015

345

Expansion of myeloid cells associated with solid tumor development is a key contributor to neoplastic progression. Despite their clinical relevance, the mechanisms controlling myeloid cell production and activity in cancer remains poorly understood. Using a multistage mouse model of breast cancer, we show that production of atypical T cell-suppressive neutrophils occurs during early tumor progression, at the onset of malignant conversion, and that these cells preferentially accumulate in peripheral tissues but not in the primary tumor. Production of these cells results from activation of a myeloid differentiation program in bone marrow (BM) by a novel mechanism in which tumor-derived granulocyte-colony stimulating factor (G-CSF) directs expansion and differentiation of hematopoietic stem cells to skew hematopoiesis toward the myeloid lineage. Chronic skewing of myeloid production occurred in parallel to a decrease in erythropoiesis in BM in mice with progressive disease. Significantly, we reveal that prolonged G-CSF stimulation is both necessary and sufficient for the distinguishing characteristics of tumor-induced immunosuppressive neutrophils. These results demonstrate that prolonged G-CSF may be responsible for both the development and activity of immunosuppressive neutrophils in cancer.