Christopher Natale

University of Pennsylvania | UP · Cell and Molecular Biology Graduate Group

Female sex and history of prior pregnancies are associated with favorable melanoma outcomes. Here, we show that much of the melanoma protective effect likely results from estrogen signaling through the G protein-coupled estrogen receptor (GPER) on melanocytes. Selective GPER activation in primary melanocytes and melanoma cells induced long-term cha...

The association between pregnancy and altered cutaneous pigmentation has been documented for over two millennia, suggesting that sex hormones play a role in regulating epidermal melanocyte (MC) homeostasis. Here we show that physiologic estrogen (17β-estradiol) and progesterone reciprocally regulate melanin synthesis. This is intriguing given that...

GPER (G protein-coupled estrogen receptor) has been reported to play roles in several areas of physiology including cancer, metabolic disorders, and cardiovascular disease. However, the understanding of where this receptor is expressed in human tissue is limited due to limited available tools and methodologies that can reliably detect GPER protein....

Melanoma risk is 30 times higher in people with lightly pigmented skin versus darkly pigmented skin. Using primary human melanocytes representing the full human skin pigment continuum and preclinical melanoma models, we show that cell-intrinsic differences between dark and light melanocytes regulate melanocyte proliferative capacity and susceptibil...

Melanoma and most other cancers occur more frequently and have worse prognosis in males compared with females. Although sex steroids are thought to be involved, classical androgen and estrogen receptors are not detectable in most melanomas. Here we show that testosterone promotes melanoma proliferation by activating ZIP9 (SLC39A9), a zinc transport...

Melanoma risk is higher for people with lightly pigmented skin (1:38) compared to those with darkly pigmented skin (1:1000). While this difference is typically attributed to the ultraviolet radiation (UVR) shielding effect of melanin pigment, here we show that other cell-intrinsic differences between dark and light MCs, independent of melanin and U...

Background and Aims Female sex is associated with lower incidence and improved clinical outcomes for most cancer types, including pancreatic ductal adenocarcinoma (PDAC). The mechanistic basis for this sex difference is unknown. We hypothesized that estrogen signaling may be responsible, despite the fact that PDAC lacks classic nuclear estrogen rec...

LNS8801 is a novel, orally bioavailable, small-molecule agonist of the G Protein Coupled Estrogen Receptor (GPER) being developed for the treatment of pancreatic ductal adenocarcinoma (PDAC) and other advanced cancers. Women have a lower incidence and improved clinical outcomes for most cancer types, including PDAC. The mechanistic basis for this s...

Female sex is associated with lower incidence and improved clinical outcomes for many cancer types, including melanoma and pancreatic ductal adenocarcinoma (PDAC). Although the mechanisms responsible for this sex difference are still emerging, we recently showed that signaling through the G protein-coupled estrogen receptor (GPER) likely contribute...

Female sex and pregnancy are associated with reduced risk of melanoma and improved stage-specific survival; however, the mechanism underlying this apparent clinical benefit is unknown. We previously discovered that pregnancy-associated 17β-estradiol drives melanocyte differentiation by activating the nonclassical G-protein coupled estrogen receptor...

Female gender, early age of first birth, and multiparity are associated with less aggressive melanoma; however, the mechanisms underlying the apparent clinical benefit are undefined. Previously we reported that 17β-estradiol drives melanocyte differentiation through G-protein coupled estrogen receptor (GPER), a nonclassical sex hormone receptor. He...

Female sex and pregnancy are associated with reduced risk of melanoma and improved stage specific survival; however, the mechanism underlying this apparent clinical benefit is unknown. We previously discovered that pregnancy-associated 17β-estradiol drives melanocyte differentiation by activating the nonclassical G-protein coupled estrogen receptor...

Proliferation and migration of epidermal keratinocytes are essential for proper cutaneous wound closure after injury. αv integrins and several of their ligands—vitronectin, TGFβ and thrombospondin—are up-regulated in healing wounds. However, the role of αv integrins in wound re-epithelialization is unknown. Here, we show that genetic depletion or a...

Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Pr...

Deletion of the entire CDKN2B-CDKN2A gene cluster is among the most common genetic events in cancer. The tumor-promoting effects are generally attributed to loss of CDKN2A-encoded p16 and p14ARF tumor suppressors. The degree to which the associated CDKN2B-encoded p15 loss contributes to human tumorigenesis is unclear. Here we show that CDKN2B is hi...

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